Tumorigenesis Risk Factors and Role of Neuroimmune Regulations

**75**

**1. Introduction**

**Chapter 4**

**Abstract**

*Marliyya S. Zayyan*

Risk Factors for Ovarian Cancer

Ovarian cancers remain a perplexing group of diseases that continue to raise questions over their etiology and clinical behavior. They are the most fatal of gynecological cancers. Despite a global lifetime risk of only 1–2%, they contribute the highest mortality and the lowest 5-year (overall) survival rate of just 35%. The three broad histological groups: epithelial, sex cord-stromal and germ cell cancers have different biologic behavior and may constitute different clinical disease entities. Of the eight subtypes in the epithelial group, high-grade serous are universally the most common and have the worst prognosis. Globally making 65–85% of all ovarian cancers, most of the focus on risk factors has been directed on the epithelial group but the importance of other primary malignancies cannot be overemphasized as a step towards understanding their etiology and clinical behavior. The normal ovary has none of the epithelia that produce the range of epithelial ovarian cancers or there is an obvious premalignant stage, symptoms are very vague, screening and early diagnosis are difficult and indeed unrewarding. No specific etiology is known for any of the histologic groups. However, commonly mentioned risk factors like increasing age, genetics, nulliparity, prolonged infertility, use of fertility drugs, high animal fat, obesity, endometriosis, polycystic ovary syndrome, previous history of cancer, use of hormone replacement therapy, pelvic inflammatory disease and smoking may not apply to all the subtypes, while factors like increasing parity, breast feeding, use of oral contraceptive pills, hysterectomy, tubal ligation and use of antioxidants may differ in the degree of protection they provide. There may also be geographical and probably racial variations in the relevance of some of the risk factors. Thorough understanding of the predisposing and protective factors of the various histologic subtypes is an important step understanding the disease and therefore improving treatment outcome or providing effective prevention.

**Keywords:** risk factors, ovarian cancers, histologic subtypes, variation

Ovarian cancer (OC) is an important public health problem with a lifetime risk of 1–2%. Recent estimates indicate that 295,414 cases are expected in 2018 with about 184,000 of victims dying from the disease [1]. This reflects an increase of over 54,000 cases in incidence and 32,000 cases in mortality compared with earlier figures [2, 3]. Public screening for ovarian cancer has been neither feasible nor beneficial due to a lack of most appropriate screening test for the range of malignancies produced by the ovary. Use of tumor markers is largely unreliable since different tumor markers are secreted by different histological varieties and up to 50% of early disease may be associated with insignificant rise of tumor markers [4, 5]. Besides tumor markers could be raised by non-malignant conditions as well

#### **Chapter 4**

## Risk Factors for Ovarian Cancer

*Marliyya S. Zayyan*

#### **Abstract**

Ovarian cancers remain a perplexing group of diseases that continue to raise questions over their etiology and clinical behavior. They are the most fatal of gynecological cancers. Despite a global lifetime risk of only 1–2%, they contribute the highest mortality and the lowest 5-year (overall) survival rate of just 35%. The three broad histological groups: epithelial, sex cord-stromal and germ cell cancers have different biologic behavior and may constitute different clinical disease entities. Of the eight subtypes in the epithelial group, high-grade serous are universally the most common and have the worst prognosis. Globally making 65–85% of all ovarian cancers, most of the focus on risk factors has been directed on the epithelial group but the importance of other primary malignancies cannot be overemphasized as a step towards understanding their etiology and clinical behavior. The normal ovary has none of the epithelia that produce the range of epithelial ovarian cancers or there is an obvious premalignant stage, symptoms are very vague, screening and early diagnosis are difficult and indeed unrewarding. No specific etiology is known for any of the histologic groups. However, commonly mentioned risk factors like increasing age, genetics, nulliparity, prolonged infertility, use of fertility drugs, high animal fat, obesity, endometriosis, polycystic ovary syndrome, previous history of cancer, use of hormone replacement therapy, pelvic inflammatory disease and smoking may not apply to all the subtypes, while factors like increasing parity, breast feeding, use of oral contraceptive pills, hysterectomy, tubal ligation and use of antioxidants may differ in the degree of protection they provide. There may also be geographical and probably racial variations in the relevance of some of the risk factors. Thorough understanding of the predisposing and protective factors of the various histologic subtypes is an important step understanding the disease and therefore improving treatment outcome or providing effective prevention.

**Keywords:** risk factors, ovarian cancers, histologic subtypes, variation

#### **1. Introduction**

Ovarian cancer (OC) is an important public health problem with a lifetime risk of 1–2%. Recent estimates indicate that 295,414 cases are expected in 2018 with about 184,000 of victims dying from the disease [1]. This reflects an increase of over 54,000 cases in incidence and 32,000 cases in mortality compared with earlier figures [2, 3]. Public screening for ovarian cancer has been neither feasible nor beneficial due to a lack of most appropriate screening test for the range of malignancies produced by the ovary. Use of tumor markers is largely unreliable since different tumor markers are secreted by different histological varieties and up to 50% of early disease may be associated with insignificant rise of tumor markers [4, 5]. Besides tumor markers could be raised by non-malignant conditions as well

as other malignancies [6–8]. Cancers of the lung, pancreas, colorectal, breast and non-Hodgkin's lymphomas are associated with a rise in CA125 [9, 10] which is also raised in benign conditions such as endometriosis, ovarian cyst, leiomyoma uteri and pelvic inflammatory disease [4, 8, 11]. Only 50% of early OC is associated with raised CA125 making it unreliable for early diagnosis. More than 75% of OC are diagnosed in late stages of disease [12–14] when prognosis is very poor. Screening did not reduce mortality in two large trials [12, 15].

The ovaries are totipotential in their ability to form wide histologic varieties of cancers with different biology, natural history and possibly mechanism of onset [16–18]. These heterogeneous tumors differ in their clinical behavior including response to treatment and prognosis. Knowledge of the cause or genesis of OCs is very scant and the available hypotheses do not explain observed disease phenomena [19, 20]. The uniqueness of OC in having no known premalignant stage, no reliable screening tool, very vague symptoms in early and advanced stages make identification of at risk group important for prevention, early diagnosis and possibly as a step towards defining its etiology.

The World Health Organization classifies ovarian cancers based on histologic origins of the cells, as epithelial, sex cord-stromal and germ cell tumors [16, 21] (**Table 1**). The epithelial ovarian cancers are made up of eight histologic subtypes with different cellular origin, pathogenesis, gene expression and response to treatment [13, 16, 17]. The most common type, serous cyst adenocarcinoma with two distinct subtypes may be arising from the fallopian tube epithelium. The high grade serous accounts for 85% of the epithelial ovarian cancers and up to 80% of


**77**

*Risk Factors for Ovarian Cancer*

epithelial cancer [25].

behavior.

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

transitional epithelium akin to that of the bladder [19].

including in patients with Peutz-Jeghers syndrome [27].

**2. Hypothesis for ovarian carcinogenesis**

germ cell tumors and the sex cord-stromal tumors.

subsequent malignant transformation [31, 32].

fore new hypothesis have been proposed [19, 34].

cancer formation [31, 33].

and epidemiology.

ovarian cancers generally [22]. It is the most challenging in terms of treatment outcome. Mucinous adenocarcinomas have cells similar to the cervical epithelium, endometrioid cancer cells resemble the endometrium, while Brenners tumors have

The fimbriated end of the fallopian tube has morphologic and molecular similarities with high grade serous ovarian cancers which also expresses TP53 signature suggesting that neoplastic process may be originating from tubal epithelium and shed into the ovary where aggressive neoplastic process proceeds [14, 19]. Low-grade serous ovarian cancers share similar histiogenesis but progress through a separate pathway and has different prognosis [18, 23, 24]. It represents less than 5% of the

The sex cord-stromal tumors are a heterogeneous group, which include several

The germ cell tumors, which include dysgerminomas, immature teratoma, embryonal tumors and endodermal sinus tumors form only 1.5–5% of OC. Approximately one-third are dysgerminomas, another third immature teratomas and a further one-third include the rest three (embryonal tumors, endodermal sinus tumors, choriocarcinoma and mixed cell types) [19, 28]. Malignant germ cell tumors of the ovary may be developing through similar pathways with testicular germ cell tumors but the

This diversity in genesis may partly explain the observed differences in clinical

Development of OC has remained a mystery since hypotheses advanced do not convincingly explain the observed phenomena. It is important to explain how other

The 'incessant ovulation' theory explains that repetitive ovulatory micro trauma to the ovarian surface in association with the tubal epithelium results in carcinogenesis through mistakes in repair of the damaged surface epithelium [29, 30]. While this hypothesis partly explain serous cystadenocarcinoma, it fails to explain other subtypes in the epithelial group and does not offer plausible explanation for the

The pituitary "gonadotropin hypothesis" indicates that high levels of estrogens and gonadotropins such as luteinizing hormone and follicle-stimulating hormone would over stimulate the ovarian epithelium causing increased proliferation and

The "inflammation hypothesis" proposes that factors such as endometriosis, pelvic inflammatory disease and other inflammatory conditions may stimulate

These theories have failed to provide plausible genesis for ovarian cancer there-

Understanding a clear etiology is far from site, a thorough global analysis of the risk factors of the disease may be a good starting point to unraveling the etiology and therefore an effective strategy towards disease control and prevention. It is however expected that the range of tumors may very well differ in risk factors

histologic subtypes (**Table 1**). Apart from adult granulosa tumor that affects women in their fifth decade, sex cord-stromal tumors mainly affect women in the second or third decade of life and account for about 5% of malignancies in women 15–24 years [26]. Several subtypes are associated with genetic predisposition,

ovarian have greater histological complexity than most solid somatic tumors.

surface epithelia form aggressive primary neoplasm in a separate organ.

#### **Table 1.**

*WHO histological classification for ovarian cancers.*

#### *Risk Factors for Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.86712*

*Tumor Progression and Metastasis*

towards defining its etiology.

**Histological**

I. Epithelial tumors

E. Brenner's F. Mixed epithelial G. Undifferentiated H. Unclassified II. Sex cord-stromal tumors A. Granulosa B. Androblastoma C. Gynandroblastoma D. Unclassified III. Lipid cell tumors IV. Germ cell tumors A. Dysgerminoma B. Endodermal sinus tumors C. Polyembroyoma D. Choriocarcinoma E. Teratoma F. Mixed tumors V. Gonadoblastoma

C. Endometrioid

A. Serous cyst adenocarcinoma B. Mucinous Cyst adenocarcinoma

D. Clear cell (mesonephroid)

VI. Soft tissues not specific to the ovary

*WHO histological classification for ovarian cancers.*

VII. Unclassified VIII. Metastatic

did not reduce mortality in two large trials [12, 15].

as other malignancies [6–8]. Cancers of the lung, pancreas, colorectal, breast and non-Hodgkin's lymphomas are associated with a rise in CA125 [9, 10] which is also raised in benign conditions such as endometriosis, ovarian cyst, leiomyoma uteri and pelvic inflammatory disease [4, 8, 11]. Only 50% of early OC is associated with raised CA125 making it unreliable for early diagnosis. More than 75% of OC are diagnosed in late stages of disease [12–14] when prognosis is very poor. Screening

The ovaries are totipotential in their ability to form wide histologic varieties of cancers with different biology, natural history and possibly mechanism of onset [16–18]. These heterogeneous tumors differ in their clinical behavior including response to treatment and prognosis. Knowledge of the cause or genesis of OCs is very scant and the available hypotheses do not explain observed disease phenomena [19, 20]. The uniqueness of OC in having no known premalignant stage, no reliable screening tool, very vague symptoms in early and advanced stages make identification of at risk group important for prevention, early diagnosis and possibly as a step

The World Health Organization classifies ovarian cancers based on histologic origins of the cells, as epithelial, sex cord-stromal and germ cell tumors [16, 21] (**Table 1**). The epithelial ovarian cancers are made up of eight histologic subtypes with different cellular origin, pathogenesis, gene expression and response to treatment [13, 16, 17]. The most common type, serous cyst adenocarcinoma with two distinct subtypes may be arising from the fallopian tube epithelium. The high grade serous accounts for 85% of the epithelial ovarian cancers and up to 80% of

**76**

**Table 1.**

ovarian cancers generally [22]. It is the most challenging in terms of treatment outcome. Mucinous adenocarcinomas have cells similar to the cervical epithelium, endometrioid cancer cells resemble the endometrium, while Brenners tumors have transitional epithelium akin to that of the bladder [19].

The fimbriated end of the fallopian tube has morphologic and molecular similarities with high grade serous ovarian cancers which also expresses TP53 signature suggesting that neoplastic process may be originating from tubal epithelium and shed into the ovary where aggressive neoplastic process proceeds [14, 19]. Low-grade serous ovarian cancers share similar histiogenesis but progress through a separate pathway and has different prognosis [18, 23, 24]. It represents less than 5% of the epithelial cancer [25].

The sex cord-stromal tumors are a heterogeneous group, which include several histologic subtypes (**Table 1**). Apart from adult granulosa tumor that affects women in their fifth decade, sex cord-stromal tumors mainly affect women in the second or third decade of life and account for about 5% of malignancies in women 15–24 years [26]. Several subtypes are associated with genetic predisposition, including in patients with Peutz-Jeghers syndrome [27].

The germ cell tumors, which include dysgerminomas, immature teratoma, embryonal tumors and endodermal sinus tumors form only 1.5–5% of OC. Approximately one-third are dysgerminomas, another third immature teratomas and a further one-third include the rest three (embryonal tumors, endodermal sinus tumors, choriocarcinoma and mixed cell types) [19, 28]. Malignant germ cell tumors of the ovary may be developing through similar pathways with testicular germ cell tumors but the ovarian have greater histological complexity than most solid somatic tumors.

This diversity in genesis may partly explain the observed differences in clinical behavior.

#### **2. Hypothesis for ovarian carcinogenesis**

Development of OC has remained a mystery since hypotheses advanced do not convincingly explain the observed phenomena. It is important to explain how other surface epithelia form aggressive primary neoplasm in a separate organ.

The 'incessant ovulation' theory explains that repetitive ovulatory micro trauma to the ovarian surface in association with the tubal epithelium results in carcinogenesis through mistakes in repair of the damaged surface epithelium [29, 30]. While this hypothesis partly explain serous cystadenocarcinoma, it fails to explain other subtypes in the epithelial group and does not offer plausible explanation for the germ cell tumors and the sex cord-stromal tumors.

The pituitary "gonadotropin hypothesis" indicates that high levels of estrogens and gonadotropins such as luteinizing hormone and follicle-stimulating hormone would over stimulate the ovarian epithelium causing increased proliferation and subsequent malignant transformation [31, 32].

The "inflammation hypothesis" proposes that factors such as endometriosis, pelvic inflammatory disease and other inflammatory conditions may stimulate cancer formation [31, 33].

These theories have failed to provide plausible genesis for ovarian cancer therefore new hypothesis have been proposed [19, 34].

Understanding a clear etiology is far from site, a thorough global analysis of the risk factors of the disease may be a good starting point to unraveling the etiology and therefore an effective strategy towards disease control and prevention. It is however expected that the range of tumors may very well differ in risk factors and epidemiology.

#### **3. Predisposing factors**

Predisposing and protective factors for ovarian cancers vary according to histologic type [13, 18]. Although most studies concentrate on epithelial ovarian cancers, particularly serous cystadenocarcinoma, which tends to form the major global disease burden, risk factors to other histologic types are important prerequisite to their genesis and will be considered in this review.

#### **4. Racial and geographical risk**

Ovarian cancer is a cosmopolitan disease as it occurs in every geographical location and in every race [1, 30]. Epithelial ovarian cancer is the commonest subtype all around the world with high-grade serous accounting for 60–85% of cases [22, 35–38].

Highest incidence of OC is found among white females in Northern and Western Europe and in North America with age adjusted incidence exceeding 8.4/100,000 [1, 30]. Recent statistics from the US show a decline in incidence from 16.6/100,000 in 1985 to 11.8/100,000 in 2018 [39]. Incidence is also high in New Zealand and among Jewish women in Israel but low in Africa and Asia with estimated rates of <3/100,000 [37]. Japan, though reported to have low incidence is experiencing a rising trend in the disease of recent [40].

All regions of North America show higher incidence of invasive ovarian cancer among white women [41].

Within Europe too, there is difference in incidence and mortality across the region. Using WHO data base of 28 European countries from 1953 to 2000, Bray et al. reported Nordic countries, Austria, Germany and the United Kingdom to have the highest trend in the 1960s but the trend tended to decline over the recent years while Southern European countries showed an upward trend. Similarly, central and eastern European countries with hitherto low incidence are experiencing a rising over time [12, 35] . In the most recent 5-year period (2003–2007), the incidence of ovarian cancer was highest in Eastern/Southern Europe, followed by Northern Europe, and Western Europe [22] Asian sub region reports lower rates than Europe and America [2, 3].

South Eastern Asia have highest rate in the subcontinent and Eastern Asia has the lowest rate.

Migration to areas of high risk increases the risk of disease therefore cultural and dietary factors may be responsible for the observed difference. Japanese immigrants to the US have equivalent risk as natives [42].Racial variations in the incidence of ovarian cancer are best observed in the USA. Age adjusted incidence rate are higher in whites than in non-whites and Indians in the USA have lowest mortality from ovarian cancer. While Caucasian Americans have higher disease incidence, African-Americans have 1.3 times higher disease mortality and lower survival rates even with equal access to care [43]. They also experienced poorer 5-year survival rates irrespective of stage of diagnosis [44, 45].

From the Surveillance Epidemiology and End Result (SEER)database (1992– 1998), AA experienced a fall in 5-year survival rates from 47.9 to 40.3%, while their Caucasian counterparts witnessed an improved survival from 40.7 to 45% in the same period. The observed disparities have been linked to interplay of socioeconomic, environmental, genetic and epigenetic factors [43].

Determining the incidence of ovarian cancer in four US populations of heterogeneous racial-ethnic composition, Weiss and Paterson found 19–42% lower incidence among Japanese, Chinese, Hispano and black women compared with white women [44]. The observed difference is primarily due to lower rates of serous and papillary tumors. Chinese women also had decreased incidence of mucinous

**79**

*Risk Factors for Ovarian Cancer*

clear cell tumors.

in low-risk countries.

**5. Age as a risk factor**

reports from European literature [35, 51].

older women of 70 years [58].

and 79 years.

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

interval (95% CI): 0.42–0.67) [46].

utilization of health facilities and rudimentary statistics.

tumors, while Hispano and black women had lower incidence of endometrioid-

The incidence of non-epithelial cancers remains fairly constant between the races; especially germ cell tumors which has remained stable in incidence for three decades [44]. However, data from SEER suggest that the incidence of sex cordstromal tumors is significantly lower among white women compared with black women (0.18 *vs.* 0.35 per 100,000 person years; relative risk, 0.53; 95% confidence

OC rates from Africa though reported to be low must be considered in the background of health circumstances in the region of lack of cancer registries, poor

Ovarian cancer is reported to be more common in developed countries than developing nations but over the last three decades, ovarian cancer incidence has remained stable in high-risk countries, while an increasing trend has been reported

Increasing age is a risk factor for ovarian cancer which is generally considered a disease of the older women. Globally, the annual incidence regardless of age is 42 cases/100,000 women. Data from US SEER, ovarian cancer is rare before the age of 40 years and incidence rises steadily after the fifth decade to reach a peak at 80–84 years, when the age specific incidence is 61.3/100,000 women. More than half of cases of ovarian cancers are diagnosed in women over 65 year [47].

In the United States, the annual incidence is 61.3 per 100,000 for women aged 75

In the UK, the overall incidence of a symptomatic ovarian cyst in a premenopausal female being malignant is approximately 1:1000 increasing to 3:1000 at the age of 50 years although 1000 women under the age of 50 years develop ovarian cancer annually in the UK [48–50]. Most diagnose are other histologic subtypes like borderline tumors and germ cell tumors. EOC are generally reported to be uncommon in young premenopausal women in the UK [50]. Women aged 65 years and above make 64% of mortality from OC [47, 50]. Young premenopausal women are more commonly affected by germ cell tumors and borderline tumors in most

Similarly, a meta-database analysis of 5055 ovarian cancer patients of 4 prospective phase III intergroup trials identified 294 (5.8%) patients under the age of 40 years from European studies. Young age appeared a strong independent protective on overall incidence of EOCs as well as prognostic factor for PFS and OS [52]. The issue of age and ovarian cancer diagnosis may however be different among non-Europeans races. Reports from India show much younger age affected than most European papers for EOC. Murtha et al. reported increased risk after 35 years with peak at ages of 55–64 years. Saini et al. have reported mean age of 55 years Basu et al. had 48.8 ± 11.2 years while Mondel had 48 years and Jindal et al. had a mean of 48 years. Malik from Pakistan found mean age for EOC to be 49.5 ± 13 years [53–57]. Mostafa et al. from Egypt reported a mean age of 47 years for epithelial ovarian cancers, with 1% of cases affecting women of 30 years and only 3% occurring in

From African subcontinent, findings contradict increasing age as a risk factor for EOC as reports show young premenopausal women to be mostly affected with serous cystadenocarcinoma, which is the most common histiotype. There is increasing report of rising incidence of ovarian cancer from Africa [38, 59–61].

#### *Risk Factors for Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.86712*

*Tumor Progression and Metastasis*

**3. Predisposing factors**

their genesis and will be considered in this review.

experiencing a rising trend in the disease of recent [40].

**4. Racial and geographical risk**

among white women [41].

the lowest rate.

irrespective of stage of diagnosis [44, 45].

nomic, environmental, genetic and epigenetic factors [43].

Predisposing and protective factors for ovarian cancers vary according to histologic type [13, 18]. Although most studies concentrate on epithelial ovarian cancers, particularly serous cystadenocarcinoma, which tends to form the major global disease burden, risk factors to other histologic types are important prerequisite to

Ovarian cancer is a cosmopolitan disease as it occurs in every geographical location and in every race [1, 30]. Epithelial ovarian cancer is the commonest subtype all around the world with high-grade serous accounting for 60–85% of cases [22, 35–38]. Highest incidence of OC is found among white females in Northern and Western Europe and in North America with age adjusted incidence exceeding 8.4/100,000 [1, 30]. Recent statistics from the US show a decline in incidence from 16.6/100,000 in 1985 to 11.8/100,000 in 2018 [39]. Incidence is also high in New Zealand and among Jewish women in Israel but low in Africa and Asia with estimated rates of <3/100,000 [37]. Japan, though reported to have low incidence is

All regions of North America show higher incidence of invasive ovarian cancer

Within Europe too, there is difference in incidence and mortality across the region. Using WHO data base of 28 European countries from 1953 to 2000, Bray et al. reported Nordic countries, Austria, Germany and the United Kingdom to have the highest trend in the 1960s but the trend tended to decline over the recent years while Southern European countries showed an upward trend. Similarly, central and eastern European countries with hitherto low incidence are experiencing a rising over time [12, 35] . In the most recent 5-year period (2003–2007), the incidence of ovarian cancer was highest in Eastern/Southern Europe, followed by Northern Europe, and Western Europe

South Eastern Asia have highest rate in the subcontinent and Eastern Asia has

From the Surveillance Epidemiology and End Result (SEER)database (1992– 1998), AA experienced a fall in 5-year survival rates from 47.9 to 40.3%, while their Caucasian counterparts witnessed an improved survival from 40.7 to 45% in the same period. The observed disparities have been linked to interplay of socioeco-

Determining the incidence of ovarian cancer in four US populations of heterogeneous racial-ethnic composition, Weiss and Paterson found 19–42% lower incidence among Japanese, Chinese, Hispano and black women compared with white women [44]. The observed difference is primarily due to lower rates of serous and papillary tumors. Chinese women also had decreased incidence of mucinous

Migration to areas of high risk increases the risk of disease therefore cultural and dietary factors may be responsible for the observed difference. Japanese immigrants to the US have equivalent risk as natives [42].Racial variations in the incidence of ovarian cancer are best observed in the USA. Age adjusted incidence rate are higher in whites than in non-whites and Indians in the USA have lowest mortality from ovarian cancer. While Caucasian Americans have higher disease incidence, African-Americans have 1.3 times higher disease mortality and lower survival rates even with equal access to care [43]. They also experienced poorer 5-year survival rates

[22] Asian sub region reports lower rates than Europe and America [2, 3].

**78**

tumors, while Hispano and black women had lower incidence of endometrioidclear cell tumors.

The incidence of non-epithelial cancers remains fairly constant between the races; especially germ cell tumors which has remained stable in incidence for three decades [44]. However, data from SEER suggest that the incidence of sex cordstromal tumors is significantly lower among white women compared with black women (0.18 *vs.* 0.35 per 100,000 person years; relative risk, 0.53; 95% confidence interval (95% CI): 0.42–0.67) [46].

OC rates from Africa though reported to be low must be considered in the background of health circumstances in the region of lack of cancer registries, poor utilization of health facilities and rudimentary statistics.

Ovarian cancer is reported to be more common in developed countries than developing nations but over the last three decades, ovarian cancer incidence has remained stable in high-risk countries, while an increasing trend has been reported in low-risk countries.

#### **5. Age as a risk factor**

Increasing age is a risk factor for ovarian cancer which is generally considered a disease of the older women. Globally, the annual incidence regardless of age is 42 cases/100,000 women. Data from US SEER, ovarian cancer is rare before the age of 40 years and incidence rises steadily after the fifth decade to reach a peak at 80–84 years, when the age specific incidence is 61.3/100,000 women. More than half of cases of ovarian cancers are diagnosed in women over 65 year [47].

In the United States, the annual incidence is 61.3 per 100,000 for women aged 75 and 79 years.

In the UK, the overall incidence of a symptomatic ovarian cyst in a premenopausal female being malignant is approximately 1:1000 increasing to 3:1000 at the age of 50 years although 1000 women under the age of 50 years develop ovarian cancer annually in the UK [48–50]. Most diagnose are other histologic subtypes like borderline tumors and germ cell tumors. EOC are generally reported to be uncommon in young premenopausal women in the UK [50]. Women aged 65 years and above make 64% of mortality from OC [47, 50]. Young premenopausal women are more commonly affected by germ cell tumors and borderline tumors in most reports from European literature [35, 51].

Similarly, a meta-database analysis of 5055 ovarian cancer patients of 4 prospective phase III intergroup trials identified 294 (5.8%) patients under the age of 40 years from European studies. Young age appeared a strong independent protective on overall incidence of EOCs as well as prognostic factor for PFS and OS [52].

The issue of age and ovarian cancer diagnosis may however be different among non-Europeans races. Reports from India show much younger age affected than most European papers for EOC. Murtha et al. reported increased risk after 35 years with peak at ages of 55–64 years. Saini et al. have reported mean age of 55 years Basu et al. had 48.8 ± 11.2 years while Mondel had 48 years and Jindal et al. had a mean of 48 years. Malik from Pakistan found mean age for EOC to be 49.5 ± 13 years [53–57].

Mostafa et al. from Egypt reported a mean age of 47 years for epithelial ovarian cancers, with 1% of cases affecting women of 30 years and only 3% occurring in older women of 70 years [58].

From African subcontinent, findings contradict increasing age as a risk factor for EOC as reports show young premenopausal women to be mostly affected with serous cystadenocarcinoma, which is the most common histiotype. There is increasing report of rising incidence of ovarian cancer from Africa [38, 59–61].

Most reports suggest EOC to be the commonest but predominantly seen in young premenopausal, generally parous women [38, 60, 61].

A global report by the International Federation of Gynecology and Obstetrics (FIGO) has noted that the highest incidence of ovarian cancer was moving towards a younger age group, although the majority of patients with epithelial cancer were more than 50 years in age [38].

It is interesting that high grade serous cyst adenocarcinoma remains the commonest variety while literature from USA, Europe, Israel and Australia find it in older women above 65 years, in Asia, the Arab world and Africa, it is observed in young premenopausal women. Research for this important difference is worthwhile.

Early menarche is considered a weak predictor of ovarian cancer risk and women whose menarche was earlier than 12 years are at increased risk of epithelial tumors [62, 63]. Meta-analysis of 22 case–control studies and 5 cohort studies has reported a statistically significant inverse association between menarcheal age and ovarian cancer risk (RR = 0.85; 95% CI: 0.75–0.97) [62], but this association is most significant in invasive serous and borderline tumors. In this respect, 'incessant ovulation' theory as possible cause of tumor genesis provides plausible explanation [30, 34]. No association was found when menarche begins after age 16 years. Late menarche has not been shown to be protective [64].

Women who experience natural late menopause are at increased risk [13, 34, 65]. Odds ratios for late natural menopause were reported as low as 1.19 and as high as 1.25 (95% CI: 0.95–1.49) [65]. These findings may suggest that earlier menarcheal age and late natural menopause might increase risk of ovarian cancer by increasing a woman's lifetime number of ovulations. Results from the Nurses' Health Study (NHS) confirmed increased risk of endometrioid epithelial cancers with late natural menopause but not of serous or mucinous cancers (RR = 1.3, 95% CI: 1.04–1.22). Furthermore, the European Prospective Study into Cancer and Nutrition Cohort (EPIC) age at menopause >52 years was associated with increased risk compared with 45 years or less [66].

#### **6. Infertility and use of ovulation induction drugs**

Infertility either by itself or in association with some of its causes like endometriosis, is a risk factor and prolonged period of infertility is associated with higher risk [67].

A large cohort study, involving 54,362 women with infertility in the Danish fertility clinics (1963–1998) used parity specific cancer incidence and reported significantly increased from infertility (1.46, 95% CI: 1.24–1.71) [68].

Whittemore et al. analyzed 12 US case–control studies between 1957 and 1985, with 2197 cases of ovarian cancer and 4144 controls and confirmed higher risk in nulligravid subfertile women compared with controls [20].

However, study by Ness with 5207 cases of ovarian cancer and 7705 controls found only a weak association between infertility and epithelial ovarian cancer (OR 1.16, 95% CI: 1.02–1.31) [69].

Drug treatment of infertility may further increase risk as untreated infertile nulliparous women have 1.5–2-fold risk, while women who received treatment and failed to conceive have even higher risk [70].

Use of ovulation induction agents like clomiphene citrate, gonadotropins are associated with three times higher general population [69] particularly prolonged use of clomiphene (for more than 12 cycles). This is associated with rise in risk for invasive and borderline cases by about 11.1-fold compared with infertile women with no clomiphene use [67].

**81**

*Risk Factors for Ovarian Cancer*

tion induction agents [71].

high grade serous.

**7. Genetic factors**

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

positively associated with non-mucinous tumors [76].

colorectal cancer (HNPCC) or Lynch II syndrome [77].

syndrome but affected families may be identified from:

• The presence of a BRCA1 or BRCA 2.

associated with their BRCA1 or BRCA 2.

• One or more cases with ovarian cancer in the family.

• One or more relatives with both breast and ovarian cancer.

PMS1, PMS2 and possibly some other yet unidentified genes).

tions in *BRCA*1 and *BRCA*2, against 10% in non-Ashkenazim [78].

pates in chromatin remodeling and crucial steps in cell cycle [79].

Use of gonadotropins is also associated with increased risk [31, 70]. There are, however, a number of studies that show no increased risk of OC with use of ovula-

However, studies that report increased risk do of borderline tumors only not

More than one-fifth of OC cases are hereditary from highly penetrant autosomal dominant genetic susceptibility [72]. Although accounting for only a limited number of cases, heredity is a strong risk factor for OC. The lifetime risk of a woman who has a first degree relative with OC is 5% compared with 1.4% in a woman without. The risk rises to 7% if two members of the family are affected [73]. These rate has been thought to be a probable underestimate as a British study has shown that where two close relatives (not necessarily first degree) are affected, the risk may be as high as 30–40% [73, 74]. The risk for confirmed carriers of BRCA at the age of 70 may be as high as 63% [73, 75]. Ovarian cancer in a first degree relative, has been shown to be a strong positive indicator of early onset epithelial cancer and

The three main clinical types of genetic ovarian cancers include site-specific, hereditary breast and/or ovarian cancer (HBOC) and hereditary non-polyposis

The first two syndromes are related to inheritance of BRCA1 and BRCA 2. Patients with HNPCC have inherited mismatch repair genes (MLH1, MLH2, MLH6,

BRCA genes are common in the Ashkenazi Jewish population where 29–41% of ovarian cancer is believed to be secondary to inheriting one of three founder muta-

BRCA 1 gene is an oncosuppressor gene located at chromosome 17q, it partici-

OC associated with BRCA mutations are diagnosed at a younger age and are of high-grade serous type. In one study, the average age at diagnosis of OC in BRCA1 and BRCA2 mutation carriers was 52 and 62 years, respectively [77, 80]. BRCA mutations do not seem to play a significant role in the development of mucinous or borderline ovarian tumors. The BRCA associated OCs also tend to have better clinical outcome with longer overall survival and recurrence-free interval than sporadic cancers [77]. There is no standard clinical definition of hereditary breast and ovarian cancer

• Several cases of breast cancer diagnosed before the age of 50 years.

• However, many women without a family history may still have a gene mutation

Lynch syndrome (LS) or hereditary non-polyposis colon cancer (HNPCC) refers to germline mutations in MMR genes (*MLH1*, *MSH2*, *MSH6*, *MLH3* and *PMS2*),

#### *Risk Factors for Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.86712*

Use of gonadotropins is also associated with increased risk [31, 70]. There are, however, a number of studies that show no increased risk of OC with use of ovulation induction agents [71].

However, studies that report increased risk do of borderline tumors only not high grade serous.

#### **7. Genetic factors**

*Tumor Progression and Metastasis*

more than 50 years in age [38].

with 45 years or less [66].

1.16, 95% CI: 1.02–1.31) [69].

with no clomiphene use [67].

failed to conceive have even higher risk [70].

risk [67].

Most reports suggest EOC to be the commonest but predominantly seen in young

A global report by the International Federation of Gynecology and Obstetrics (FIGO) has noted that the highest incidence of ovarian cancer was moving towards a younger age group, although the majority of patients with epithelial cancer were

It is interesting that high grade serous cyst adenocarcinoma remains the commonest variety while literature from USA, Europe, Israel and Australia find it in older women above 65 years, in Asia, the Arab world and Africa, it is observed in young premenopausal women. Research for this important difference is worthwhile. Early menarche is considered a weak predictor of ovarian cancer risk and women whose menarche was earlier than 12 years are at increased risk of epithelial tumors [62, 63]. Meta-analysis of 22 case–control studies and 5 cohort studies has reported a statistically significant inverse association between menarcheal age and ovarian cancer risk (RR = 0.85; 95% CI: 0.75–0.97) [62], but this association is most significant in invasive serous and borderline tumors. In this respect, 'incessant ovulation' theory as possible cause of tumor genesis provides plausible explanation [30, 34]. No association was found when menarche begins after age 16 years. Late

Women who experience natural late menopause are at increased risk [13, 34, 65]. Odds ratios for late natural menopause were reported as low as 1.19 and as high as 1.25 (95% CI: 0.95–1.49) [65]. These findings may suggest that earlier menarcheal age and late natural menopause might increase risk of ovarian cancer by increasing a woman's lifetime number of ovulations. Results from the Nurses' Health Study (NHS) confirmed increased risk of endometrioid epithelial cancers with late natural menopause but not of serous or mucinous cancers (RR = 1.3, 95% CI: 1.04–1.22). Furthermore, the European Prospective Study into Cancer and Nutrition Cohort (EPIC) age at menopause >52 years was associated with increased risk compared

Infertility either by itself or in association with some of its causes like endometriosis, is a risk factor and prolonged period of infertility is associated with higher

A large cohort study, involving 54,362 women with infertility in the Danish fertility clinics (1963–1998) used parity specific cancer incidence and reported

Whittemore et al. analyzed 12 US case–control studies between 1957 and 1985, with 2197 cases of ovarian cancer and 4144 controls and confirmed higher risk in

However, study by Ness with 5207 cases of ovarian cancer and 7705 controls found only a weak association between infertility and epithelial ovarian cancer (OR

Drug treatment of infertility may further increase risk as untreated infertile nulliparous women have 1.5–2-fold risk, while women who received treatment and

Use of ovulation induction agents like clomiphene citrate, gonadotropins are associated with three times higher general population [69] particularly prolonged use of clomiphene (for more than 12 cycles). This is associated with rise in risk for invasive and borderline cases by about 11.1-fold compared with infertile women

significantly increased from infertility (1.46, 95% CI: 1.24–1.71) [68].

premenopausal, generally parous women [38, 60, 61].

menarche has not been shown to be protective [64].

**6. Infertility and use of ovulation induction drugs**

nulligravid subfertile women compared with controls [20].

**80**

More than one-fifth of OC cases are hereditary from highly penetrant autosomal dominant genetic susceptibility [72]. Although accounting for only a limited number of cases, heredity is a strong risk factor for OC. The lifetime risk of a woman who has a first degree relative with OC is 5% compared with 1.4% in a woman without. The risk rises to 7% if two members of the family are affected [73]. These rate has been thought to be a probable underestimate as a British study has shown that where two close relatives (not necessarily first degree) are affected, the risk may be as high as 30–40% [73, 74]. The risk for confirmed carriers of BRCA at the age of 70 may be as high as 63% [73, 75]. Ovarian cancer in a first degree relative, has been shown to be a strong positive indicator of early onset epithelial cancer and positively associated with non-mucinous tumors [76].

The three main clinical types of genetic ovarian cancers include site-specific, hereditary breast and/or ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC) or Lynch II syndrome [77].

The first two syndromes are related to inheritance of BRCA1 and BRCA 2. Patients with HNPCC have inherited mismatch repair genes (MLH1, MLH2, MLH6, PMS1, PMS2 and possibly some other yet unidentified genes).

BRCA genes are common in the Ashkenazi Jewish population where 29–41% of ovarian cancer is believed to be secondary to inheriting one of three founder mutations in *BRCA*1 and *BRCA*2, against 10% in non-Ashkenazim [78].

BRCA 1 gene is an oncosuppressor gene located at chromosome 17q, it participates in chromatin remodeling and crucial steps in cell cycle [79].

OC associated with BRCA mutations are diagnosed at a younger age and are of high-grade serous type. In one study, the average age at diagnosis of OC in BRCA1 and BRCA2 mutation carriers was 52 and 62 years, respectively [77, 80]. BRCA mutations do not seem to play a significant role in the development of mucinous or borderline ovarian tumors. The BRCA associated OCs also tend to have better clinical outcome with longer overall survival and recurrence-free interval than sporadic cancers [77].

There is no standard clinical definition of hereditary breast and ovarian cancer syndrome but affected families may be identified from:


Lynch syndrome (LS) or hereditary non-polyposis colon cancer (HNPCC) refers to germline mutations in MMR genes (*MLH1*, *MSH2*, *MSH6*, *MLH3* and *PMS2*),

which lead to the loss of expression of one of the MMR proteins. Clinically, LS is associated with higher risk of colorectal cancers that have specific predilection to location proximal to splenic flexure [72, 81]. Confirmed case of Lynch syndrome is associated with 6–10% life time risk of OC of early onset. MLH1 carriers are often diagnosed of ovarian cancer at average age of 52 years and MLH2 carriers at age of 45 years [82, 83].

HNPCC syndrome is also associated with cancers of the stomach, small bowel, hepatobiliary tract, pancreas, renal pelvis, ureter, breast, prostate and brain (particularly glioblastoma) [72, 84]. The OCs associated with LS are commonly endometrioid and clear cell varieties [82, 85] and tend to be diagnosed at a relatively early stage with high stage-specific survival rate compared with non LS type [86, 87].

The Li-Fraumeni syndrome is an autosomal dominant syndrome characterized by heterozygous germline mutation in TP53. It is the most frequently mutated gene in human cancer thus the syndrome is associated with development of multiple cancers at young age. About 50% will develop first tumor at age of 30 years [88] and up to 35% will develop multiple tumors in their lifetime [89]. Li-Fraumeni syndrome associated OC, though not the most common but tend to occur at around 39.5 years [90].

Peutz-Jeghers syndrome(PJS) is a rare autosomal dominant condition occurring in 1 in 25,000–30,000 livebirths [91] characterized by benign hamartomatous intestinal polyps with very low tendency to malignancy, cutaneous lesions increased risk of OC in addition to cancers of breast, colon, rectum, pancreas, stomach, testicles and lungs. Tumor suppressor gene STK11(LKB1), located on chromosome 19p13.3 is responsible for this syndrome. OC risk is as high as 18–21% [92]. The ovarian cancers associated with this syndrome are sex cord tumor with annular tubules (SCTATs) in addition to a range of other gynecological cancers [92, 93].

Mutations in double strand breaks repair system like *CHEK2, RAD51, BRIP1* and *PALB2* are also associated with increased risk of various types of ovarian cancer [89, 94]. To date, more than 16 genes are known to be involved in the mechanism of hereditary ovarian tumorigenesis and new ones are being discovered [77, 95].

#### **8. Use of perineal talc**

Talc, a metamorphic mineral composed of silicon, magnesium and oxygen, is a common component of genital powders. Applied by women for moisture absorption to prevent perineal chafing and rashes, talc has similarities to and co-occurs with asbestos in its natural form, which is a known carcinogen [96, 97]. Contamination of talc with asbestos was hypothesized to have a causal role in ovarian carcinogenesis [13, 98]. The finding of talc materials in ovarian cancer specimens supports this argument [99]. The International Agency for Research on Cancer(IARC) in 2006, classified genital talc use as possibly carcinogenic to humans based on evidence from epidemiologic studies (carcinogen group 2B) [100, 101].

Although the biological basis of talc carcinogenicity is not clear, direct physical contact with ovarian epithelium may cause chronic inflammation and retrograde transport of talc particles through the reproductive tract as suggested by some workers may occur [98]. An immune mechanism may also be the case.

Several case–control studies report association between perineal talc use and ovarian cancer and data from Women Health Initiative support this association also support this fact [98, 102–104]. Furthermore, a prospective study has confirmed association with serous cystadenocarcinoma and talc use. However asbestos-free talc has been in use in cosmetic products at least in most developed countries and later case–control studies show no association between use of talc and ovarian cancer [104]. Other case–control studies found increased risk by 92% that is a relative risk of 1.92 [98]. A study by Cook et al. reported 1.60 relative risk of ovarian cancer with use than non-use. This is an increase of 60%. Finally, a meta-analysis of about 20 published

**83**

*Risk Factors for Ovarian Cancer*

**9. Diet and ovarian cancer**

ovarian cancer [116].

risk [123–126].

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

works reported 35% increased risk of cancer in women who used talc [102]. Scientific evidence has weighed heavily against the makers of talc products who recently lost over 4 billion dollars to a group of 22 women who developed ovarian cancer following

Diet has been directly or indirectly related to risk of ovarian cancer though very

few studies specify the histologic subtype in relation to dietary types. Diet may be modifying the risk of ovarian cancer through effect on endogenous hormones, antioxidant activity or other anticarcinogenic mechanisms. There is however a unanimous finding of reduced incidence of ovarian cancer with higher intake of vegetables especially for epithelial ovarian cancer [106–111]. The average finding is a reduction of risk by about more than 50%. High dietary fiber, carotenoids total

Dairy products have received conflicting results. While over the years, studies showed no associations between dairy intake and ovarian cancer of any type [113, 114]. Faber et al. using the Danish population-based case–control studies reported increased risk especially with milk and lactose but decreased risk with cheese [115]. An interesting study by Merritt et al. using data from New England case–control study examined including histological subtypes and tumor aggression in relation to intake of dairy foods. They reported decreased risk of serous borderline and mucinous cancer with higher intake of calcium and vitamin D. High Vitamin D intake was also found to be inversely related to serous borderline and endometrioid cancers [116]. Merritt et al. found no evidence between lactose intake and risk of

High intake of total fat, animal fat, cholesterol and saturated fats may be associated with increased risk. Meta-analysis of 16 independent studies reported significant increase in risk of ovarian cancer with high intake of total saturated and trans fats with serous cancers being especially susceptible to dietary fats than other histologic subtypes [117, 118]. Huncharek and Kupelnick reported a RR of 1.70 or an increased risk of 70% in patients with high fat intake [117], however Bertone et al. found no association with intake of fats alone but associated increased with when combined with high intake of eggs [119]. High intake of eggs alone are reported to increase risk [111, 120]. This effect has been linked to high dietary cholesterol which may be increasing risk of ovarian cancer through increased circulating estrogens [111, 121]. Although the link between ovarian cancer and high intake of meat has been controversial with some studies finding no association [122], majority report positive association between high intake of red and processed meat with epithelial ovarian cancer, while poultry and fish have either no relative increase or observed reduction in

High alcohol consumption has been studied in reasonable depth and only few studies show no association [127] while others show a reduction in risk with minimal and moderate intake of alcohol [128, 129]. The observed phenomenon may be due to the anti-oxidants in the wine and alcohol rather than the alcohol itself [130]. While tea consumption has not been associated with risk of ovarian cancer, coffee is

High dietary intake of B carotene is reported to be protective against epithelial ovarian cancer; in a meta-analysis of over 3782 subjects, a modest 16% reduced risk was found [133]. Supplemental selenium (>20 μg daily) is associated with 30% risk reduction [134]. This fact, however, does not support use of selenium as a preventive strategy [135]. These antioxidants may be reducing risk by limiting oxidative

associated with modest reduction of risk [131, 132].

stress to the ovarian epithelium.

talc use adding a court evidence to ovarian carcinogenesis by talc [105].

ligands and phytochemicals are associated with reduced risk [112].

works reported 35% increased risk of cancer in women who used talc [102]. Scientific evidence has weighed heavily against the makers of talc products who recently lost over 4 billion dollars to a group of 22 women who developed ovarian cancer following talc use adding a court evidence to ovarian carcinogenesis by talc [105].

#### **9. Diet and ovarian cancer**

*Tumor Progression and Metastasis*

**8. Use of perineal talc**

which lead to the loss of expression of one of the MMR proteins. Clinically, LS is associated with higher risk of colorectal cancers that have specific predilection to location proximal to splenic flexure [72, 81]. Confirmed case of Lynch syndrome is associated with 6–10% life time risk of OC of early onset. MLH1 carriers are often diagnosed of ovarian cancer at average age of 52 years and MLH2 carriers at age of 45 years [82, 83]. HNPCC syndrome is also associated with cancers of the stomach, small bowel, hepatobiliary tract, pancreas, renal pelvis, ureter, breast, prostate and brain (particularly glioblastoma) [72, 84]. The OCs associated with LS are commonly endometrioid and clear cell varieties [82, 85] and tend to be diagnosed at a relatively early stage with high stage-specific survival rate compared with non LS type [86, 87]. The Li-Fraumeni syndrome is an autosomal dominant syndrome characterized by heterozygous germline mutation in TP53. It is the most frequently mutated gene in human cancer thus the syndrome is associated with development of multiple cancers at young age. About 50% will develop first tumor at age of 30 years [88] and up to 35% will develop multiple tumors in their lifetime [89]. Li-Fraumeni syndrome associated OC, though not the most common but tend to occur at around 39.5 years [90]. Peutz-Jeghers syndrome(PJS) is a rare autosomal dominant condition occurring in 1 in 25,000–30,000 livebirths [91] characterized by benign hamartomatous intestinal polyps with very low tendency to malignancy, cutaneous lesions increased risk of OC in addition to cancers of breast, colon, rectum, pancreas, stomach, testicles and lungs. Tumor suppressor gene STK11(LKB1), located on chromosome 19p13.3 is responsible for this syndrome. OC risk is as high as 18–21% [92]. The ovarian cancers associated with this syndrome are sex cord tumor with annular tubules (SCTATs) in addition to a range of other gynecological cancers [92, 93].

Mutations in double strand breaks repair system like *CHEK2, RAD51, BRIP1* and *PALB2* are also associated with increased risk of various types of ovarian cancer [89, 94]. To date, more than 16 genes are known to be involved in the mechanism of hereditary ovarian tumorigenesis and new ones are being discovered [77, 95].

Talc, a metamorphic mineral composed of silicon, magnesium and oxygen, is a common component of genital powders. Applied by women for moisture absorption to prevent perineal chafing and rashes, talc has similarities to and co-occurs with asbestos in its natural form, which is a known carcinogen [96, 97]. Contamination of talc with asbestos was hypothesized to have a causal role in ovarian carcinogenesis [13, 98]. The finding of talc materials in ovarian cancer specimens supports this argument [99]. The International Agency for Research on Cancer(IARC) in 2006, classified genital talc use as possibly carcinogenic to humans based on evidence from

Although the biological basis of talc carcinogenicity is not clear, direct physical contact with ovarian epithelium may cause chronic inflammation and retrograde transport of talc particles through the reproductive tract as suggested by some

Several case–control studies report association between perineal talc use and ovarian cancer and data from Women Health Initiative support this association also support this fact [98, 102–104]. Furthermore, a prospective study has confirmed association with serous cystadenocarcinoma and talc use. However asbestos-free talc has been in use in cosmetic products at least in most developed countries and later case–control studies show no association between use of talc and ovarian cancer [104]. Other case–control studies found increased risk by 92% that is a relative risk of 1.92 [98]. A study by Cook et al. reported 1.60 relative risk of ovarian cancer with use than non-use. This is an increase of 60%. Finally, a meta-analysis of about 20 published

epidemiologic studies (carcinogen group 2B) [100, 101].

workers may occur [98]. An immune mechanism may also be the case.

**82**

Diet has been directly or indirectly related to risk of ovarian cancer though very few studies specify the histologic subtype in relation to dietary types. Diet may be modifying the risk of ovarian cancer through effect on endogenous hormones, antioxidant activity or other anticarcinogenic mechanisms. There is however a unanimous finding of reduced incidence of ovarian cancer with higher intake of vegetables especially for epithelial ovarian cancer [106–111]. The average finding is a reduction of risk by about more than 50%. High dietary fiber, carotenoids total ligands and phytochemicals are associated with reduced risk [112].

Dairy products have received conflicting results. While over the years, studies showed no associations between dairy intake and ovarian cancer of any type [113, 114]. Faber et al. using the Danish population-based case–control studies reported increased risk especially with milk and lactose but decreased risk with cheese [115]. An interesting study by Merritt et al. using data from New England case–control study examined including histological subtypes and tumor aggression in relation to intake of dairy foods. They reported decreased risk of serous borderline and mucinous cancer with higher intake of calcium and vitamin D. High Vitamin D intake was also found to be inversely related to serous borderline and endometrioid cancers [116]. Merritt et al. found no evidence between lactose intake and risk of ovarian cancer [116].

High intake of total fat, animal fat, cholesterol and saturated fats may be associated with increased risk. Meta-analysis of 16 independent studies reported significant increase in risk of ovarian cancer with high intake of total saturated and trans fats with serous cancers being especially susceptible to dietary fats than other histologic subtypes [117, 118]. Huncharek and Kupelnick reported a RR of 1.70 or an increased risk of 70% in patients with high fat intake [117], however Bertone et al. found no association with intake of fats alone but associated increased with when combined with high intake of eggs [119]. High intake of eggs alone are reported to increase risk [111, 120]. This effect has been linked to high dietary cholesterol which may be increasing risk of ovarian cancer through increased circulating estrogens [111, 121].

Although the link between ovarian cancer and high intake of meat has been controversial with some studies finding no association [122], majority report positive association between high intake of red and processed meat with epithelial ovarian cancer, while poultry and fish have either no relative increase or observed reduction in risk [123–126].

High alcohol consumption has been studied in reasonable depth and only few studies show no association [127] while others show a reduction in risk with minimal and moderate intake of alcohol [128, 129]. The observed phenomenon may be due to the anti-oxidants in the wine and alcohol rather than the alcohol itself [130]. While tea consumption has not been associated with risk of ovarian cancer, coffee is associated with modest reduction of risk [131, 132].

High dietary intake of B carotene is reported to be protective against epithelial ovarian cancer; in a meta-analysis of over 3782 subjects, a modest 16% reduced risk was found [133]. Supplemental selenium (>20 μg daily) is associated with 30% risk reduction [134]. This fact, however, does not support use of selenium as a preventive strategy [135]. These antioxidants may be reducing risk by limiting oxidative stress to the ovarian epithelium.

The effect of vitamin D, particularly D3, has been of interest because of its ability to cause apoptosis of cancer cells in vitro and the demonstrated increased risk of ovarian cancer in vitamin D deficient Europeans [136], more research is necessary to define clinical implication of these findings as some researchers propose supplementation of vitamin D for preventive purposes [137].

#### **10. Smoking**

Association between cigarette smoking and ovarian cancer is not as clear as other cancers like lungs oropharynx and lungs that are very well documented [138]. However, metabolites of nicotine which are potent hydrocarbons and carcinogens like cotidine and benzopyrene have been isolated in follicular fluid and OC has been induced in rodents with cyclical hydrocarbons [139].

Cigarette smoking is associated with increased risk of mucinous ovarian cancers [140–143] but the effects on other histologic types is less clear. A Norwegian study, found increased risk of invasive borderline cancers in addition to mucinous [140]. Smokers however have a deficit of endometrioid tumors.

Survival of patients who smoke is also found to be worse than that of nonsmokers [142, 144]. Studies have confirmed the increased risk of mucinous epithelial cancers in smokers to be directly proportional to the pack-years of smoking [145, 146]. A twofold increased risk of mucinous epithelial cancers is the generally observed phenomenon [141, 143, 146], but could be up to fourfold increase in women who have smoked for 40 years or more [146].

There is a suggestion however that with the deficit in clear cell and endometrioid cancer and despite the increase in borderline and mucinous cancer smoking may not be associated with overall increase in ovarian cancer mortality [144].

#### **11. Endometriosis and risk of ovarian cancer**

OC prevalence in women with endometriosis is higher than the general population 1.32–1.9 [147]. A recent systemic review agrees with this modest increase in risk of endometrioid, borderline and clear cell cancers with endometriosis [148]. Some reports suggest about two to threefold increase in risk [149]. This association between endometriosis and OC is not a proof of causality for the histiotypes.

It is more common in patients with longstanding or recurrent endometriosis and removal of endometrioma is not preventive towards development of OC [150]. The increased risk might be due to high estrogen concentration or due to gene mutations caused by oxidative stress due to iron in the endometriotic cyst [151].

#### **12. Polycystic ovarian syndrome**

PCOS is the commonest endocrine disease in women of reproductive age with incidence of about 20% [152]. Associated with infertility, obesity and abnormal gonadotropin secretion, PCOS is associated with 2.5-fold increased risk of epithelial ovarian cancer [153]. The risk of ovarian cancer in women with PCOS is greatest in lean women and those who never used oral contraceptive pills [153, 154].

A systemic review involving eight studies and a meta-analysis found increased incidence of borderline serous cancer in patients with PCOS [155]. Proteomic biomarkers for identification of patients with PCOS who are at increased risk of ovarian cancer may be useful for early diagnosis but the clinical use of these markers need further verification [156].

**85**

*Risk Factors for Ovarian Cancer*

mode of administration.

women (BMI > 30 kg/m2

HR = 1.17, 95% CI: 1.03–1.32) [169].

**15. Obesity**

5 kg/m<sup>2</sup>

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

Inflammation has been implicated in ovarian carcinogenesis but studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent with some studies reporting positive association [157, 158] and others excluding such association [159, 160]. A pooled reanalysis of 13 studies reported increased risk of borderline ovarian tumors in women who had multiple episodes of pelvic inflammation [157]. This association may be pronounced among Asian women [158]. Rasmussen et al. in a population-based cohort study recently reported increase in risk of serous ovarian cancer in patients with PID [157]. Therefore we can conclude that repeated episodes of PID is associated with statistically significant risk of borderline and serous cancers but not nonepithelial cancers which have been found not to be associated with PID [158].

**14. Hormone replacement therapy (Hrt) and risk of ovarian cancer**

Women who use menopausal hormone therapy are at an increased risk for ovarian cancer. A review and meta-analysis of data published between 1966 and 2006 concluded that current use of postmenopausal hormone therapy (HT) increased the risk of ovarian cancer by 30% compared with never use of HT [161]. Estrogen alone was thought to confer higher risk than combined estrogen and progesterone which is refuted by finding from data from million women study [162, 163]. Recent studies indicate that using a combination of estrogen and progestin for 5 or more years significantly increases the risk of serous and endometrioid OC in women with intact uterus, but for women who have had hysterectomy, 10 or more years of use is associated with increased risk [161, 164, 165]. In a recent pooled analysis of 52 epidemiological studies, the risk of serous cancer was 51.4% and that of endometrioid was 48.6% [164]. The increase has been interpreted to mean one extra OC in 1000 users and one extra mortality in 1700 user [166]. There is more risk with prolonged use irrespective of the type of HRT, regimes used or

Obesity may be increasing risk of ovarian cancer significantly [166–168]. Obese

increase in BMI (Collaborative Study). Higher BMI in young adulthood is

Evidence from meta-analysis of 14 studies shows that slightly worse survival in obese women with ovarian cancer compared to non-obese women (pooled

Obesity may be increasing this risk for ovarian cancer through increasing inflammatory biomarkers and increase in hormonal factors especially androgens

Histologic subtypes associated with obesity include low-grade serous, mucinous tumors and endometrioid cancers. No association was found between high grade serous and obesity therefore reducing BMI is unlikely to reduce the incidence of

therapy (MHR) had 25–80% increased risk compared with women with normal BMI (18.5–24.9) no relationship between BMI and OC in women with family history. Obesity is associated with an almost 80% higher risk of ovarian cancer in women 50–71 who had not taken hormones after menopause. For women who have not used HRT, evidence shows risk of ovarian cancer to increase by 10% with every

reported to increase risk of premenopausal ovarian cancers [167].

which is important in development of mucinous tumors [170].

) who have not used menopausal hormone replacement

**13. Pelvic inflammatory disease**

#### **13. Pelvic inflammatory disease**

*Tumor Progression and Metastasis*

**10. Smoking**

mentation of vitamin D for preventive purposes [137].

induced in rodents with cyclical hydrocarbons [139].

Smokers however have a deficit of endometrioid tumors.

women who have smoked for 40 years or more [146].

**11. Endometriosis and risk of ovarian cancer**

**12. Polycystic ovarian syndrome**

ers need further verification [156].

The effect of vitamin D, particularly D3, has been of interest because of its ability to cause apoptosis of cancer cells in vitro and the demonstrated increased risk of ovarian cancer in vitamin D deficient Europeans [136], more research is necessary to define clinical implication of these findings as some researchers propose supple-

Association between cigarette smoking and ovarian cancer is not as clear as other cancers like lungs oropharynx and lungs that are very well documented [138]. However, metabolites of nicotine which are potent hydrocarbons and carcinogens like cotidine and benzopyrene have been isolated in follicular fluid and OC has been

Cigarette smoking is associated with increased risk of mucinous ovarian cancers [140–143] but the effects on other histologic types is less clear. A Norwegian study, found increased risk of invasive borderline cancers in addition to mucinous [140].

There is a suggestion however that with the deficit in clear cell and endometrioid cancer and despite the increase in borderline and mucinous cancer smoking may

OC prevalence in women with endometriosis is higher than the general population 1.32–1.9 [147]. A recent systemic review agrees with this modest increase in risk of endometrioid, borderline and clear cell cancers with endometriosis [148]. Some reports suggest about two to threefold increase in risk [149]. This association between endometriosis and OC is not a proof of causality for the histiotypes.

It is more common in patients with longstanding or recurrent endometriosis and removal of endometrioma is not preventive towards development of OC [150]. The increased risk might be due to high estrogen concentration or due to gene mutations

PCOS is the commonest endocrine disease in women of reproductive age with incidence of about 20% [152]. Associated with infertility, obesity and abnormal gonadotropin secretion, PCOS is associated with 2.5-fold increased risk of epithelial ovarian cancer [153]. The risk of ovarian cancer in women with PCOS is greatest in

A systemic review involving eight studies and a meta-analysis found increased

Survival of patients who smoke is also found to be worse than that of nonsmokers [142, 144]. Studies have confirmed the increased risk of mucinous epithelial cancers in smokers to be directly proportional to the pack-years of smoking [145, 146]. A twofold increased risk of mucinous epithelial cancers is the generally observed phenomenon [141, 143, 146], but could be up to fourfold increase in

not be associated with overall increase in ovarian cancer mortality [144].

caused by oxidative stress due to iron in the endometriotic cyst [151].

lean women and those who never used oral contraceptive pills [153, 154].

incidence of borderline serous cancer in patients with PCOS [155]. Proteomic biomarkers for identification of patients with PCOS who are at increased risk of ovarian cancer may be useful for early diagnosis but the clinical use of these mark-

**84**

Inflammation has been implicated in ovarian carcinogenesis but studies investigating the association between pelvic inflammatory disease (PID) and ovarian cancer risk are few and inconsistent with some studies reporting positive association [157, 158] and others excluding such association [159, 160]. A pooled reanalysis of 13 studies reported increased risk of borderline ovarian tumors in women who had multiple episodes of pelvic inflammation [157]. This association may be pronounced among Asian women [158]. Rasmussen et al. in a population-based cohort study recently reported increase in risk of serous ovarian cancer in patients with PID [157]. Therefore we can conclude that repeated episodes of PID is associated with statistically significant risk of borderline and serous cancers but not nonepithelial cancers which have been found not to be associated with PID [158].

#### **14. Hormone replacement therapy (Hrt) and risk of ovarian cancer**

Women who use menopausal hormone therapy are at an increased risk for ovarian cancer. A review and meta-analysis of data published between 1966 and 2006 concluded that current use of postmenopausal hormone therapy (HT) increased the risk of ovarian cancer by 30% compared with never use of HT [161]. Estrogen alone was thought to confer higher risk than combined estrogen and progesterone which is refuted by finding from data from million women study [162, 163]. Recent studies indicate that using a combination of estrogen and progestin for 5 or more years significantly increases the risk of serous and endometrioid OC in women with intact uterus, but for women who have had hysterectomy, 10 or more years of use is associated with increased risk [161, 164, 165]. In a recent pooled analysis of 52 epidemiological studies, the risk of serous cancer was 51.4% and that of endometrioid was 48.6% [164]. The increase has been interpreted to mean one extra OC in 1000 users and one extra mortality in 1700 user [166]. There is more risk with prolonged use irrespective of the type of HRT, regimes used or mode of administration.

#### **15. Obesity**

Obesity may be increasing risk of ovarian cancer significantly [166–168]. Obese women (BMI > 30 kg/m2 ) who have not used menopausal hormone replacement therapy (MHR) had 25–80% increased risk compared with women with normal BMI (18.5–24.9) no relationship between BMI and OC in women with family history. Obesity is associated with an almost 80% higher risk of ovarian cancer in women 50–71 who had not taken hormones after menopause. For women who have not used HRT, evidence shows risk of ovarian cancer to increase by 10% with every 5 kg/m<sup>2</sup> increase in BMI (Collaborative Study). Higher BMI in young adulthood is reported to increase risk of premenopausal ovarian cancers [167].

Evidence from meta-analysis of 14 studies shows that slightly worse survival in obese women with ovarian cancer compared to non-obese women (pooled HR = 1.17, 95% CI: 1.03–1.32) [169].

Obesity may be increasing this risk for ovarian cancer through increasing inflammatory biomarkers and increase in hormonal factors especially androgens which is important in development of mucinous tumors [170].

Histologic subtypes associated with obesity include low-grade serous, mucinous tumors and endometrioid cancers. No association was found between high grade serous and obesity therefore reducing BMI is unlikely to reduce the incidence of

high grade serous cancers [171]. Moreover, obese women with HGSC have poorer outcome than their non-obese counter parts [172].

*Risk Factors for Ovarian Cancer*

**87**

**Author details**

**17. Conclusion**

Zaria, Nigeria

Marliyya S. Zayyan

provided the original work is properly cited.

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Oncology Department of Obstetrics and Gynecology, Ahmadu Bello University,

\*Address all correspondence to: marliyya.zayyan@gmail.com

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

been blamed in ovarian carcinogenesis.

oophorectomy may reduce risk by up to 67% [184, 185].

**16.4 Hysterectomy/tubal ligation**

**16.5 Physical activity and exercise**

nous tumors [187].

inactivity [188, 189].

Therefore while HRT is associated with increasing risk, the pills are associated with reduced risk a position both have similar active ingredients and estrogen has

Observational epidemiologic evidence strongly support tubal ligation and hysterectomy to be associated with a decrease in the risk of ovarian cancer, by approximately 26–30% [184]. Having fallopian tubes tied hysterectomy and unilateral

Patients with BRCA1 but not with BRCA2 are found to benefit from the protection conferred by tubal ligation to OC [186]. Tubal ligation and hysterectomy reduce risk of low grade more than high grade serous cancers. Risk of endometrioid cancer is almost halved. Tubal ligation is not observed to reduce the risk of muci-

Physical activity may be beneficial in both risk reduction of inflammation, decreasing body fat and frequency of ovulation. Survivors of ovarian cancer may also experience general health benefit of physical activity [188]. The specific effect of physical exercise on ovarian cancer in general and the various histologic subtypes have shown inconsistent results. The most consistent result obtained by research is that of increasing risk by prolonged sedentary life style physical

Considering direct effect of physical activity however, some studies report no effect on the risk of ovarian cancer [190, 191] while other studies report risk reduction [190, 191]. The reduction of risk may be to epithelial cancers. Physical activity

The risk of ovarian cancer in women is modified by a number of biologic, hormonal, lifestyle and geographic factors the extent of which differs between the histologic varieties. There may be racial or regional variation in the extent to which these factor increase risk or protect against particularly the most common histologic subtype.

may not be affecting sex cord-stromal and germ cell cancers of the ovary.

Recent systemic review of 43 studies involving more than 3 million women concludes that the evidence is inconsistent that obesity is a definite risk factor for ovarian cancer [173]. This finding may be due to the dominance of HGSC which risk is not affected by obesity.

#### **16. Protective factors that reduce risk of ovarian cancer.**

#### **16.1 Pregnancy**

Pregnancy is thought to be protective against ovarian cancer [13, 47, 65]. Pregnancy whether uncompleted or term confers a protective benefit against epithelial ovarian cancer. Increasing parity is associated with a reduction in the risk of ovarian cancer [36, 63, 65, 174]. Pregnancy may be protective against all histological subtypes. A Swedish study has reported reduced risk for epithelial, stromal and germ cell tumors, but less consistent decrease in borderline cancers [63].

However, it appears that the protective effect of pregnancy (and breast feeding) so called reproductive factors, may be more significant in the West, parts of the US and among Jewish women as reports of ovarian cancer of all histologic subtypes in parous women in developing countries is so widespread and requires further research [38, 53, 55, 57, 59, 60]. The significance of this phenomenon is that the protective effect of pregnancy may be lost in the face of other more important risk factors that need to be defined.

All theories of ovarian carcinogenesis are not plausible explanation for the observed protective effect of pregnancy, therefore pregnancy-induced clearance of malignant cells has been proposed [63] which must to be case in all races to be an acceptable hypothesis.

#### **16.2 Breastfeeding**

Breast feeding exerts a strong protective effect with long-term breast feeding being more protective especially against epithelial cancers [175]. The mechanism may be by suppression of gonadotropins through unovulation, resulting in depressed production of plasma estradiol and unovulatory cycles [65, 176]. Breastfeeding also reduces the levels of gonadotropins, especially luteinizing hormone [176], which may be causal mechanism for ovarian carcinogenesis [177].

Meta-analysis of 12 US studies and 9 studies from developed countries showed an inverse association between breastfeeding and ovarian cancer risk [175]. Women who breast fed for up to 6 months showed duration-dependent benefit with women who breastfed for long having more protection. Breast feeding may be reducing risk of epithelial cancers by up to 30% compared with women who did not breast feed.

#### **16.3 Oral contraceptives**

The use of oral contraceptives decreases the risk of developing OC and the benefit may be enjoyed up to 25–30 years after stopping the pill [178, 179]. COCP use is associated with about a 40–50% lower risk compared with never use [178, 180]. Length of pill use appears to influence the degree of protection, with a relative risk of 0.4 for more than 5 years reported in pooled European and US studies [178, 181].

The protective benefit may be experienced even in high risk women though there is not enough evidence for use of the pill for chemoprophylaxis [180, 182, 183]. Women who use the pills for more than 5 years enjoy more protection of about 50% reduction [179]. This protection is enjoyed by women of all ages and parities.

*Tumor Progression and Metastasis*

is not affected by obesity.

**16.1 Pregnancy**

acceptable hypothesis.

**16.3 Oral contraceptives**

**16.2 Breastfeeding**

outcome than their non-obese counter parts [172].

**16. Protective factors that reduce risk of ovarian cancer.**

high grade serous cancers [171]. Moreover, obese women with HGSC have poorer

Recent systemic review of 43 studies involving more than 3 million women concludes that the evidence is inconsistent that obesity is a definite risk factor for ovarian cancer [173]. This finding may be due to the dominance of HGSC which risk

Pregnancy is thought to be protective against ovarian cancer [13, 47, 65]. Pregnancy whether uncompleted or term confers a protective benefit against epithelial ovarian cancer. Increasing parity is associated with a reduction in the risk of ovarian cancer [36, 63, 65, 174]. Pregnancy may be protective against all histological subtypes. A Swedish study has reported reduced risk for epithelial, stromal and

However, it appears that the protective effect of pregnancy (and breast feeding) so called reproductive factors, may be more significant in the West, parts of the US and among Jewish women as reports of ovarian cancer of all histologic subtypes in parous women in developing countries is so widespread and requires further research [38, 53, 55, 57, 59, 60]. The significance of this phenomenon is that the protective effect of pregnancy may be lost in the face of other more important risk factors that need to be defined. All theories of ovarian carcinogenesis are not plausible explanation for the observed protective effect of pregnancy, therefore pregnancy-induced clearance of malignant cells has been proposed [63] which must to be case in all races to be an

Breast feeding exerts a strong protective effect with long-term breast feeding being more protective especially against epithelial cancers [175]. The mechanism may be by suppression of gonadotropins through unovulation, resulting in depressed production of plasma estradiol and unovulatory cycles [65, 176]. Breastfeeding also reduces the levels of gonadotropins, especially luteinizing hormone [176], which may be causal mechanism for ovarian carcinogenesis [177]. Meta-analysis of 12 US studies and 9 studies from developed countries showed an inverse association between breastfeeding and ovarian cancer risk [175]. Women who breast fed for up to 6 months showed duration-dependent benefit with women who breastfed for long having more protection. Breast feeding may be reducing risk of epithelial cancers by up to 30% compared with women who did not breast feed.

The use of oral contraceptives decreases the risk of developing OC and the benefit may be enjoyed up to 25–30 years after stopping the pill [178, 179]. COCP use is associated with about a 40–50% lower risk compared with never use [178, 180]. Length of pill use appears to influence the degree of protection, with a relative risk of 0.4 for more than 5 years reported in pooled European and US studies [178, 181]. The protective benefit may be experienced even in high risk women though there

is not enough evidence for use of the pill for chemoprophylaxis [180, 182, 183]. Women who use the pills for more than 5 years enjoy more protection of about 50% reduction [179]. This protection is enjoyed by women of all ages and parities.

germ cell tumors, but less consistent decrease in borderline cancers [63].

**86**

Therefore while HRT is associated with increasing risk, the pills are associated with reduced risk a position both have similar active ingredients and estrogen has been blamed in ovarian carcinogenesis.

#### **16.4 Hysterectomy/tubal ligation**

Observational epidemiologic evidence strongly support tubal ligation and hysterectomy to be associated with a decrease in the risk of ovarian cancer, by approximately 26–30% [184]. Having fallopian tubes tied hysterectomy and unilateral oophorectomy may reduce risk by up to 67% [184, 185].

Patients with BRCA1 but not with BRCA2 are found to benefit from the protection conferred by tubal ligation to OC [186]. Tubal ligation and hysterectomy reduce risk of low grade more than high grade serous cancers. Risk of endometrioid cancer is almost halved. Tubal ligation is not observed to reduce the risk of mucinous tumors [187].

#### **16.5 Physical activity and exercise**

Physical activity may be beneficial in both risk reduction of inflammation, decreasing body fat and frequency of ovulation. Survivors of ovarian cancer may also experience general health benefit of physical activity [188]. The specific effect of physical exercise on ovarian cancer in general and the various histologic subtypes have shown inconsistent results. The most consistent result obtained by research is that of increasing risk by prolonged sedentary life style physical inactivity [188, 189].

Considering direct effect of physical activity however, some studies report no effect on the risk of ovarian cancer [190, 191] while other studies report risk reduction [190, 191]. The reduction of risk may be to epithelial cancers. Physical activity may not be affecting sex cord-stromal and germ cell cancers of the ovary.

#### **17. Conclusion**

The risk of ovarian cancer in women is modified by a number of biologic, hormonal, lifestyle and geographic factors the extent of which differs between the histologic varieties. There may be racial or regional variation in the extent to which these factor increase risk or protect against particularly the most common histologic subtype.

### **Author details**

#### Marliyya S. Zayyan

Oncology Department of Obstetrics and Gynecology, Ahmadu Bello University, Zaria, Nigeria

\*Address all correspondence to: marliyya.zayyan@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. n.d. DOI: 10.3322/caac.21492

[2] Jacques F, Isabelle S, Rajesh D, Sultan E, Colin M, Marise R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 2014;**136**:E359-E386. DOI: 10.1002/ ijc.29210

[3] Malvezzi M, Carioli G, Rodriguez T, Negri E, La Vecchia C. Global trends and predictions in ovarian cancer mortality. 2016;**27**. DOI: 10.1093/annonc/mdw306

[4] Kumar B, Davies-Humphreys J. Tumour markers and ovarian cancer screening. The Obstetrician and Gynaecologist. 2011;**2**:41-44. DOI: 10.1576/toag.2000.2.4.41

[5] Alberico S, Facca MC, Millo R, Radillo L, Mandruzzato GP. Tumoral markers (CA 125--CEA) in the screening of ovarian cancer. European Journal of Gynaecological Oncology. 1988;**9**:485-489

[6] Bairey O, Blickstein D, Stark P, Prokocimer M, Nativ HM, Kirgner I, et al. Serum CA 125 as a prognostic factor in non-Hodgkin's lymphoma. Leukemia and Lymphoma. 2003;**44**:1733-1738. DOI: 10.1080/1042819031000104079

[7] Fritsche HA, Bast RC. CA 125 in ovarian cancer: Advances and controversy. Clinical Chemistry. 1998;**44**:1379-1380

[8] Pepin K, del Carmen M, Brown A, Dizon DS. CA 125 and epithelial ovarian cancer: Role in screening, diagnosis, and surveillance. Journal of Hematology and Oncology. 2014;**10**

[9] Eagle K, Ledermann JA. Tumor markers in ovarian malignancies. The Oncologist. 1997;**2**:324-329

[10] Berek JS, Bast RC. Ovarian cancer screening. The use of serial complementary tumor markers to improve sensitivity and specificity for early detection. Cancer. 1995;**76**:2092-2096

[11] Bast RC. Status of tumor markers in ovarian cancer screening. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2003;**21**:200s-205s. DOI: 10.1200/JCO.2003.01.068

[12] La Vecchia C. Ovarian cancer: Epidemiology and risk factors. European Journal of Cancer Prevention. 2017;**26**:55-62. DOI: 10.1097/ CEJ.0000000000000217

[13] Reid BM, Permuth JB, Sellers TA. Epidemiology of ovarian cancer: A review. Cancer Biology and Medicine. 2017;**14**:9-32

[14] Holschneider CH, Berek JS. Ovarian cancer: Epidemiology, biology, and prognostic factors. Seminars in Surgical Oncology. 2000;**19**:3-10. DOI: 10.1002/1098-2388(200007/08)19: 1<3::AID-SSU2>3.0.CO;2-S

[15] Jacobs IJ, Menon U, Ryan A, Gentry-Maharaj A, Burnell M, Kalsi JK, et al. Ovarian cancer screening and mortality in the UK collaborative trial of ovarian cancer screening (UKCTOCS): A randomised controlled trial. Lancet (London, England). 2016;**387**:945-956. DOI: 10.1016/S0140-6736(15)01224-6

[16] Meinhold-Heerlein I, Fotopoulou C, Harter P, Kurzeder C, Mustea A, Wimberger P, et al. The new WHO

**89**

ijc.30676

*Risk Factors for Ovarian Cancer*

s00404-016-4035-8

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

serous carcinoma of the ovary:

[24] Vang R, Shih I-M, Kurman RJ. Ovarian low-grade and high-grade serous carcinoma: Pathogenesis,

PAP.0b013e3181b4fffa

for diagnosis and treatment.

[26] Schultz KAP, Harris AK, Schneider DT, Young RH, Brown J, Gershenson DM, et al. Ovarian sex cord-stromal tumors. Journal of Oncology Practice/American Society of Clinical Oncology. 2016;**12**:940-946.

DOI: 10.1200/JOP.2016.016261

ovarian cancer: What we know.

[28] Low JJH, Ilancheran A, Ng JS. Malignant ovarian germ-cell tumours. Best Practice and Research. Clinical Obstetrics and Gynaecology. 2012;**26**:347-355. DOI: 10.1016/j.

discussion S11-13

bpobgyn.2012.01.002

2013;**5**:292-297

[27] Boyd J. Specific keynote: Hereditary

Gynecologic Oncology. 2003;**88**:S8-S10;

[29] Fathalla MF. Incessant ovulation—A factor in ovarian neoplasia? Lancet (London, England). 1971;**2**:163

[30] Fathalla MF. Incessant ovulation and ovarian cancer—A hypothesis re-visited. Facts Views Vis ObGyn.

10.1148/rg.313105066

clinicopathologic and molecular biologic features, and diagnostic problems. Advances in Anatomic Pathology. 2009;**16**:267-282. DOI: 10.1097/

[25] Lalwani N, Prasad SR, Vikram R, Shanbhogue AK, Huettner PC, Fasih N. Histologic, molecular, and cytogenetic features of ovarian cancers: Implications

Radiographics. 2011;**31**:625-646. DOI:

Clinicopathologic analysis of 52 invasive cases and identification of a possible noninvasive intermediate lesion. The American Journal of Surgical Pathology. 2016;**40**:1165-1176. DOI: 10.1097/ PAS.0000000000000693

classification of ovarian, fallopian tube, and primary peritoneal cancer and its clinical implications. Archives of Gynecology and Obstetrics. 2016;**293**:695-700. DOI: 10.1007/

[17] Prat J, D'Angelo E, Espinosa I. Ovarian carcinomas: At least five different diseases with distinct histological features and molecular genetics. Human Pathology. 2018;**80**:11- 27. DOI: 10.1016/j.humpath.2018.06.018

[18] A Soslow R. Histologic subtypes of ovarian carcinoma: An overview. International Journal of Gynecological Pathology. 2008;**27**:161-174. DOI: 10.1097/PGP.0b013e31815ea812

[19] Kurman R, Shih I-M. The origin and pathogenesis of epithelial ovarian cancer: A proposed unifying theory. The American Journal of Surgical Pathology.

2010;**34**:433-443. DOI: 10.1097/

[20] Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Collaborative Ovarian Cancer Group. The The American Journal of Epidemiology

[21] WHO classification of ovarian neoplasms n.d. Available from: http:// www.pathologyoutlines.com/topic/ ovarytumorwhoclassif.html [Accessed:

[22] Coburn SB, Bray F, Sherman ME, Trabert B. International patterns and trends in ovarian cancer incidence, overall and by histologic subtype. International Journal of Cancer. 2017;**140**:2451-2460. DOI: 10.1002/

[23] Ahn G, Folkins AK, McKenney JK,

Longacre TA. Low-grade

PAS.0b013e3181cf3d79

1992;136:1212-1220

16 September 2018]

#### *Risk Factors for Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.86712*

classification of ovarian, fallopian tube, and primary peritoneal cancer and its clinical implications. Archives of Gynecology and Obstetrics. 2016;**293**:695-700. DOI: 10.1007/ s00404-016-4035-8

[17] Prat J, D'Angelo E, Espinosa I. Ovarian carcinomas: At least five different diseases with distinct histological features and molecular genetics. Human Pathology. 2018;**80**:11- 27. DOI: 10.1016/j.humpath.2018.06.018

[18] A Soslow R. Histologic subtypes of ovarian carcinoma: An overview. International Journal of Gynecological Pathology. 2008;**27**:161-174. DOI: 10.1097/PGP.0b013e31815ea812

[19] Kurman R, Shih I-M. The origin and pathogenesis of epithelial ovarian cancer: A proposed unifying theory. The American Journal of Surgical Pathology. 2010;**34**:433-443. DOI: 10.1097/ PAS.0b013e3181cf3d79

[20] Whittemore AS, Harris R, Itnyre J. Characteristics relating to ovarian cancer risk: Collaborative analysis of 12 US case-control studies. IV. The pathogenesis of epithelial ovarian cancer. Collaborative Ovarian Cancer Group. The The American Journal of Epidemiology 1992;136:1212-1220

[21] WHO classification of ovarian neoplasms n.d. Available from: http:// www.pathologyoutlines.com/topic/ ovarytumorwhoclassif.html [Accessed: 16 September 2018]

[22] Coburn SB, Bray F, Sherman ME, Trabert B. International patterns and trends in ovarian cancer incidence, overall and by histologic subtype. International Journal of Cancer. 2017;**140**:2451-2460. DOI: 10.1002/ ijc.30676

[23] Ahn G, Folkins AK, McKenney JK, Longacre TA. Low-grade

serous carcinoma of the ovary: Clinicopathologic analysis of 52 invasive cases and identification of a possible noninvasive intermediate lesion. The American Journal of Surgical Pathology. 2016;**40**:1165-1176. DOI: 10.1097/ PAS.0000000000000693

[24] Vang R, Shih I-M, Kurman RJ. Ovarian low-grade and high-grade serous carcinoma: Pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Advances in Anatomic Pathology. 2009;**16**:267-282. DOI: 10.1097/ PAP.0b013e3181b4fffa

[25] Lalwani N, Prasad SR, Vikram R, Shanbhogue AK, Huettner PC, Fasih N. Histologic, molecular, and cytogenetic features of ovarian cancers: Implications for diagnosis and treatment. Radiographics. 2011;**31**:625-646. DOI: 10.1148/rg.313105066

[26] Schultz KAP, Harris AK, Schneider DT, Young RH, Brown J, Gershenson DM, et al. Ovarian sex cord-stromal tumors. Journal of Oncology Practice/American Society of Clinical Oncology. 2016;**12**:940-946. DOI: 10.1200/JOP.2016.016261

[27] Boyd J. Specific keynote: Hereditary ovarian cancer: What we know. Gynecologic Oncology. 2003;**88**:S8-S10; discussion S11-13

[28] Low JJH, Ilancheran A, Ng JS. Malignant ovarian germ-cell tumours. Best Practice and Research. Clinical Obstetrics and Gynaecology. 2012;**26**:347-355. DOI: 10.1016/j. bpobgyn.2012.01.002

[29] Fathalla MF. Incessant ovulation—A factor in ovarian neoplasia? Lancet (London, England). 1971;**2**:163

[30] Fathalla MF. Incessant ovulation and ovarian cancer—A hypothesis re-visited. Facts Views Vis ObGyn. 2013;**5**:292-297

**88**

*Tumor Progression and Metastasis*

**References**

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. n.d. DOI: 10.3322/caac.21492 surveillance. Journal of Hematology and

[9] Eagle K, Ledermann JA. Tumor markers in ovarian malignancies. The

Oncologist. 1997;**2**:324-329

[10] Berek JS, Bast RC. Ovarian cancer screening. The use of serial complementary tumor markers to improve sensitivity and specificity for early detection. Cancer.

[11] Bast RC. Status of tumor markers in ovarian cancer screening. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2003;**21**:200s-205s. DOI:

Oncology. 2014;**10**

1995;**76**:2092-2096

10.1200/JCO.2003.01.068

2017;**26**:55-62. DOI: 10.1097/ CEJ.0000000000000217

2017;**14**:9-32

[12] La Vecchia C. Ovarian cancer: Epidemiology and risk factors.

European Journal of Cancer Prevention.

[13] Reid BM, Permuth JB, Sellers TA. Epidemiology of ovarian cancer: A review. Cancer Biology and Medicine.

[14] Holschneider CH, Berek JS. Ovarian cancer: Epidemiology, biology, and prognostic factors. Seminars in

Surgical Oncology. 2000;**19**:3-10. DOI: 10.1002/1098-2388(200007/08)19:

Gentry-Maharaj A, Burnell M, Kalsi JK, et al. Ovarian cancer screening and mortality in the UK collaborative trial of ovarian cancer screening (UKCTOCS): A randomised controlled trial. Lancet (London, England). 2016;**387**:945-956. DOI: 10.1016/S0140-6736(15)01224-6

[16] Meinhold-Heerlein I, Fotopoulou C,

Harter P, Kurzeder C, Mustea A, Wimberger P, et al. The new WHO

1<3::AID-SSU2>3.0.CO;2-S

[15] Jacobs IJ, Menon U, Ryan A,

[2] Jacques F, Isabelle S, Rajesh D, Sultan E, Colin M, Marise R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 2014;**136**:E359-E386. DOI: 10.1002/

[3] Malvezzi M, Carioli G, Rodriguez T, Negri E, La Vecchia C. Global trends and predictions in ovarian cancer mortality. 2016;**27**. DOI: 10.1093/annonc/mdw306

[4] Kumar B, Davies-Humphreys J. Tumour markers and ovarian cancer screening. The Obstetrician and Gynaecologist. 2011;**2**:41-44. DOI:

[5] Alberico S, Facca MC, Millo R, Radillo L, Mandruzzato GP. Tumoral markers (CA 125--CEA) in the

[6] Bairey O, Blickstein D, Stark P, Prokocimer M, Nativ HM, Kirgner I, et al. Serum CA 125 as a prognostic factor in non-Hodgkin's lymphoma.

[7] Fritsche HA, Bast RC. CA 125 in ovarian cancer: Advances and controversy. Clinical Chemistry.

[8] Pepin K, del Carmen M, Brown A, Dizon DS. CA 125 and epithelial ovarian cancer: Role in screening, diagnosis, and

Leukemia and Lymphoma. 2003;**44**:1733-1738. DOI: 10.1080/1042819031000104079

1998;**44**:1379-1380

screening of ovarian cancer. European Journal of Gynaecological Oncology.

10.1576/toag.2000.2.4.41

1988;**9**:485-489

ijc.29210

[31] Choi J-H, Wong AST, Huang H-F, PCK L. Gonadotropins and ovarian cancer. Endocrine Reviews. 2007;**28**:440-461. DOI: 10.1210/ er.2006-0036

[32] Lee AW, Tyrer JP, Doherty JA, Stram DA, Kupryjanczyk J, Dansonka-Mieszkowska A, et al. Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study. Gynecologic Oncology. 2015;**136**:542-548. DOI: 10.1016/j. ygyno.2014.12.017

[33] Ness RB, Cottreau C. Possible role of ovarian epithelial inflammation in ovarian cancer. Journal of the National Cancer Institute. 1999;**91**:1459-1467. DOI: 10.1093/jnci/91.17.1459

[34] Purdie DM, Bain CJ, Siskind V, Webb PM, Green AC. Ovulation and risk of epithelial ovarian cancer. International Journal of Cancer. 2003;**104**:228-232. DOI: 10.1002/ijc.10927

[35] Bray F, Loos AH, Tognazzo S, La Vecchia C. Ovarian cancer in Europe: Cross-sectional trends in incidence and mortality in 28 countries, 1953- 2000. International Journal of Cancer. 2005;**113**:977-990. DOI: 10.1002/ ijc.20649

[36] Albrektsen G, Heuch I, Kvåle G. Reproductive factors and incidence of epithelial ovarian cancer: A Norwegian prospective study. Cancer Causes and Control. 1996;**7**:421-427. DOI: 10.1007/ BF00052668

[37] Keinan-Boker L, Silverman BG, Walsh PM, Gavin AT, Hayes C. Time trends in the incidence and mortality of ovarian cancer in Ireland, Northern Ireland, and Israel, 1994-2013. International Journal of Gynecological Cancer. 2017;**27**:1628-1636. DOI: 10.1097/IGC.0000000000001079

[38] Iyoke C, Ugwu G, Ezugwu E, Onah N, Ugwu O, Okafor O. Incidence, pattern and management of ovarian cancer at a tertiary medical center in Enugu, south East Nigeria. Annals of Medical and Health Sciences Research. 2013;**3**:417-421. DOI: 10.4103/2141-9248.117947

[39] Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA: A Cancer Journal for Clinicians. 2018;**68**:284-296. DOI: 10.3322/ caac.21456

[40] Yamagami W, Nagase S, Takahashi F, Ino K, Hachisuga T, Aoki D, et al. Clinical statistics of gynecologic cancers in Japan. Journal of Gynecologic Oncology. 2017;**28**:e32. DOI: 10.3802/ jgo.2017.28.e32

[41] Goodman MT, Howe HL, Tung KH, Hotes J, Miller BA, Coughlin SS, et al. Incidence of ovarian cancer by race and ethnicity in the United States, 1992- 1997. Cancer. 2003;**97**:2676-2685. DOI: 10.1002/cncr.11349

[42] Weiderpass E, Sandin S, Inoue M, Shimazu T, Iwasaki M, Sasazuki S, et al. Risk factors for epithelial ovarian cancer in Japan—Results from the Japan public health center-based prospective study cohort. International Journal of Oncology. 2012;**40**:21-30. DOI: 10.3892/ ijo.2011.1194

[43] Srivastava A, McKinnon W, Wood ME. Risk of breast and ovarian cancer in women with strong family histories. Oncology Williston Park N. 2001;**15**:889-902; discussion 902, 905-7, 911-3

[44] Weiss NS, Peterson AS. Racial variation in the incidence of ovarian cancer in the United States. American Journal of Epidemiology. 1978;**107**:91- 95. DOI: 10.1093/oxfordjournals.aje. a112522

[45] Stewart SL, Harewood R, Matz M, Rim SH, Sabatino SA, Ward KC, et al.

**91**

*Risk Factors for Ovarian Cancer*

10.1002/cncr.31027

2018]

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

Disparities in ovarian cancer survival in the United States (2001-2009): Findings from the CONCORD-2 study. Cancer. 2017;**123**(Suppl 24):5138-5159. DOI:

of the AGO Study Group, GINECO and NSGO. The European Journal of Cancer. 1990, 2016;**66**:114-124. DOI: 10.1016/j.

[53] Murthy NS, Shalini S, Suman G, Pruthvish S, Mathew A. Changing trends in incidence of ovarian

cancer—The Indian scenario. The Asian Pacific Journal of Cancer Prevention.

ejca.2016.07.014

2009;**10**:1025-1030

2009;**46**:28-33

n.d.:8

[54] Saini SK. Clinical Cancer Investigation Journal n.d. Available from: http://www.ccij-online.org/ article.asp?issn=2278-0513;year=2016; volume=5;issue=1;spage=20;epage=24;a ulast=Saini [Accessed: 03 August 2018]

[55] Basu P, De P, Mandal S, Ray K, Biswas J. Study of "patterns of care" of ovarian cancer patients in a specialized cancer institute in Kolkata, eastern India. Indian Journal of Cancer.

[56] Jindal D, Sahasrabhojanee M, Jindal M, D'Souza J. Epidemiology of epithelial ovarian cancer: A tertiary hospital based study in Goa, India. International Journal of Reproduction,

Contraception, Obstetrics and Gynecology. 2017;**6**:2541. DOI: 10.18203/2320-1770.ijrcog20172348

[57] Malik IA. A prospective study of clinico-pathological features of epithelial ovarian cancer in Pakistan

[58] Mostafa MF, El-etreby N, Awad N. Retrospective analysis evaluating ovarian cancer cases presented at the clinical oncology department, Alexandria University. Alexandria Journal of Medicine. 2012;**48**:353-360. DOI: 10.1016/j.

[59] Zayyan MS, Ahmed SA, Oguntayo AO, Kolawole AO,

Olasinde TA. Epidemiology of ovarian cancers in Zaria, northern Nigeria: A

ajme.2012.07.001

[46] SEER Cancer Statistics Review 1973-1997—Previous Version—SEER Cancer Statistics n.d. Available from: https://seer.cancer.gov/archive/ csr/1973\_1997/ [Accessed: 02 August

[47] Doufekas K, Olaitan A. Clinical epidemiology of epithelial ovarian cancer in the UK. International Journal of Women's Health. 2014;**6**:537-545.

DOI: 10.2147/IJWH.S40894

[48] Morowitz M, Huff D, von Allmen D. Epithelial ovarian tumors in children: A retrospective analysis.

Journal of Pediatric Surgery.

[49] Bhattacharyya NK, De A, Bera P, Mongal S, Chakraborty S, Bandopadhyay R. Ovarian tumors

in pediatric age group—A

Oncology. 2010;**31**:54

2003;**38**:331-335; discussion 331-335. DOI: 10.1053/jpsu.2003.50103

clinicopathologic study of 10 years' cases in West Bengal, India. The Indian Journal of Medical and Paediatric

[50] Ovarian Cancer: Recognition and Initial Management | Guidance and Guidelines | NICE n.d. Available from: https://www.nice.org.uk/Guidance/ cg122 [Accessed: 03 August 2018]

[51] Vecchia CL, Levi F, Lucchini F, Negri E, Franceschi S. Descriptive

[52] Klar M, Hasenburg A, Hasanov M, Hilpert F, Meier W, Pfisterer J, et al. Prognostic factors in young ovarian cancer patients: An analysis of four prospective phase III intergroup trials

epidemiology of ovarian cancer in Europe. Gynecologic Oncology. 1992;**46**:208-215. DOI: 10.1016/0090-8258(92)90257-J

*Risk Factors for Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.86712*

*Tumor Progression and Metastasis*

er.2006-0036

ygyno.2014.12.017

[31] Choi J-H, Wong AST, Huang H-F, PCK L. Gonadotropins and ovarian cancer. Endocrine Reviews. 2007;**28**:440-461. DOI: 10.1210/

pattern and management of ovarian cancer at a tertiary medical center in Enugu, south East Nigeria. Annals of Medical and Health Sciences Research. 2013;**3**:417-421. DOI: 10.4103/2141-9248.117947

[39] Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, et al. Ovarian cancer statistics, 2018. CA: A Cancer Journal for Clinicians. 2018;**68**:284-296. DOI: 10.3322/

Takahashi F, Ino K, Hachisuga T, Aoki D, et al. Clinical statistics of gynecologic cancers in Japan. Journal of Gynecologic Oncology. 2017;**28**:e32. DOI: 10.3802/

[41] Goodman MT, Howe HL, Tung KH, Hotes J, Miller BA, Coughlin SS, et al. Incidence of ovarian cancer by race and ethnicity in the United States, 1992- 1997. Cancer. 2003;**97**:2676-2685. DOI:

[42] Weiderpass E, Sandin S, Inoue M, Shimazu T, Iwasaki M, Sasazuki S, et al. Risk factors for epithelial ovarian cancer in Japan—Results from the Japan public health center-based prospective study cohort. International Journal of Oncology. 2012;**40**:21-30. DOI: 10.3892/

[43] Srivastava A, McKinnon W, Wood ME. Risk of breast and ovarian cancer in women with strong family histories. Oncology Williston Park N. 2001;**15**:889-902; discussion 902, 905-7,

[44] Weiss NS, Peterson AS. Racial variation in the incidence of ovarian cancer in the United States. American Journal of Epidemiology. 1978;**107**:91- 95. DOI: 10.1093/oxfordjournals.aje.

[45] Stewart SL, Harewood R, Matz M, Rim SH, Sabatino SA, Ward KC, et al.

[40] Yamagami W, Nagase S,

caac.21456

jgo.2017.28.e32

10.1002/cncr.11349

ijo.2011.1194

911-3

a112522

[32] Lee AW, Tyrer JP, Doherty JA, Stram DA, Kupryjanczyk J, Dansonka-Mieszkowska A, et al. Evaluating the ovarian cancer

gonadotropin hypothesis: A candidate gene study. Gynecologic Oncology. 2015;**136**:542-548. DOI: 10.1016/j.

[33] Ness RB, Cottreau C. Possible role of ovarian epithelial inflammation in ovarian cancer. Journal of the National Cancer Institute. 1999;**91**:1459-1467.

DOI: 10.1093/jnci/91.17.1459

DOI: 10.1002/ijc.10927

ijc.20649

BF00052668

[34] Purdie DM, Bain CJ, Siskind V, Webb PM, Green AC. Ovulation and risk of epithelial ovarian cancer. International Journal of Cancer. 2003;**104**:228-232.

[35] Bray F, Loos AH, Tognazzo S, La Vecchia C. Ovarian cancer in Europe: Cross-sectional trends in incidence and mortality in 28 countries, 1953- 2000. International Journal of Cancer. 2005;**113**:977-990. DOI: 10.1002/

[36] Albrektsen G, Heuch I, Kvåle G. Reproductive factors and incidence of epithelial ovarian cancer: A Norwegian prospective study. Cancer Causes and Control. 1996;**7**:421-427. DOI: 10.1007/

[37] Keinan-Boker L, Silverman BG, Walsh PM, Gavin AT, Hayes C. Time trends in the incidence and mortality of ovarian cancer in Ireland, Northern

International Journal of Gynecological Cancer. 2017;**27**:1628-1636. DOI: 10.1097/IGC.0000000000001079

Ireland, and Israel, 1994-2013.

[38] Iyoke C, Ugwu G, Ezugwu E, Onah N, Ugwu O, Okafor O. Incidence,

**90**

Disparities in ovarian cancer survival in the United States (2001-2009): Findings from the CONCORD-2 study. Cancer. 2017;**123**(Suppl 24):5138-5159. DOI: 10.1002/cncr.31027

[46] SEER Cancer Statistics Review 1973-1997—Previous Version—SEER Cancer Statistics n.d. Available from: https://seer.cancer.gov/archive/ csr/1973\_1997/ [Accessed: 02 August 2018]

[47] Doufekas K, Olaitan A. Clinical epidemiology of epithelial ovarian cancer in the UK. International Journal of Women's Health. 2014;**6**:537-545. DOI: 10.2147/IJWH.S40894

[48] Morowitz M, Huff D, von Allmen D. Epithelial ovarian tumors in children: A retrospective analysis. Journal of Pediatric Surgery. 2003;**38**:331-335; discussion 331-335. DOI: 10.1053/jpsu.2003.50103

[49] Bhattacharyya NK, De A, Bera P, Mongal S, Chakraborty S, Bandopadhyay R. Ovarian tumors in pediatric age group—A clinicopathologic study of 10 years' cases in West Bengal, India. The Indian Journal of Medical and Paediatric Oncology. 2010;**31**:54

[50] Ovarian Cancer: Recognition and Initial Management | Guidance and Guidelines | NICE n.d. Available from: https://www.nice.org.uk/Guidance/ cg122 [Accessed: 03 August 2018]

[51] Vecchia CL, Levi F, Lucchini F, Negri E, Franceschi S. Descriptive epidemiology of ovarian cancer in Europe. Gynecologic Oncology. 1992;**46**:208-215. DOI: 10.1016/0090-8258(92)90257-J

[52] Klar M, Hasenburg A, Hasanov M, Hilpert F, Meier W, Pfisterer J, et al. Prognostic factors in young ovarian cancer patients: An analysis of four prospective phase III intergroup trials

of the AGO Study Group, GINECO and NSGO. The European Journal of Cancer. 1990, 2016;**66**:114-124. DOI: 10.1016/j. ejca.2016.07.014

[53] Murthy NS, Shalini S, Suman G, Pruthvish S, Mathew A. Changing trends in incidence of ovarian cancer—The Indian scenario. The Asian Pacific Journal of Cancer Prevention. 2009;**10**:1025-1030

[54] Saini SK. Clinical Cancer Investigation Journal n.d. Available from: http://www.ccij-online.org/ article.asp?issn=2278-0513;year=2016; volume=5;issue=1;spage=20;epage=24;a ulast=Saini [Accessed: 03 August 2018]

[55] Basu P, De P, Mandal S, Ray K, Biswas J. Study of "patterns of care" of ovarian cancer patients in a specialized cancer institute in Kolkata, eastern India. Indian Journal of Cancer. 2009;**46**:28-33

[56] Jindal D, Sahasrabhojanee M, Jindal M, D'Souza J. Epidemiology of epithelial ovarian cancer: A tertiary hospital based study in Goa, India. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2017;**6**:2541. DOI: 10.18203/2320-1770.ijrcog20172348

[57] Malik IA. A prospective study of clinico-pathological features of epithelial ovarian cancer in Pakistan n.d.:8

[58] Mostafa MF, El-etreby N, Awad N. Retrospective analysis evaluating ovarian cancer cases presented at the clinical oncology department, Alexandria University. Alexandria Journal of Medicine. 2012;**48**:353-360. DOI: 10.1016/j. ajme.2012.07.001

[59] Zayyan MS, Ahmed SA, Oguntayo AO, Kolawole AO, Olasinde TA. Epidemiology of ovarian cancers in Zaria, northern Nigeria: A

10-year study. International Journal of Women's Health. 2017;**9**:855-860. DOI: 10.2147/IJWH.S130340

[60] Abuidris DO, Weng H-Y, Elhaj AM, Eltayeb EA, Elsanousi M, Ibnoof RS, et al. Incidence and survival rates of ovarian cancer in low-income women in Sudan. Molecular and Clinical Oncology. 2016;**5**:823-828. DOI: 10.3892/mco.2016.1068

[61] Akakpo PK, Derkyi-Kwarteng L, Gyasi RK, Quayson SE, Naporo S, Anim JT. A pathological and clinical study of 706 primary tumours of the ovary in the largest tertiary hospital in Ghana. BMC Womens Health. 2017;**17**:34. DOI: 10.1186/ s12905-017-0389-8

[62] Gong T-T, Wu Q-J, Vogtmann E, Lin B, Wang Y-L. Age at menarche and risk of ovarian cancer: A meta-analysis of epidemiological studies. International Journal of Cancer. 2013;**132**:2894-2900. DOI: 10.1002/ijc.27952

[63] Adami HO, Hsieh CC, Lambe M, Trichopoulos D, Leon D, Persson I, et al. Parity, age at first childbirth, and risk of ovarian cancer. Lancet (London, England). 1994;**344**:1250-1254

[64] Yancik R. Ovarian cancer. Age contrasts in incidence, histology, disease stage at diagnosis, and mortality. Cancer. 1993;**71**:517-523

[65] Riman T, Nilsson S, Persson IR. Review of epidemiological evidence for reproductive and hormonal factors in relation to the risk of epithelial ovarian malignancies. Acta Obstetricia et Gynecologica Scandinavica. 2004;**83**:783-795. DOI: 10.1111/j.0001-6349.2004.00550.x

[66] Riboli E. The European Prospective Investigation into Cancer and Nutrition (EPIC): Plans and progress. The Journal of Nutrition. 2001;**131**:170S-175S. DOI: 10.1093/jn/131.1.170S

[67] Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. The New England Journal of Medicine. 1994;**331**:771-776. DOI: 10.1056/ NEJM199409223311204

[68] Jensen A, Sharif H, Frederiksen K, Kjær SK. Use of fertility drugs and risk of ovarian cancer: Danish population based cohort study. BMJ. 2009;**338**: 580-583

[69] Ness RB, Cramer DW, Goodman MT, Kjaer SK, Mallin K, Mosgaard BJ, et al. Infertility, fertility drugs, and ovarian cancer: A pooled analysis of case-control studies. American Journal of Epidemiology. 2002;**155**:217-224

[70] Mosgaard BJ, Lidegaard Ø, Kjaer SK, Schou G, Andersen AN. Infertility, fertility drugs, and invasive ovarian cancer: A case-control study. Fertility and Sterility. 1997;**67**:1005-1012. DOI: 10.1016/S0015-0282(97)81431-8

[71] Tomao F, Lo Russo G, Spinelli GP, Stati V, Prete AA, Prinzi N, et al. Fertility drugs, reproductive strategies and ovarian cancer risk. Journal of Ovarian Research. 2014;**7**:51. DOI: 10.1186/1757-2215-7-51

[72] Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, et al. Hereditary ovarian carcinoma: Heterogeneity, molecular genetics, pathology, and management. Molecular Oncology. 2009;**3**:97-137. DOI: 10.1016/j. molonc.2009.02.004

[73] Foulkes WD, Narod SA. Ovarian cancer risk and family history. The Lancet. 1997;**349**:878. DOI: 10.1016/ S0140-6736(05)61782-5

[74] Kerlikowske K, Brown JS, Grady DG. Should women with familial ovarian cancer undergo prophylactic oophorectomy? Obstetrics and Gynecology. 1992;**80**:700-707

**93**

*Risk Factors for Ovarian Cancer*

2018]

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

[75] Family History of Ovarian Cancer an overview | ScienceDirect Topics n.d. Available from: https://www. sciencedirect.com/topics/medicineand-dentistry/family-history-of[83] Vasen HF, Stormorken A, Menko FH, Nagengast FM,

10.1200/JCO.2001.19.20.4074

DOI: 10.1038/sj.ejhg.5201584

10.1002/ijc.23508

sj.modpathol.3800017

PAP.0b013e3182a92cf8

[85] Watson P, Vasen HFA, Mecklin J-P, Bernstein I, Aarnio M, Järvinen HJ, et al. The risk of extra-colonic, extraendometrial cancer in the Lynch syndrome. The International Journal of Cancer. 2008;**123**:444-449. DOI:

[86] Liu J, Albarracin CT, Chang K-H, Thompson-Lanza JA, Zheng W, Gershenson DM, et al. Microsatellite instability and expression of hMLH1 and hMSH2 proteins in ovarian endometrioid cancer. Modern

Pathology. 2004;**17**:75-80. DOI: 10.1038/

[87] Chui MH, Gilks CB, Cooper K, Clarke BA. Identifying Lynch syndrome in patients with ovarian carcinoma: The significance of tumor subtype. Advances in Anatomic Pathology. 2013;**20**:378-386. DOI: 10.1097/

[88] Beyond Li-Fraumeni syndrome: Clinical characteristics of families with p53 germline mutations. Journal of Clinical Oncology. n.d. 26(15\_suppl). Available from: http://ascopubs.org/doi/ abs/10.1200/jco.2008.26.15\_suppl.11031

[Accessed: 12 November 2018]

[84] Lynch HT, Boland CR, Gong G, Shaw TG, Lynch PM, Fodde R, et al. Phenotypic and genotypic heterogeneity in the Lynch syndrome: Diagnostic, surveillance and management implications. European Journal of Human Genetics. 2006;**14**:390-402.

Kleibeuker JH, Griffioen G, et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: A study of hereditary nonpolyposis colorectal cancer families. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2001;**19**:4074-4080. DOI:

ovarian-cancer [Accessed: 03 November

[77] Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, et al. Hereditary ovarian cancer: Not only BRCA 1 and 2 genes. BioMed Research International. 2015. DOI:

[78] Robles-díaz L, Goldfrank DJ, Kauff ND, Robson M, Offit K.

Hereditary ovarian cancer in Ashkenazi Jews. Familial Cancer. 2004;**3**:259-264. DOI: 10.1007/s10689-004-9552-0

[79] Villella JA, Parmar M, Donohue K, Fahey C, Piver MS, Rodabaugh K. Role of prophylactic hysterectomy in patients at high risk for hereditary cancers. Gynecologic Oncology. 2006;**102**:475- 479. DOI: 10.1016/j.ygyno.2006.01.006

[80] Osman MA. Genetic cancer ovary. Clinical Ovarian and Other Gynecologic Cancer. 2014;**7**:1-7. DOI: 10.1016/j.

[81] Lynch HT, Krush AJ. Heredity and adenocarcinoma of the colon. Gastroenterology. 1967;**53**:517-527

[82] Watson P, Bützow R, Lynch HT, Mecklin JP, Järvinen HJ, Vasen HF, et al. The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecologic Oncology. 2001;**82**:223-228. DOI: 10.1006/

10.1155/2015/341723

cogc.2014.12.006

gyno.2001.6279

[76] Soegaard M, Frederiksen K, Jensen A, Høgdall E, Høgdall C, Blaakaer J, et al. Risk of ovarian cancer in women with first-degree relatives with cancer. Acta Obstetricia et Gynecologica Scandinavica. 2009;**88**:449-456. DOI: 10.1080/00016340902807207

*Risk Factors for Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.86712*

*Tumor Progression and Metastasis*

10.2147/IJWH.S130340

10.3892/mco.2016.1068

s12905-017-0389-8

DOI: 10.1002/ijc.27952

10-year study. International Journal of Women's Health. 2017;**9**:855-860. DOI: [67] Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. The New England Journal of Medicine. 1994;**331**:771-776. DOI: 10.1056/

[68] Jensen A, Sharif H, Frederiksen K, Kjær SK. Use of fertility drugs and risk of ovarian cancer: Danish population based cohort study. BMJ. 2009;**338**:

NEJM199409223311204

[69] Ness RB, Cramer DW,

2002;**155**:217-224

Goodman MT, Kjaer SK, Mallin K, Mosgaard BJ, et al. Infertility, fertility drugs, and ovarian cancer: A pooled analysis of case-control studies. American Journal of Epidemiology.

[70] Mosgaard BJ, Lidegaard Ø, Kjaer SK, Schou G, Andersen AN. Infertility, fertility drugs, and invasive ovarian cancer: A case-control study. Fertility and Sterility. 1997;**67**:1005-1012. DOI: 10.1016/S0015-0282(97)81431-8

[71] Tomao F, Lo Russo G, Spinelli GP, Stati V, Prete AA, Prinzi N, et al. Fertility drugs, reproductive strategies and ovarian cancer risk. Journal of Ovarian Research. 2014;**7**:51. DOI:

[72] Lynch HT, Casey MJ, Snyder CL, Bewtra C, Lynch JF, Butts M, et al. Hereditary ovarian carcinoma: Heterogeneity, molecular genetics, pathology, and management. Molecular Oncology. 2009;**3**:97-137. DOI: 10.1016/j.

[73] Foulkes WD, Narod SA. Ovarian cancer risk and family history. The Lancet. 1997;**349**:878. DOI: 10.1016/

Grady DG. Should women with familial ovarian cancer undergo prophylactic oophorectomy? Obstetrics and Gynecology. 1992;**80**:700-707

10.1186/1757-2215-7-51

molonc.2009.02.004

S0140-6736(05)61782-5

[74] Kerlikowske K, Brown JS,

580-583

[60] Abuidris DO, Weng H-Y, Elhaj AM, Eltayeb EA, Elsanousi M, Ibnoof RS, et al. Incidence and survival rates of ovarian cancer in low-income women in Sudan. Molecular and Clinical Oncology. 2016;**5**:823-828. DOI:

[61] Akakpo PK, Derkyi-Kwarteng L, Gyasi RK, Quayson SE, Naporo S, Anim JT. A pathological and clinical study of 706 primary tumours of the ovary in the largest tertiary hospital in Ghana. BMC Womens Health. 2017;**17**:34. DOI: 10.1186/

[62] Gong T-T, Wu Q-J, Vogtmann E, Lin B, Wang Y-L. Age at menarche and risk of ovarian cancer: A meta-analysis of epidemiological studies. International Journal of Cancer. 2013;**132**:2894-2900.

[63] Adami HO, Hsieh CC, Lambe M, Trichopoulos D, Leon D, Persson I, et al. Parity, age at first childbirth, and risk of ovarian cancer. Lancet (London,

England). 1994;**344**:1250-1254

[64] Yancik R. Ovarian cancer. Age contrasts in incidence, histology, disease

stage at diagnosis, and mortality.

[65] Riman T, Nilsson S, Persson IR. Review of epidemiological evidence for reproductive and hormonal factors in relation to the risk of epithelial ovarian malignancies. Acta Obstetricia et Gynecologica Scandinavica. 2004;**83**:783-795. DOI: 10.1111/j.0001-6349.2004.00550.x

[66] Riboli E. The European Prospective Investigation into Cancer and Nutrition (EPIC): Plans and progress. The Journal of Nutrition. 2001;**131**:170S-175S. DOI:

Cancer. 1993;**71**:517-523

10.1093/jn/131.1.170S

**92**

[75] Family History of Ovarian Cancer an overview | ScienceDirect Topics n.d. Available from: https://www. sciencedirect.com/topics/medicineand-dentistry/family-history-ofovarian-cancer [Accessed: 03 November 2018]

[76] Soegaard M, Frederiksen K, Jensen A, Høgdall E, Høgdall C, Blaakaer J, et al. Risk of ovarian cancer in women with first-degree relatives with cancer. Acta Obstetricia et Gynecologica Scandinavica. 2009;**88**:449-456. DOI: 10.1080/00016340902807207

[77] Toss A, Tomasello C, Razzaboni E, Contu G, Grandi G, Cagnacci A, et al. Hereditary ovarian cancer: Not only BRCA 1 and 2 genes. BioMed Research International. 2015. DOI: 10.1155/2015/341723

[78] Robles-díaz L, Goldfrank DJ, Kauff ND, Robson M, Offit K. Hereditary ovarian cancer in Ashkenazi Jews. Familial Cancer. 2004;**3**:259-264. DOI: 10.1007/s10689-004-9552-0

[79] Villella JA, Parmar M, Donohue K, Fahey C, Piver MS, Rodabaugh K. Role of prophylactic hysterectomy in patients at high risk for hereditary cancers. Gynecologic Oncology. 2006;**102**:475- 479. DOI: 10.1016/j.ygyno.2006.01.006

[80] Osman MA. Genetic cancer ovary. Clinical Ovarian and Other Gynecologic Cancer. 2014;**7**:1-7. DOI: 10.1016/j. cogc.2014.12.006

[81] Lynch HT, Krush AJ. Heredity and adenocarcinoma of the colon. Gastroenterology. 1967;**53**:517-527

[82] Watson P, Bützow R, Lynch HT, Mecklin JP, Järvinen HJ, Vasen HF, et al. The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecologic Oncology. 2001;**82**:223-228. DOI: 10.1006/ gyno.2001.6279

[83] Vasen HF, Stormorken A, Menko FH, Nagengast FM, Kleibeuker JH, Griffioen G, et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: A study of hereditary nonpolyposis colorectal cancer families. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2001;**19**:4074-4080. DOI: 10.1200/JCO.2001.19.20.4074

[84] Lynch HT, Boland CR, Gong G, Shaw TG, Lynch PM, Fodde R, et al. Phenotypic and genotypic heterogeneity in the Lynch syndrome: Diagnostic, surveillance and management implications. European Journal of Human Genetics. 2006;**14**:390-402. DOI: 10.1038/sj.ejhg.5201584

[85] Watson P, Vasen HFA, Mecklin J-P, Bernstein I, Aarnio M, Järvinen HJ, et al. The risk of extra-colonic, extraendometrial cancer in the Lynch syndrome. The International Journal of Cancer. 2008;**123**:444-449. DOI: 10.1002/ijc.23508

[86] Liu J, Albarracin CT, Chang K-H, Thompson-Lanza JA, Zheng W, Gershenson DM, et al. Microsatellite instability and expression of hMLH1 and hMSH2 proteins in ovarian endometrioid cancer. Modern Pathology. 2004;**17**:75-80. DOI: 10.1038/ sj.modpathol.3800017

[87] Chui MH, Gilks CB, Cooper K, Clarke BA. Identifying Lynch syndrome in patients with ovarian carcinoma: The significance of tumor subtype. Advances in Anatomic Pathology. 2013;**20**:378-386. DOI: 10.1097/ PAP.0b013e3182a92cf8

[88] Beyond Li-Fraumeni syndrome: Clinical characteristics of families with p53 germline mutations. Journal of Clinical Oncology. n.d. 26(15\_suppl). Available from: http://ascopubs.org/doi/ abs/10.1200/jco.2008.26.15\_suppl.11031 [Accessed: 12 November 2018]

[89] Hisada M, Garber JE, Fung CY, Fraumeni JF, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. Journal of the National Cancer Institute. 1998;**90**:606-611

[90] Varley JM, Evans DG, Birch JM. Li-Fraumeni syndrome—A molecular and clinical review. British Journal of Cancer. 1997;**76**:1-14

[91] Oral and Maxillofacial Pathology. 3rd ed. n.d. Available from: https:// www.elsevier.com/books/oraland-maxillofacial-pathology/ neville/978-1-4160-3435-3 [Accessed: 13 November 2018]

[92] Banno K, Kisu I, Yanokura M, Masuda K, Ueki A, Kobayashi Y, et al. Hereditary gynecological tumors associated with Peutz-Jeghers syndrome (review). Oncology Letters. 2013;**6**:1184-1188. DOI: 10.3892/ ol.2013.1527

[93] Papp J, Kovacs ME, Solyom S, Kasler M, Børresen-Dale A-L, Olah E. High prevalence of germline STK11mutations in Hungarian Peutz-Jeghers syndrome patients. BMC Medical Genetics. 2010;**11**:169. DOI: 10.1186/1471-2350-11-169

[94] Prat J, Ribé A, Gallardo A. Hereditary ovarian cancer. Human Pathology. 2005;**36**:861-870. DOI: 10.1016/j.humpath.2005.06.006

[95] Fackenthal JD, Zhang J, Zhang B, Zheng Y, Hagos F, Burrill DR, et al. High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients. International Journal of Cancer. 2012;**131**:1114-1123. DOI: 10.1002/ijc.27326

[96] Schmolz G. The carcinogenic effect of asbestos. Offentliche Gesundheitswesen. 1989;**51**:614-620

[97] Barrett JC, Lamb PW, Wiseman RW. Multiple mechanisms for the

carcinogenic effects of asbestos and other mineral fibers. Environmental Health Perspectives. 1989;**81**:81-89

[98] Cramer DW, Vitonis AF, Terry KL, Welch WR, Titus LJ. The association between talc use and ovarian cancer: A retrospective case-control study in Two US States. Epidemiology (Cambridge, Mass.). 2016;**27**:334-346. DOI: 10.1097/ EDE.0000000000000434

[99] Cramer DW, Welch WR, Berkowitz RS, Godleski JJ. Presence of talc in pelvic lymph nodes of a woman with ovarian cancer and longterm genital exposure to cosmetic talc. Obstetrics and Gynecology. 2007;**110**:498-501. DOI: 10.1097/01. AOG.0000262902.80861.a0

[100] IARC Monographs Volume 100C Asbestos (Chrysotile, Amosite, Crocidolite, Tremolite, Actinolite and Anthophyllite) – IARC n.d. Available from: https://monographs.iarc.fr/ iarc-monographs-volume-100casbestos-chrysotile-amosite-crocidolitetremolite-actinolite-and-anthophyllite/ [Accessed: 13 November 2018]

[101] Asbestos and Cancer Risk n.d. Available from: https://www.cancer. org/cancer/cancer-causes/asbestos.html [Accessed: 13 November 2018]

[102] Muscat JE, Huncharek MS. Perineal talc use and ovarian cancer: A critical review. The European Journal of Cancer Prevention. 2008;**17**:139-146. DOI: 10.1097/CEJ.0b013e32811080ef

[103] Gertig DM, Hunter DJ, Cramer DW, Colditz GA, Speizer FE, Willett WC, et al. Prospective study of talc use and ovarian cancer. The Journal of the National Cancer Institute. 2000;**92**:249- 252. DOI: 10.1093/jnci/92.3.249

[104] Berge W, Mundt K, Luu H, Boffetta P. Genital use of talc and risk of ovarian cancer: A meta-analysis. European Journal of Cancer

**95**

*Risk Factors for Ovarian Cancer*

CEJ.0000000000000340

13 November 2018]

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

Prevention. 2018;**27**:248. DOI: 10.1097/

study of diet and the risk of ovarian cancer. Cancer Epidemiology, Biomarkers and Prevention. 2004:8

[112] McCann SE, Freudenheim JL, Marshall JR, Graham S. Risk of human ovarian cancer is related to dietary intake of selected nutrients, phytochemicals and food groups. The Journal of Nutrition. 2003;**133**:1937- 1942. DOI: 10.1093/jn/133.6.1937

[113] Genkinger JM, Hunter DJ,

Biomarkers and Prevention.

[114] Mommers M, Schouten LJ, Goldbohm RA, van den Brandt PA. Dairy consumption and ovarian cancer risk in the Netherlands cohort study on diet and cancer. British Journal of Cancer. 2006;**94**:165-170. DOI: 10.1038/

9965.EPI-05-0484

sj.bjc.6602890

Spiegelman D, Anderson KE, Arslan A, Beeson WL, et al. Dairy products and ovarian cancer: A pooled analysis of 12 cohort studies. Cancer Epidemiology,

2006;**15**:364-372. DOI: 10.1158/1055-

[115] Faber MT, Jensen A, Søgaard M, Høgdall E, Høgdall C, Blaakaer J, et al. Use of dairy products, lactose, and calcium and risk of ovarian cancer— Results from a Danish case-control study. Acta Oncologica (Stockholm, Sweden). 2012;**51**:454-464. DOI: 10.3109/0284186X.2011.636754

[116] Merritt MA, Cramer DW, Vitonis AF, Titus LJ, Terry KL. Dairy foods and nutrients in relation to risk of ovarian cancer and major histological subtypes. International Journal of Cancer. 2013;**132**:1114-1124. DOI:

[117] Huncharek M, Kupelnick B. Dietary fat intake and risk of epithelial ovarian cancer: A meta-analysis of 6,689 subjects from 8 observational studies. Nutrition and Cancer. 2001;**40**:87-91. DOI: 10.1207/

10.1002/ijc.27701

S15327914NC402\_2

[105] Kennerly M, Esq. The Science Connecting Talcum Powder And Ovarian Cancer. Litig Trial Lawyer Blog 2016. Available from: https://www. litigationandtrial.com/2016/05/articles/ attorney/consumer-protection/talcumpowder-ovarian-cancer/ [Accessed:

[106] Zhang M, Yang ZY, Binns CW, Lee AH. Diet and ovarian cancer risk: A case-control study in China. British Journal of Cancer. 2002;**86**:712-717.

DOI: 10.1038/sj.bjc.6600085

[107] Plagens-Rotman K, Chmaj-Wierzchowska K, Pięta B, Bojar I. Modifiable lifestyle factors and ovarian cancer incidence in women. Annals of Agricultural and Environmental Medicine. 2018;**25**:36-40. DOI: 10.5604/12321966.1233565

[108] Schulz M, Lahmann PH, Boeing H, Hoffmann K, Allen N, Key TJA, et al. Fruit and vegetable consumption and risk of epithelial ovarian cancer: The European prospective investigation into cancer and nutrition. Cancer Epidemiology, Biomarkers and Prevention. 2005;**14**:2531-2535. DOI: 10.1158/1055-9965.EPI-05-0159

[109] Han B, Li X, Yu T. Cruciferous vegetables consumption and the risk of ovarian cancer: A metaanalysis of observational studies. Diagnostic Pathology. 2014;**9**:7. DOI:

[110] Tang L, Lee AH, Su D, Binns CW. Fruit and vegetable consumption associated with reduced risk of epithelial ovarian cancer in southern Chinese women. Gynecologic Oncology.

2014;**132**:241-247. DOI: 10.1016/j.

[111] Pan SY, Ugnat A-M, Mao Y, Wen SW, Johnson KC. A case-control

10.1186/1746-1596-9-7

ygyno.2013.10.020

*Risk Factors for Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.86712*

*Tumor Progression and Metastasis*

[89] Hisada M, Garber JE, Fung CY, Fraumeni JF, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. Journal of the National Cancer Institute. 1998;**90**:606-611

carcinogenic effects of asbestos and other mineral fibers. Environmental Health Perspectives. 1989;**81**:81-89

[98] Cramer DW, Vitonis AF, Terry KL, Welch WR, Titus LJ. The association between talc use and ovarian cancer: A retrospective case-control study in Two US States. Epidemiology (Cambridge, Mass.). 2016;**27**:334-346. DOI: 10.1097/

EDE.0000000000000434

[99] Cramer DW, Welch WR, Berkowitz RS, Godleski JJ. Presence of talc in pelvic lymph nodes of a woman with ovarian cancer and longterm genital exposure to cosmetic talc. Obstetrics and Gynecology. 2007;**110**:498-501. DOI: 10.1097/01.

AOG.0000262902.80861.a0

[100] IARC Monographs Volume 100C Asbestos (Chrysotile, Amosite, Crocidolite, Tremolite, Actinolite and Anthophyllite) – IARC n.d. Available from: https://monographs.iarc.fr/ iarc-monographs-volume-100c-

[Accessed: 13 November 2018]

[Accessed: 13 November 2018]

252. DOI: 10.1093/jnci/92.3.249

[104] Berge W, Mundt K, Luu H, Boffetta P. Genital use of talc and risk of ovarian cancer: A meta-analysis. European Journal of Cancer

[101] Asbestos and Cancer Risk n.d. Available from: https://www.cancer. org/cancer/cancer-causes/asbestos.html

asbestos-chrysotile-amosite-crocidolitetremolite-actinolite-and-anthophyllite/

[102] Muscat JE, Huncharek MS. Perineal talc use and ovarian cancer: A critical review. The European Journal of Cancer Prevention. 2008;**17**:139-146. DOI: 10.1097/CEJ.0b013e32811080ef

[103] Gertig DM, Hunter DJ, Cramer DW, Colditz GA, Speizer FE, Willett WC, et al. Prospective study of talc use and ovarian cancer. The Journal of the National Cancer Institute. 2000;**92**:249-

[90] Varley JM, Evans DG, Birch JM. Li-Fraumeni syndrome—A molecular and clinical review. British Journal of

[91] Oral and Maxillofacial Pathology. 3rd ed. n.d. Available from: https:// www.elsevier.com/books/oraland-maxillofacial-pathology/

neville/978-1-4160-3435-3 [Accessed:

syndrome (review). Oncology Letters. 2013;**6**:1184-1188. DOI: 10.3892/

[92] Banno K, Kisu I, Yanokura M, Masuda K, Ueki A, Kobayashi Y, et al. Hereditary gynecological tumors associated with Peutz-Jeghers

[93] Papp J, Kovacs ME, Solyom S, Kasler M, Børresen-Dale A-L, Olah E. High prevalence of germline STK11mutations in Hungarian Peutz-Jeghers syndrome patients. BMC Medical Genetics. 2010;**11**:169. DOI:

10.1186/1471-2350-11-169

10.1002/ijc.27326

[94] Prat J, Ribé A, Gallardo A. Hereditary ovarian cancer. Human Pathology. 2005;**36**:861-870. DOI: 10.1016/j.humpath.2005.06.006

[95] Fackenthal JD, Zhang J, Zhang B, Zheng Y, Hagos F, Burrill DR, et al. High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients. International Journal of Cancer. 2012;**131**:1114-1123. DOI:

[96] Schmolz G. The carcinogenic effect of asbestos. Offentliche Gesundheitswesen. 1989;**51**:614-620

Multiple mechanisms for the

[97] Barrett JC, Lamb PW, Wiseman RW.

Cancer. 1997;**76**:1-14

13 November 2018]

ol.2013.1527

**94**

Prevention. 2018;**27**:248. DOI: 10.1097/ CEJ.0000000000000340

[105] Kennerly M, Esq. The Science Connecting Talcum Powder And Ovarian Cancer. Litig Trial Lawyer Blog 2016. Available from: https://www. litigationandtrial.com/2016/05/articles/ attorney/consumer-protection/talcumpowder-ovarian-cancer/ [Accessed: 13 November 2018]

[106] Zhang M, Yang ZY, Binns CW, Lee AH. Diet and ovarian cancer risk: A case-control study in China. British Journal of Cancer. 2002;**86**:712-717. DOI: 10.1038/sj.bjc.6600085

[107] Plagens-Rotman K, Chmaj-Wierzchowska K, Pięta B, Bojar I. Modifiable lifestyle factors and ovarian cancer incidence in women. Annals of Agricultural and Environmental Medicine. 2018;**25**:36-40. DOI: 10.5604/12321966.1233565

[108] Schulz M, Lahmann PH, Boeing H, Hoffmann K, Allen N, Key TJA, et al. Fruit and vegetable consumption and risk of epithelial ovarian cancer: The European prospective investigation into cancer and nutrition. Cancer Epidemiology, Biomarkers and Prevention. 2005;**14**:2531-2535. DOI: 10.1158/1055-9965.EPI-05-0159

[109] Han B, Li X, Yu T. Cruciferous vegetables consumption and the risk of ovarian cancer: A metaanalysis of observational studies. Diagnostic Pathology. 2014;**9**:7. DOI: 10.1186/1746-1596-9-7

[110] Tang L, Lee AH, Su D, Binns CW. Fruit and vegetable consumption associated with reduced risk of epithelial ovarian cancer in southern Chinese women. Gynecologic Oncology. 2014;**132**:241-247. DOI: 10.1016/j. ygyno.2013.10.020

[111] Pan SY, Ugnat A-M, Mao Y, Wen SW, Johnson KC. A case-control study of diet and the risk of ovarian cancer. Cancer Epidemiology, Biomarkers and Prevention. 2004:8

[112] McCann SE, Freudenheim JL, Marshall JR, Graham S. Risk of human ovarian cancer is related to dietary intake of selected nutrients, phytochemicals and food groups. The Journal of Nutrition. 2003;**133**:1937- 1942. DOI: 10.1093/jn/133.6.1937

[113] Genkinger JM, Hunter DJ, Spiegelman D, Anderson KE, Arslan A, Beeson WL, et al. Dairy products and ovarian cancer: A pooled analysis of 12 cohort studies. Cancer Epidemiology, Biomarkers and Prevention. 2006;**15**:364-372. DOI: 10.1158/1055- 9965.EPI-05-0484

[114] Mommers M, Schouten LJ, Goldbohm RA, van den Brandt PA. Dairy consumption and ovarian cancer risk in the Netherlands cohort study on diet and cancer. British Journal of Cancer. 2006;**94**:165-170. DOI: 10.1038/ sj.bjc.6602890

[115] Faber MT, Jensen A, Søgaard M, Høgdall E, Høgdall C, Blaakaer J, et al. Use of dairy products, lactose, and calcium and risk of ovarian cancer— Results from a Danish case-control study. Acta Oncologica (Stockholm, Sweden). 2012;**51**:454-464. DOI: 10.3109/0284186X.2011.636754

[116] Merritt MA, Cramer DW, Vitonis AF, Titus LJ, Terry KL. Dairy foods and nutrients in relation to risk of ovarian cancer and major histological subtypes. International Journal of Cancer. 2013;**132**:1114-1124. DOI: 10.1002/ijc.27701

[117] Huncharek M, Kupelnick B. Dietary fat intake and risk of epithelial ovarian cancer: A meta-analysis of 6,689 subjects from 8 observational studies. Nutrition and Cancer. 2001;**40**:87-91. DOI: 10.1207/ S15327914NC402\_2

[118] Qiu W, Lu H, Qi Y, Wang X. Dietary fat intake and ovarian cancer risk: A meta-analysis of epidemiological studies. Oncotarget. 2016;**7**:37390- 37406. DOI: 10.18632/oncotarget.8940

[119] Bertone ER, Rosner BA, Hunter DJ, Stampfer MJ, Speizer FE, Colditz GA, et al. Dietary fat intake and ovarian cancer in a cohort of US women. American Journal of Epidemiology. 2002;**156**:22-31. DOI: 10.1093/aje/ kwf008

[120] Keum N, Lee DH, Marchand N, Oh H, Liu H, Aune D, et al. Egg intake and cancers of the breast, ovary and prostate: A dose–response meta-analysis of prospective observational studies. The British Journal of Nutrition. 2015;**114**:1099-1107. DOI: 10.1017/ S0007114515002135

[121] Risch HA, Jain M, Marrett LD, Howe GR. Dietary fat intake and risk of epithelial ovarian cancer. The Journal of the National Cancer Institute. 1994;**86**:1409-1415. DOI: 10.1093/ jnci/86.18.1409

[122] Gilsing AM, Weijenberg MP, Goldbohm RA, van den Brandt PA, Schouten LJ. Consumption of dietary fat and meat and risk of ovarian cancer in the Netherlands cohort study. The American Journal of Clinical Nutrition. 2011;**93**:118-126. DOI: 10.3945/ ajcn.2010.29888

[123] Meat consumption and cancer risk: A critical review of published metaanalyses. Critical Reviews in Oncology/ Hematology. 2016;**97**:1-14. DOI: 10.1016/j.critrevonc.2015.11.008

[124] Kushi LH, Mink PJ, Folsom AR, Anderson KE, Zheng W, Lazovich D, et al. Prospective study of diet and ovarian cancer. American Journal of Epidemiology. 1999;**149**:21-31

[125] Wallin A, Orsini N, Wolk A. Red and processed meat consumption

and risk of ovarian cancer: A doseresponse meta-analysis of prospective studies. British Journal of Cancer. 2011;**104**:1196-1201. DOI: 10.1038/ bjc.2011.49

[126] Kolahdooz F, van der Pols JC, Bain CJ, Marks GC, Hughes MC, Whiteman DC, et al. Meat, fish, and ovarian cancer risk: Results from 2 Australian case-control studies, a systematic review, and meta-analysis. The American Journal of Clinical Nutrition. 2010;**91**:1752-1763. DOI: 10.3945/ajcn.2009.28415

[127] Chang ET, Canchola AJ, Lee VS, Clarke CA, Purdie DM, Reynolds P, et al. Wine and other alcohol consumption and risk of ovarian cancer in the California Teachers Study cohort. Cancer Causes Control. 2007;**18**:91-103. DOI: 10.1007/s10552-006-0083-x

[128] Schouten LJ, Zeegers MPA, Goldbohm RA, van den Brandt PA. Alcohol and ovarian cancer risk: Results from the Netherlands cohort study. Cancer Causes and Control. 2004;**15**:201-209. DOI: 10.1023/B:CACO. 0000019512.71560.2b

[129] Gwinn ML, Webster LA, Lee NC, Layde PM, Rubin GL. Alcohol consumption and ovarian cancer risk. American Journal of Epidemiology. 1986;**123**:759-766. DOI: 10.1093/ oxfordjournals.aje.a114304

[130] Webb PM, Purdie DM, Bain CJ, Green AC. Alcohol, wine, and risk of epithelial ovarian cancer. Cancer Epidemiology, Biomarkers and Prevention. 2004;**13**:592-599

[131] Gosvig CF, Kjaer SK, Blaakær J, Høgdall E, Høgdall C, Jensen A. Coffee, tea, and caffeine consumption and risk of epithelial ovarian cancer and borderline ovarian tumors: Results from a Danish case-control study. Acta Oncologica. 2015;**54**:1144-1151. DOI: 10.3109/0284186X.2014.1001035

**97**

*Risk Factors for Ovarian Cancer*

10.1002/cncr.23275

[132] Tworoger SS, Gertig DM, Gates MA, Hecht JL, Hankinson SE. Caffeine, alcohol, smoking, and the risk of incident epithelial ovarian cancer. Cancer. 2008;**112**:1169-1177. DOI:

[133] Huncharek M, Klassen H, Kupelnick B. Dietary beta-carotene intake and the risk of epithelial ovarian cancer: A meta-analysis of 3,782 subjects from five observational studies. Vivo Athens Greece. 2001;**15**:339-343

[134] Terry PD, Qin B, Camacho F, Moorman PG, Alberg AJ, Barnholtz-Sloan JS, et al. Supplemental selenium may decrease ovarian cancer risk in African-American women. The Journal of Nutrition. 2017;**147**:621-627. DOI:

10.3945/jn.116.243279

[135] Dennert G, Zwahlen M,

cancer. Cochrane Database of Systematic Reviews. 2011:CD005195. DOI: 10.1002/14651858.CD005195.pub2

1630. DOI: 10.1093/ije/dyw207

Yuan L, Sheng X. The role of vitamin D in ovarian cancer: Epidemiology, molecular mechanism and prevention. Journal of Ovarian Research. 2018;**11**. DOI: 10.1186/s13048-018-0443-7

[138] Loeb LA. Tobacco causes human cancers—A concept founded on epidemiology and an insightful experiment now requires translation worldwide. Cancer Research. 2016;**76**:765-766. DOI: 10.1158/0008-

[139] Marchbanks PA, Wilson H, Bastos E, Cramer DW, Schildkraut JM,

[137] Guo H, Guo J, Xie W,

5472.CAN-16-0149

Brinkman M, Vinceti M, Zeegers MPA, Horneber M. Selenium for preventing

[136] Ong J-S, Cuellar-Partida G, Lu Y, Fasching PA, Hein A, Burghaus S, et al. Association of vitamin D levels and risk of ovarian cancer: A Mendelian randomization study. International Journal of Epidemiology. 2016;**45**:1619-

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

Peterson HB. Cigarette smoking and epithelial ovarian cancer by histologic type. Obstetrics and Gynecology.

[140] Licaj I, Jacobsen BK, Selmer RM,

Gram IT. Smoking and risk of ovarian cancer by histological subtypes: An analysis among 300000 Norwegian women. British Journal of Cancer. 2017;**116**:270-276. DOI: 10.1038/

[141] Zhang Y, Coogan PF, Palmer JR, Strom BL, Rosenberg L. Cigarette smoking and increased risk of mucinous epithelial ovarian cancer. American Journal of Epidemiology. 2004;**159**:133-

[142] Faber MT, Kjær SK, Dehlendorff C,

Høgdall E, et al. Cigarette smoking and risk of ovarian cancer: A pooled analysis of 21 case–control studies. Cancer Causes Control CCC. 2013;**24**. DOI:

139. DOI: 10.1093/aje/kwh015

Chang-Claude J, Andersen KK,

10.1007/s10552-013-0174-4

ijc.26235

[143] Gram IT, Lukanova A, Brill I, Braaten T, Lund E, Lundin E, et al. Cigarette smoking and risk of histological subtypes of epithelial ovarian cancer in the EPIC cohort study. International Journal of Cancer. 2012;**130**:2204-2210. DOI: 10.1002/

[144] Ovarian cancer and smoking: individual participant meta-analysis including 28 114 women with ovarian cancer from 51 epidemiological studies. The Lancet Oncology. 2012;**13**:946-956. DOI: 10.1016/S1470-2045(12)70322-4

[145] Modugno F, Ness RB, Cottreau CM. Cigarette smoking and the risk of mucinous and nonmucinous epithelial

(Cambridge, Mass.). 2002;**13**:467-471

[146] Terry PD, Miller AB, Jones JG, Rohan TE. Cigarette smoking and the

ovarian cancer. Epidemiology

Maskarinec G, Weiderpass E,

2000;**95**:255-260

bjc.2016.418

#### *Risk Factors for Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.86712*

*Tumor Progression and Metastasis*

kwf008

S0007114515002135

jnci/86.18.1409

ajcn.2010.29888

[118] Qiu W, Lu H, Qi Y, Wang X. Dietary fat intake and ovarian cancer risk: A meta-analysis of epidemiological studies. Oncotarget. 2016;**7**:37390- 37406. DOI: 10.18632/oncotarget.8940

[119] Bertone ER, Rosner BA, Hunter DJ, Stampfer MJ, Speizer FE, Colditz GA, et al. Dietary fat intake and ovarian cancer in a cohort of US women. American Journal of Epidemiology. 2002;**156**:22-31. DOI: 10.1093/aje/

and risk of ovarian cancer: A doseresponse meta-analysis of prospective studies. British Journal of Cancer. 2011;**104**:1196-1201. DOI: 10.1038/

[126] Kolahdooz F, van der Pols JC, Bain CJ, Marks GC, Hughes MC, Whiteman DC, et al. Meat, fish, and ovarian cancer risk: Results from 2 Australian case-control studies, a systematic review, and meta-analysis. The American Journal of Clinical Nutrition. 2010;**91**:1752-1763. DOI:

[127] Chang ET, Canchola AJ, Lee VS, Clarke CA, Purdie DM, Reynolds P, et al. Wine and other alcohol consumption and risk of ovarian cancer in the California Teachers Study cohort. Cancer Causes Control. 2007;**18**:91-103. DOI: 10.1007/s10552-006-0083-x

[128] Schouten LJ, Zeegers MPA, Goldbohm RA, van den Brandt PA. Alcohol and ovarian cancer risk: Results from the Netherlands cohort study. Cancer Causes and Control.

0000019512.71560.2b

2004;**15**:201-209. DOI: 10.1023/B:CACO.

[129] Gwinn ML, Webster LA, Lee NC,

consumption and ovarian cancer risk. American Journal of Epidemiology. 1986;**123**:759-766. DOI: 10.1093/ oxfordjournals.aje.a114304

[130] Webb PM, Purdie DM, Bain CJ, Green AC. Alcohol, wine, and risk of epithelial ovarian cancer. Cancer Epidemiology, Biomarkers and Prevention. 2004;**13**:592-599

[131] Gosvig CF, Kjaer SK, Blaakær J, Høgdall E, Høgdall C, Jensen A. Coffee, tea, and caffeine consumption and risk of epithelial ovarian cancer and borderline ovarian tumors: Results from a Danish case-control study. Acta Oncologica. 2015;**54**:1144-1151. DOI: 10.3109/0284186X.2014.1001035

Layde PM, Rubin GL. Alcohol

10.3945/ajcn.2009.28415

bjc.2011.49

[120] Keum N, Lee DH, Marchand N, Oh H, Liu H, Aune D, et al. Egg intake and cancers of the breast, ovary and prostate: A dose–response meta-analysis of prospective observational studies. The British Journal of Nutrition. 2015;**114**:1099-1107. DOI: 10.1017/

[121] Risch HA, Jain M, Marrett LD, Howe GR. Dietary fat intake and risk of epithelial ovarian cancer. The Journal of the National Cancer Institute. 1994;**86**:1409-1415. DOI: 10.1093/

[122] Gilsing AM, Weijenberg MP, Goldbohm RA, van den Brandt PA, Schouten LJ. Consumption of dietary fat and meat and risk of ovarian cancer in the Netherlands cohort study. The American Journal of Clinical Nutrition.

2011;**93**:118-126. DOI: 10.3945/

[123] Meat consumption and cancer risk: A critical review of published metaanalyses. Critical Reviews in Oncology/ Hematology. 2016;**97**:1-14. DOI: 10.1016/j.critrevonc.2015.11.008

[124] Kushi LH, Mink PJ, Folsom AR, Anderson KE, Zheng W, Lazovich D, et al. Prospective study of diet and ovarian cancer. American Journal of Epidemiology. 1999;**149**:21-31

[125] Wallin A, Orsini N, Wolk A. Red and processed meat consumption

**96**

[132] Tworoger SS, Gertig DM, Gates MA, Hecht JL, Hankinson SE. Caffeine, alcohol, smoking, and the risk of incident epithelial ovarian cancer. Cancer. 2008;**112**:1169-1177. DOI: 10.1002/cncr.23275

[133] Huncharek M, Klassen H, Kupelnick B. Dietary beta-carotene intake and the risk of epithelial ovarian cancer: A meta-analysis of 3,782 subjects from five observational studies. Vivo Athens Greece. 2001;**15**:339-343

[134] Terry PD, Qin B, Camacho F, Moorman PG, Alberg AJ, Barnholtz-Sloan JS, et al. Supplemental selenium may decrease ovarian cancer risk in African-American women. The Journal of Nutrition. 2017;**147**:621-627. DOI: 10.3945/jn.116.243279

[135] Dennert G, Zwahlen M, Brinkman M, Vinceti M, Zeegers MPA, Horneber M. Selenium for preventing cancer. Cochrane Database of Systematic Reviews. 2011:CD005195. DOI: 10.1002/14651858.CD005195.pub2

[136] Ong J-S, Cuellar-Partida G, Lu Y, Fasching PA, Hein A, Burghaus S, et al. Association of vitamin D levels and risk of ovarian cancer: A Mendelian randomization study. International Journal of Epidemiology. 2016;**45**:1619- 1630. DOI: 10.1093/ije/dyw207

[137] Guo H, Guo J, Xie W, Yuan L, Sheng X. The role of vitamin D in ovarian cancer: Epidemiology, molecular mechanism and prevention. Journal of Ovarian Research. 2018;**11**. DOI: 10.1186/s13048-018-0443-7

[138] Loeb LA. Tobacco causes human cancers—A concept founded on epidemiology and an insightful experiment now requires translation worldwide. Cancer Research. 2016;**76**:765-766. DOI: 10.1158/0008- 5472.CAN-16-0149

[139] Marchbanks PA, Wilson H, Bastos E, Cramer DW, Schildkraut JM, Peterson HB. Cigarette smoking and epithelial ovarian cancer by histologic type. Obstetrics and Gynecology. 2000;**95**:255-260

[140] Licaj I, Jacobsen BK, Selmer RM, Maskarinec G, Weiderpass E, Gram IT. Smoking and risk of ovarian cancer by histological subtypes: An analysis among 300000 Norwegian women. British Journal of Cancer. 2017;**116**:270-276. DOI: 10.1038/ bjc.2016.418

[141] Zhang Y, Coogan PF, Palmer JR, Strom BL, Rosenberg L. Cigarette smoking and increased risk of mucinous epithelial ovarian cancer. American Journal of Epidemiology. 2004;**159**:133- 139. DOI: 10.1093/aje/kwh015

[142] Faber MT, Kjær SK, Dehlendorff C, Chang-Claude J, Andersen KK, Høgdall E, et al. Cigarette smoking and risk of ovarian cancer: A pooled analysis of 21 case–control studies. Cancer Causes Control CCC. 2013;**24**. DOI: 10.1007/s10552-013-0174-4

[143] Gram IT, Lukanova A, Brill I, Braaten T, Lund E, Lundin E, et al. Cigarette smoking and risk of histological subtypes of epithelial ovarian cancer in the EPIC cohort study. International Journal of Cancer. 2012;**130**:2204-2210. DOI: 10.1002/ ijc.26235

[144] Ovarian cancer and smoking: individual participant meta-analysis including 28 114 women with ovarian cancer from 51 epidemiological studies. The Lancet Oncology. 2012;**13**:946-956. DOI: 10.1016/S1470-2045(12)70322-4

[145] Modugno F, Ness RB, Cottreau CM. Cigarette smoking and the risk of mucinous and nonmucinous epithelial ovarian cancer. Epidemiology (Cambridge, Mass.). 2002;**13**:467-471

[146] Terry PD, Miller AB, Jones JG, Rohan TE. Cigarette smoking and the risk of invasive epithelial ovarian cancer in a prospective cohort study. European Journal of Cancer (Oxford, England: 1990). 2003;**39**:1157-1164

[147] Sayasneh A, Tsivos D, Crawford R. Endometriosis and ovarian cancer: A systematic review. ISRN Obstetrics and Gynecology. 2011;**2011**. DOI: 10.5402/2011/140310

[148] Zafrakas M, Grimbizis G, Timologou A, Tarlatzis BC. Endometriosis and ovarian cancer risk: A systematic review of epidemiological studies. Frontiers in Surgery. 2014;**1**. DOI: 10.3389/fsurg.2014.00014

[149] Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Cancer risk after a hospital discharge diagnosis of endometriosis. American Journal of Obstetrics and Gynecology. 1997;**176**:572-579

[150] Vercellini P, Somigliana E, Buggio L, Bolis G, Fedele L. Endometriosis and ovarian cancer. The Lancet Oncology. 2012;**13**:e188-e189. DOI: 10.1016/S1470-2045(12)70198-5

[151] Brilhante AVM, Augusto KL, Portela MC, Sucupira LCG, Oliveira LAF, Pouchaim AJMV, et al. Endometriosis and ovarian cancer: An integrative review (endometriosis and ovarian cancer). Asian Pacific Journal of Cancer Prevention. 2017;**18**:11-16. DOI: 10.22034/ APJCP.2017.18.1.11

[152] The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertility and Sterility. 2004;**81**:19-25. DOI: 10.1016/j. fertnstert.2003.10.004

[153] Schildkraut J. Epithelial ovarian cancer risk among women with

polycystic ovary syndrome. Obstetrics and Gynecology. 1996;**88**:554-559. DOI: 10.1016/0029-7844(96)00226-8

[154] Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): Arguably the most common endocrinopathy is associated with significant morbidity in women. The Journal of Clinical Endocrinology and Metabolism. 1999;**84**:1897-1899. DOI: 10.1210/ jcem.84.6.5803

[155] Harris HR, Terry KL. Polycystic ovary syndrome and risk of endometrial, ovarian, and breast cancer: A systematic review. Fertility Research and Practice. 2016;**2**:14. DOI: 10.1186/ s40738-016-0029-2

[156] Galazis N, Olaleye O, Haoula Z, Layfield R, Atiomo W. Proteomic biomarkers for ovarian cancer risk in women with polycystic ovary syndrome: A systematic review and biomarker database integration. Fertility and Sterility. 2012;**98**:1590-1601.e1. DOI: 10.1016/j. fertnstert.2012.08.002

[157] Rasmussen CB, Kjaer SK, Albieri V, Bandera EV, Doherty JA, Høgdall E, et al. Pelvic inflammatory disease and the risk of ovarian cancer and borderline ovarian tumors: A pooled analysis of 13 case-control studies. American Journal of Epidemiology. 2017;**185**:8-20. DOI: 10.1093/aje/kww161

[158] Zhou Z, Zeng F, Yuan J, Tang J, Colditz GA, Tworoger SS, et al. Pelvic inflammatory disease and the risk of ovarian cancer: A meta-analysis. Cancer Causes Control. 2017;**28**:415-428. DOI: 10.1007/s10552-017-0873-3

[159] Parazzini F, Vecchia CL, Negri E, Moroni S, Dal Pino D, Fedele L. Pelvic inflammatory disease and risk of ovarian cancer. Cancer Epidemiology, Biomarkers and Prevention. 1996;**5**:667-669

**99**

*Risk Factors for Ovarian Cancer*

10.1002/ijc.23017

sj.bjc.6603527

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

[160] Merritt MA, Green AC, Nagle CM, Webb PM, Australian Cancer study (ovarian Cancer), Australian ovarian Cancer study group. Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer. International Journal of Cancer. 2008;**122**:170-176. DOI:

individual participant meta-analysis of 52 epidemiological studies. Lancet (London, England). 2015;**385**:1835-1842. DOI: 10.1016/S0140-6736(14)61687-1

Kolahdooz F, Webb PM. Obesity and the risk of epithelial ovarian cancer: A systematic review and metaanalysis. European Journal of Cancer. 2007;**43**:690-709. DOI: 10.1016/j.

Renehan AG. Body mass index, hormone replacement therapy, and endometrial cancer risk: A meta-analysis. Cancer Epidemiology, Biomarkers and Prevention. 2010;**19**:3119-3130. DOI: 10.1158/1055-9965.EPI-10-0832

[167] Olsen CM, Green AC, Whiteman DC, Sadeghi S,

[168] Crosbie EJ, Zwahlen M, Kitchener HC, Egger M,

[169] Olsen CM, Nagle CM,

ERC-12-0395

Whiteman DC, Ness R, Pearce CL, Pike MC, et al. Obesity and risk of ovarian cancer subtypes: Evidence from the Ovarian Cancer Association Consortium. Endocrine-Related Cancer. 2013;**20**:251-262. DOI: 10.1530/

[170] Tworoger SS, Huang T. Obesity and ovarian cancer. Recent Results in Cancer Research. 2016;**208**:155-176. DOI: 10.1007/978-3-319-42542-9\_9

[171] Jochem C, Schlecht I, Leitzmann M. Epidemiologic relationship between obesity and ovarian cancer. In:

Berger NA, Klopp AH, Lu KH, editors. Focus on Gynecologic Malignancies. Vol. 13. Cham: Springer International Publishing; 2018. pp. 21-30. DOI: 10.1007/978-3-319-63483-8\_2

[172] Nagle CM, Dixon SC, Jensen A, Kjaer SK, Modugno F, deFazio A, et al. Obesity and survival among women with ovarian cancer: Results from the Ovarian Cancer Association Consortium. British Journal of Cancer.

ejca.2006.11.010

[161] Greiser CM, Greiser EM, Dören M. Menopausal hormone therapy and risk of ovarian cancer: Systematic review and meta-analysis. Human Reproduction Update. 2007;**13**:453-463.

DOI: 10.1093/humupd/dmm012

[162] Danforth KN, Tworoger SS, Hecht JL, Rosner BA, Colditz GA, Hankinson SE. A prospective study of postmenopausal hormone use and ovarian cancer risk. British Journal of Cancer. 2007;**96**:151-156. DOI: 10.1038/

[163] Beral V, Million Women Study Collaborators, Bull D, Green J,

[164] Lee AW, Ness RB, Roman LD, Terry KL, Schildkraut JM, Chang-Claude J, et al. Association between menopausal estrogen-only therapy and ovarian carcinoma Risk. Obstetrics and Gynecology. 2016;**127**:828-836. DOI: 10.1097/AOG.0000000000001387

[165] Hormone Replacement Therapy May Increase Ovarian Cancer Risk. Medscape n.d. Available from: http:// www.medscape.com/viewarticle/839758

[Accessed: 01 December 2018]

[166] Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Gaitskell K, Hermon C, Moser K, Reeves G, et al. Menopausal hormone use and ovarian cancer risk:

Reeves G. Ovarian cancer and hormone replacement therapy in the million women study. Lancet (London, England). 2007;**369**:1703-1710. DOI: 10.1016/S0140-6736(07)60534-0

#### *Risk Factors for Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.86712*

*Tumor Progression and Metastasis*

1990). 2003;**39**:1157-1164

10.5402/2011/140310

[148] Zafrakas M, Grimbizis G,

10.3389/fsurg.2014.00014

1997;**176**:572-579

APJCP.2017.18.1.11

fertnstert.2003.10.004

risk of invasive epithelial ovarian cancer in a prospective cohort study. European Journal of Cancer (Oxford, England:

polycystic ovary syndrome. Obstetrics and Gynecology. 1996;**88**:554-559. DOI:

[154] Carmina E, Lobo RA. Polycystic ovary syndrome (PCOS): Arguably the most common endocrinopathy is associated with significant morbidity in women. The Journal of Clinical Endocrinology and Metabolism. 1999;**84**:1897-1899. DOI: 10.1210/

[155] Harris HR, Terry KL. Polycystic

endometrial, ovarian, and breast cancer: A systematic review. Fertility Research and Practice. 2016;**2**:14. DOI: 10.1186/

[157] Rasmussen CB, Kjaer SK, Albieri V, Bandera EV, Doherty JA, Høgdall E, et al. Pelvic inflammatory disease and the risk of ovarian cancer and borderline ovarian tumors: A pooled analysis of 13 case-control studies. American Journal of Epidemiology. 2017;**185**:8-20. DOI:

[158] Zhou Z, Zeng F, Yuan J, Tang J, Colditz GA, Tworoger SS, et al. Pelvic inflammatory disease and the risk of ovarian cancer: A meta-analysis. Cancer Causes Control. 2017;**28**:415-428. DOI:

[159] Parazzini F, Vecchia CL, Negri E, Moroni S, Dal Pino D, Fedele L. Pelvic inflammatory disease and risk of ovarian cancer. Cancer Epidemiology,

ovary syndrome and risk of

[156] Galazis N, Olaleye O, Haoula Z, Layfield R, Atiomo W. Proteomic biomarkers for ovarian cancer risk in women with polycystic ovary syndrome: A systematic review and biomarker database integration. Fertility and Sterility. 2012;**98**:1590-1601.e1. DOI: 10.1016/j.

fertnstert.2012.08.002

10.1093/aje/kww161

10.1007/s10552-017-0873-3

Biomarkers and Prevention.

1996;**5**:667-669

10.1016/0029-7844(96)00226-8

jcem.84.6.5803

s40738-016-0029-2

[147] Sayasneh A, Tsivos D, Crawford R. Endometriosis and ovarian cancer: A systematic review. ISRN Obstetrics and Gynecology. 2011;**2011**. DOI:

Timologou A, Tarlatzis BC. Endometriosis and ovarian cancer risk: A systematic review of epidemiological studies. Frontiers in Surgery. 2014;**1**. DOI:

[149] Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Cancer risk after a hospital discharge diagnosis of endometriosis. American Journal of Obstetrics and Gynecology.

[150] Vercellini P, Somigliana E, Buggio L, Bolis G, Fedele L.

[151] Brilhante AVM, Augusto KL, Portela MC, Sucupira LCG,

Oliveira LAF, Pouchaim AJMV, et al. Endometriosis and ovarian cancer: An integrative review (endometriosis and ovarian cancer). Asian Pacific Journal of Cancer Prevention. 2017;**18**:11-16. DOI: 10.22034/

[152] The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertility and Sterility. 2004;**81**:19-25. DOI: 10.1016/j.

[153] Schildkraut J. Epithelial ovarian cancer risk among women with

Endometriosis and ovarian cancer. The Lancet Oncology. 2012;**13**:e188-e189. DOI: 10.1016/S1470-2045(12)70198-5

**98**

[160] Merritt MA, Green AC, Nagle CM, Webb PM, Australian Cancer study (ovarian Cancer), Australian ovarian Cancer study group. Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer. International Journal of Cancer. 2008;**122**:170-176. DOI: 10.1002/ijc.23017

[161] Greiser CM, Greiser EM, Dören M. Menopausal hormone therapy and risk of ovarian cancer: Systematic review and meta-analysis. Human Reproduction Update. 2007;**13**:453-463. DOI: 10.1093/humupd/dmm012

[162] Danforth KN, Tworoger SS, Hecht JL, Rosner BA, Colditz GA, Hankinson SE. A prospective study of postmenopausal hormone use and ovarian cancer risk. British Journal of Cancer. 2007;**96**:151-156. DOI: 10.1038/ sj.bjc.6603527

[163] Beral V, Million Women Study Collaborators, Bull D, Green J, Reeves G. Ovarian cancer and hormone replacement therapy in the million women study. Lancet (London, England). 2007;**369**:1703-1710. DOI: 10.1016/S0140-6736(07)60534-0

[164] Lee AW, Ness RB, Roman LD, Terry KL, Schildkraut JM, Chang-Claude J, et al. Association between menopausal estrogen-only therapy and ovarian carcinoma Risk. Obstetrics and Gynecology. 2016;**127**:828-836. DOI: 10.1097/AOG.0000000000001387

[165] Hormone Replacement Therapy May Increase Ovarian Cancer Risk. Medscape n.d. Available from: http:// www.medscape.com/viewarticle/839758 [Accessed: 01 December 2018]

[166] Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Gaitskell K, Hermon C, Moser K, Reeves G, et al. Menopausal hormone use and ovarian cancer risk:

individual participant meta-analysis of 52 epidemiological studies. Lancet (London, England). 2015;**385**:1835-1842. DOI: 10.1016/S0140-6736(14)61687-1

[167] Olsen CM, Green AC, Whiteman DC, Sadeghi S, Kolahdooz F, Webb PM. Obesity and the risk of epithelial ovarian cancer: A systematic review and metaanalysis. European Journal of Cancer. 2007;**43**:690-709. DOI: 10.1016/j. ejca.2006.11.010

[168] Crosbie EJ, Zwahlen M, Kitchener HC, Egger M, Renehan AG. Body mass index, hormone replacement therapy, and endometrial cancer risk: A meta-analysis. Cancer Epidemiology, Biomarkers and Prevention. 2010;**19**:3119-3130. DOI: 10.1158/1055-9965.EPI-10-0832

[169] Olsen CM, Nagle CM, Whiteman DC, Ness R, Pearce CL, Pike MC, et al. Obesity and risk of ovarian cancer subtypes: Evidence from the Ovarian Cancer Association Consortium. Endocrine-Related Cancer. 2013;**20**:251-262. DOI: 10.1530/ ERC-12-0395

[170] Tworoger SS, Huang T. Obesity and ovarian cancer. Recent Results in Cancer Research. 2016;**208**:155-176. DOI: 10.1007/978-3-319-42542-9\_9

[171] Jochem C, Schlecht I, Leitzmann M. Epidemiologic relationship between obesity and ovarian cancer. In: Berger NA, Klopp AH, Lu KH, editors. Focus on Gynecologic Malignancies. Vol. 13. Cham: Springer International Publishing; 2018. pp. 21-30. DOI: 10.1007/978-3-319-63483-8\_2

[172] Nagle CM, Dixon SC, Jensen A, Kjaer SK, Modugno F, deFazio A, et al. Obesity and survival among women with ovarian cancer: Results from the Ovarian Cancer Association Consortium. British Journal of Cancer. 2015;**113**:817-826. DOI: 10.1038/ bjc.2015.245

[173] Foong KW, Bolton H. Obesity and ovarian cancer risk: A systematic review. Post Reproductive Health. 2017;**23**:183- 198. DOI: 10.1177/2053369117709225

[174] Wentzensen N, Poole EM, Trabert B, White E, Arslan AA, Patel AV, et al. Ovarian cancer risk factors by histologic subtype: An analysis from the ovarian Cancer Cohort Consortium. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2016;**34**:2888-2898. DOI: 10.1200/ JCO.2016.66.8178

[175] Luan N-N, Wu Q-J, Gong T-T, Vogtmann E, Wang Y-L, Lin B. Breastfeeding and ovarian cancer risk: A meta-analysis of epidemiologic studies. The American Journal of Clinical Nutrition. 2013;**98**:1020-1031. DOI: 10.3945/ajcn.113.062794

[176] McNeilly AS. Lactational control of reproduction. Reproduction, Fertility, and Development. 2001;**13**:583-590

[177] Stadel BV. The etiology and prevention of ovarian cancer. American Journal of Obstetrics and Gynecology. 1975;**123**:772-774. DOI: 10.1016/0002-9378(75)90509-8

[178] Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Doll R, Hermon C, Peto R, Reeves G. Ovarian cancer and oral contraceptives: Collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet (London, England). 2008;**371**:303-314. DOI: 10.1016/ S0140-6736(08)60167-1

[179] Why do Oral Contraceptives Prevent Ovarian Cancer? - Full Text View - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/

show/NCT02155777 [Accessed: |19 November 2018]

[180] Tsilidis KK, Allen NE, Key TJ, Dossus L, Lukanova A, Bakken K, et al. Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European prospective investigation into cancer and nutrition. 2011;**1442**. DOI: 10.1038/ bjc.2011.371

[181] Bosetti C, Negri E, Trichopoulos D, Franceschi S, Beral V, Tzonou A, et al. Long-term effects of oral contraceptives on ovarian cancer risk. International Journal of Cancer. 2002;**102**:262-265. DOI: 10.1002/ijc.10696

[182] Moorman PG, Havrilesky LJ, Gierisch JM, Coeytaux RR, Lowery WJ, Peragallo Urrutia R, et al. Oral contraceptives and risk of ovarian cancer and breast cancer among highrisk women: A systematic review and meta-analysis. Journal of Clinical Oncology. 2013;**31**:4188-4198. DOI: 10.1200/JCO.2013.48.9021

[183] Ferris JS, Daly MB, Buys SS, Genkinger JM, Liao Y, Terry MB. Oral contraceptive and reproductive risk factors for ovarian cancer within sisters in the breast cancer family registry. British Journal of Cancer. 2014;**110**:1074-1080. DOI: 10.1038/ bjc.2013.803

[184] Rice MS, Hankinson SE, Tworoger SS. Tubal ligation, hysterectomy, unilateral oophorectomy, and risk of ovarian cancer in the nurses' health studies. Fertility and Sterility. 2014;**102**:192-198.e3. DOI: 10.1016/j. fertnstert.2014.03.041

[185] Chan JK, Urban R, Capra AM, Jacoby V, Osann K, Whittemore A, et al. Ovarian cancer rates after hysterectomy with and without salpingooophorectomy. Obstetrics and Gynecology. 2014;**123**:65-72. DOI: 10.1097/AOG.0000000000000061

**101**

*Risk Factors for Ovarian Cancer*

S0140-6736(00)04642-0

[187] Gaitskell K, Green J, Pirie K, Reeves G. Tubal ligation and ovarian

Substantial variation by histological type. International Journal of Cancer. 2016;**138**:1076-1084. DOI: 10.1002/

[188] Hannan LM, Leitzmann MF, Lacey JV, Colbert LH, Albanes D, Schatzkin A, et al. Physical activity and risk of ovarian cancer: A prospective cohort study in the United States. Cancer Epidemiology and Prevention

Biomarkers. 2004;**13**:765-770

[189] Moorman PG, Jones LW, Akushevich L, Schildkraut JM. Recreational physical activity and ovarian cancer risk and survival. Annals of Epidemiology. 2011;**21**:178-187. DOI: 10.1016/j.annepidem.2010.10.014

2001;**91**:407-411

ijc.21157

[190] Tavani A, Gallus S, La Vecchia C, Dal Maso L, Negri E, Pelucchi C, et al. Physical activity and risk of ovarian cancer: An Italian case-control study. International Journal of Cancer.

[191] Pan SY, Ugnat A-M, Mao Y.

International Journal of Cancer. 2005;**117**:300-307. DOI: 10.1002/

Physical activity and the risk of ovarian cancer: A case-control study in Canada.

cancer risk in a large cohort:

ijc.29856

*DOI: http://dx.doi.org/10.5772/intechopen.86712*

[186] Narod SA, Sun P, Ghadirian P, Lynch H, Isaacs C, Garber J, et al. Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: A case-control study. The Lancet. 2001;**357**:1467-1470. DOI: 10.1016/

*Risk Factors for Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.86712*

*Tumor Progression and Metastasis*

bjc.2015.245

JCO.2016.66.8178

2015;**113**:817-826. DOI: 10.1038/

[174] Wentzensen N, Poole EM, Trabert B, White E, Arslan AA, Patel AV, et al. Ovarian cancer risk factors by histologic subtype: An analysis from the ovarian Cancer Cohort Consortium. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2016;**34**:2888-2898. DOI: 10.1200/

[175] Luan N-N, Wu Q-J, Gong T-T, Vogtmann E, Wang Y-L,

DOI: 10.3945/ajcn.113.062794

[177] Stadel BV. The etiology and prevention of ovarian cancer. American Journal of Obstetrics and Gynecology. 1975;**123**:772-774. DOI: 10.1016/0002-9378(75)90509-8

[178] Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Doll R, Hermon C, Peto R, Reeves G. Ovarian cancer and oral contraceptives: Collaborative

reanalysis of data from 45

S0140-6736(08)60167-1

[179] Why do Oral Contraceptives Prevent Ovarian Cancer? - Full Text View - ClinicalTrials.gov n.d. Available from: https://clinicaltrials.gov/ct2/

epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet (London, England). 2008;**371**:303-314. DOI: 10.1016/

Lin B. Breastfeeding and ovarian cancer risk: A meta-analysis of epidemiologic studies. The American Journal of Clinical Nutrition. 2013;**98**:1020-1031.

[176] McNeilly AS. Lactational control of reproduction. Reproduction, Fertility, and Development. 2001;**13**:583-590

[173] Foong KW, Bolton H. Obesity and ovarian cancer risk: A systematic review. Post Reproductive Health. 2017;**23**:183- 198. DOI: 10.1177/2053369117709225

show/NCT02155777 [Accessed:

[181] Bosetti C, Negri E, Trichopoulos D, Franceschi S, Beral V, Tzonou A, et al. Long-term effects of oral contraceptives on ovarian cancer risk. International Journal of Cancer. 2002;**102**:262-265.

[180] Tsilidis KK, Allen NE, Key TJ, Dossus L, Lukanova A, Bakken K, et al. Oral contraceptive use and reproductive factors and risk of ovarian cancer in the European prospective investigation into cancer and nutrition. 2011;**1442**. DOI: 10.1038/


bjc.2011.371

DOI: 10.1002/ijc.10696

10.1200/JCO.2013.48.9021

bjc.2013.803

[183] Ferris JS, Daly MB, Buys SS, Genkinger JM, Liao Y, Terry MB. Oral contraceptive and reproductive risk factors for ovarian cancer within sisters in the breast cancer family registry. British Journal of Cancer. 2014;**110**:1074-1080. DOI: 10.1038/

[184] Rice MS, Hankinson SE, Tworoger SS. Tubal ligation,

fertnstert.2014.03.041

with and without salpingooophorectomy. Obstetrics and Gynecology. 2014;**123**:65-72. DOI: 10.1097/AOG.0000000000000061

hysterectomy, unilateral oophorectomy, and risk of ovarian cancer in the nurses' health studies. Fertility and Sterility. 2014;**102**:192-198.e3. DOI: 10.1016/j.

[185] Chan JK, Urban R, Capra AM, Jacoby V, Osann K, Whittemore A, et al. Ovarian cancer rates after hysterectomy

[182] Moorman PG, Havrilesky LJ, Gierisch JM, Coeytaux RR,

Lowery WJ, Peragallo Urrutia R, et al. Oral contraceptives and risk of ovarian cancer and breast cancer among highrisk women: A systematic review and meta-analysis. Journal of Clinical Oncology. 2013;**31**:4188-4198. DOI:

**100**

[186] Narod SA, Sun P, Ghadirian P, Lynch H, Isaacs C, Garber J, et al. Tubal ligation and risk of ovarian cancer in carriers of BRCA1 or BRCA2 mutations: A case-control study. The Lancet. 2001;**357**:1467-1470. DOI: 10.1016/ S0140-6736(00)04642-0

[187] Gaitskell K, Green J, Pirie K, Reeves G. Tubal ligation and ovarian cancer risk in a large cohort: Substantial variation by histological type. International Journal of Cancer. 2016;**138**:1076-1084. DOI: 10.1002/ ijc.29856

[188] Hannan LM, Leitzmann MF, Lacey JV, Colbert LH, Albanes D, Schatzkin A, et al. Physical activity and risk of ovarian cancer: A prospective cohort study in the United States. Cancer Epidemiology and Prevention Biomarkers. 2004;**13**:765-770

[189] Moorman PG, Jones LW, Akushevich L, Schildkraut JM. Recreational physical activity and ovarian cancer risk and survival. Annals of Epidemiology. 2011;**21**:178-187. DOI: 10.1016/j.annepidem.2010.10.014

[190] Tavani A, Gallus S, La Vecchia C, Dal Maso L, Negri E, Pelucchi C, et al. Physical activity and risk of ovarian cancer: An Italian case-control study. International Journal of Cancer. 2001;**91**:407-411

[191] Pan SY, Ugnat A-M, Mao Y. Physical activity and the risk of ovarian cancer: A case-control study in Canada. International Journal of Cancer. 2005;**117**:300-307. DOI: 10.1002/ ijc.21157

**Chapter 5**

**Abstract**

**1. Introduction**

**103**

Appendiceal Neuroendocrine

*Marco Clementi, Renato Pietroletti, Andrea Ciarrocchi,*

*Federica d'Ascanio, Guido Rindi and Francesco Carlei*

Tumors and Anorectal Melanoma

Tumor growth and spread are a complicated matter and are the result of many interconnected factors. The analysis of patterns emerging from highly numerous populations might help shed some light on such an intricate mechanism. In this respect, our studies are mostly based on the SEER database, a nation representative dataset collecting data regarding the US population, over a very long time span. This approach is revealed to be particularly useful for rare tumors, as prospective studies are not feasible. Here, we present the results and the clinical implications of our inquires: we show the impact on overall survival of several morphological and demographic characteristics of various malignancies including anorectal melanoma and neuroendocrine tumors of the appendix. The impact of surgical treatment is

discussed as well. Finally, we endorse the need to find more reliable markers of tumor biology, such as genetic patterns, to tailor an effective multidisciplinary treatment.

Tumor progression is the result of several complex and interrelated mechanisms.

Rare tumors are particularly difficult to investigate, since prospective analyses are not easy to plan due to the small number of patients observed and treated. Therefore, reliable prognostic information are lacking or are controversial. Neuroendocrine tumor in general and those located in the appendix in particular are subjected to several controversies. Size and histology of appendiceal carcinoids, for instance, seem to influence heavily lymphatic spread and thus prognosis. Surgical strategy is debated in consequence of such features with the aim of obtaining adequate lymph node harvesting to establish a correct stadiation and prognosis.

**Keywords:** neuroendocrine tumors of the appendix, anorectal melanoma,

Apart from stage of the disease, biologic features of the neoplastic cell play a relevant role. Size, location, grading, cell differentiation, genotype mutation, and expression of oncogene are well-known features of the primary tumor all responsible for tumor progression and disease aggressiveness. Progression of the disease may occur either as a result of local growth and invasion or by means of distant spread of the disease in targeted organs via lymphatic or venous outflow. The two phenomena are a consequence of specific biologic features of the neoplastic cell and

multidisciplinary treatment, lymph node spread, carcinoid tumors

thus may occur independently from each other.

#### **Chapter 5**

## Appendiceal Neuroendocrine Tumors and Anorectal Melanoma

*Marco Clementi, Renato Pietroletti, Andrea Ciarrocchi, Federica d'Ascanio, Guido Rindi and Francesco Carlei*

#### **Abstract**

Tumor growth and spread are a complicated matter and are the result of many interconnected factors. The analysis of patterns emerging from highly numerous populations might help shed some light on such an intricate mechanism. In this respect, our studies are mostly based on the SEER database, a nation representative dataset collecting data regarding the US population, over a very long time span. This approach is revealed to be particularly useful for rare tumors, as prospective studies are not feasible. Here, we present the results and the clinical implications of our inquires: we show the impact on overall survival of several morphological and demographic characteristics of various malignancies including anorectal melanoma and neuroendocrine tumors of the appendix. The impact of surgical treatment is discussed as well. Finally, we endorse the need to find more reliable markers of tumor biology, such as genetic patterns, to tailor an effective multidisciplinary treatment.

**Keywords:** neuroendocrine tumors of the appendix, anorectal melanoma, multidisciplinary treatment, lymph node spread, carcinoid tumors

#### **1. Introduction**

Tumor progression is the result of several complex and interrelated mechanisms. Apart from stage of the disease, biologic features of the neoplastic cell play a relevant role. Size, location, grading, cell differentiation, genotype mutation, and expression of oncogene are well-known features of the primary tumor all responsible for tumor progression and disease aggressiveness. Progression of the disease may occur either as a result of local growth and invasion or by means of distant spread of the disease in targeted organs via lymphatic or venous outflow. The two phenomena are a consequence of specific biologic features of the neoplastic cell and thus may occur independently from each other.

Rare tumors are particularly difficult to investigate, since prospective analyses are not easy to plan due to the small number of patients observed and treated. Therefore, reliable prognostic information are lacking or are controversial. Neuroendocrine tumor in general and those located in the appendix in particular are subjected to several controversies. Size and histology of appendiceal carcinoids, for instance, seem to influence heavily lymphatic spread and thus prognosis. Surgical strategy is debated in consequence of such features with the aim of obtaining adequate lymph node harvesting to establish a correct stadiation and prognosis.

As far as recto-anal melanoma is concerned, prognosis is very poor due to frequent diagnostic delay and rarity of the disease leading to misdiagnosis and advanced stage at presentation. However, in spite of poor prognosis, extensive surgery is still advocated although the experiences reported in the literature are very limited and sparse, undoubtedly weak to support such aggressive approach.

Thus, since high-quality data regarding rare diseases such as appendiceal carcinoids or anorectal melanoma neither are presently available nor can be obtained prospectively in a short time, a reasonable approach to partially overcome such limitations is to analyze a pool of data in large tumor registry, collecting retrospective cases. In order to maximize the statistical power of the study, potential confounders by means of multivariate analysis must be taken into account. Mathematical models can be adopted to achieve such a goal; in particular Cox regression models or matching populations by the propensity score can be successfully adopted. Populations can be described by using descriptive statistical methods for categorical and continuous variables.

We planned a study on appendiceal carcinoids and anorectal melanoma accessing the Surveillance, Epidemiology, and End Results (SEER) database, a dataset collecting a large amount of data pertaining cancer in the US population over a time span of decades.

We were able to demonstrate the impact on overall survival of different morphological and demographic characteristics of anorectal melanoma and neuroendocrine tumors of the appendix [1–4], discussing their impact on surgical treatment and prognosis.

We accessed the SEER database to retrieve the data to analyze. Then, we selected the variables that we wanted to introduce in our models to assess their impact on survival. In any statistical test performed, P < 0.05 was considered significant. The covariates we focused on were demographic and morphologic. In most occasions, we retrieved data on age of the patients, gender, stage of disease, ethnicity, tumor size, and lymph node invasion.

#### **2. Melanoma of the anorectum**

Melanoma of the anorectum has a dismal prognosis since frequent early metastases make any treatment ineffective, despite a multimodal approach [5]. The rectum and anal canal represent the third most common primary site of origin [6]. The resemblance to benign common conditions such as hemorrhoids often delays the diagnosis, strongly impairing the possibility of treatment with intention to cure (**Figure 1**) (**Table 1**).

Site of origin is a determining prognostic factor for cutaneous melanoma [7]. With regard to mucosal melanomas, vulvar tumors proved a better outcome than those originating from the vagina [8]. Our interest was based on the fact that although most of the tumors arise in the anal canal, a not negligible percentage of the neoplasia is located more proximally in the rectum [9]. It seems reasonable that distal tumors could have a better prognosis, because they are clinically apparent sooner than more proximal masses. The latter, in fact, tend to become apparent only when symptoms of occlusion of the large intestine ensue. Moreover, anorectal melanomas arising in the anus/anal canal or rectum drain in different lymph node chains. To verify such hypothesis, we investigated the impact of site of origin on overall survival. Bello et al. [10] showed different patterns of local recurrence: anorectal melanoma recurred more often systemically, whereas tumors of the anal canal recurred first at inguinal lymph nodes. However, the overall survival did not vary between the groups. Our results confirmed that the site of origin along the rectum and anal canal does not influence survival (P = 0.164).

Stage of disease did not prove to have an impact on survival (P = 0.880 for regional stage and P = 0.347 for distant stage). However, our results should be considered with caution, given that we had to use the SEER historical stage classification to obtain data consistent through time. In fact, the TNM has been changing over time, and we decided to avoid its use, in order to not reduce the overall number of cases available for final analysis. In other studies, stage showed a signif-

**Category P value Hazard ratio Confidence interval** Site of origin (rectum) 0.275 1.233 0.845–1.798 Gender (male) 0.707 0.932 0.646–1.344 Size 0.519 1.000 0.998–1.001 Race (other) 0.019 2.291 1.148–4.575 Race (White) 0.824 0.945 0.571–1.562 LN rate 0.027 1.873 1.076–3.261 Age 0.150 1.010 0.997–1.023 Surgical intervention (APR/AR) 0.194 0.783 0.541–1.133 Stage (regional) 0.880 1.035 0.659–1.628 Stage (distant) 0.347 1.241 0.792–1.945 Radiation (performed) 0.150 1.461 0.870–2.452 Lymphadenectomy (performed) 0.904 0.977 0.663–1.438

icant impact on survival [11, 12].

*Cox regression model for anorectal melanoma.*

**Figure 1.**

**Table 1.**

**105**

*Survival curve for patients affected by anorectal melanoma.*

*Appendiceal Neuroendocrine Tumors and Anorectal Melanoma*

*DOI: http://dx.doi.org/10.5772/intechopen.90434*

**Figure 1.** *Survival curve for patients affected by anorectal melanoma.*


#### **Table 1.**

As far as recto-anal melanoma is concerned, prognosis is very poor due to frequent diagnostic delay and rarity of the disease leading to misdiagnosis and advanced stage at presentation. However, in spite of poor prognosis, extensive surgery is still advocated although the experiences reported in the literature are very limited and sparse, undoubtedly weak to support such aggressive approach. Thus, since high-quality data regarding rare diseases such as appendiceal carcinoids or anorectal melanoma neither are presently available nor can be obtained prospectively in a short time, a reasonable approach to partially overcome such limitations is to analyze a pool of data in large tumor registry, collecting retrospective cases. In order to maximize the statistical power of the study, potential con-

founders by means of multivariate analysis must be taken into account. Mathematical models can be adopted to achieve such a goal; in particular Cox regression models or matching populations by the propensity score can be successfully adopted. Populations can be described by using descriptive statistical methods

We planned a study on appendiceal carcinoids and anorectal melanoma accessing the Surveillance, Epidemiology, and End Results (SEER) database, a dataset collecting a large amount of data pertaining cancer in the US population

We were able to demonstrate the impact on overall survival of different morphological and demographic characteristics of anorectal melanoma and neuroendocrine tumors of the appendix [1–4], discussing their impact on surgical treatment

Melanoma of the anorectum has a dismal prognosis since frequent early metas-

Site of origin is a determining prognostic factor for cutaneous melanoma [7]. With regard to mucosal melanomas, vulvar tumors proved a better outcome than those originating from the vagina [8]. Our interest was based on the fact that although most of the tumors arise in the anal canal, a not negligible percentage of the neoplasia is located more proximally in the rectum [9]. It seems reasonable that distal tumors could have a better prognosis, because they are clinically apparent sooner than more proximal masses. The latter, in fact, tend to become apparent only when symptoms of occlusion of the large intestine ensue. Moreover, anorectal melanomas arising in the anus/anal canal or rectum drain in different lymph node chains. To verify such hypothesis, we investigated the impact of site of origin on overall survival. Bello et al. [10] showed different patterns of local recurrence: anorectal melanoma recurred more often systemically, whereas tumors of the anal canal recurred first at inguinal lymph nodes. However, the overall survival did not vary between the groups. Our results confirmed that the site of origin along the

tases make any treatment ineffective, despite a multimodal approach [5]. The rectum and anal canal represent the third most common primary site of origin [6]. The resemblance to benign common conditions such as hemorrhoids often delays the diagnosis, strongly impairing the possibility of treatment with intention to cure

rectum and anal canal does not influence survival (P = 0.164).

We accessed the SEER database to retrieve the data to analyze. Then, we selected the variables that we wanted to introduce in our models to assess their impact on survival. In any statistical test performed, P < 0.05 was considered significant. The covariates we focused on were demographic and morphologic. In most occasions, we retrieved data on age of the patients, gender, stage of disease,

for categorical and continuous variables.

ethnicity, tumor size, and lymph node invasion.

**2. Melanoma of the anorectum**

(**Figure 1**) (**Table 1**).

**104**

over a time span of decades.

*Tumor Progression and Metastasis*

and prognosis.

*Cox regression model for anorectal melanoma.*

Stage of disease did not prove to have an impact on survival (P = 0.880 for regional stage and P = 0.347 for distant stage). However, our results should be considered with caution, given that we had to use the SEER historical stage classification to obtain data consistent through time. In fact, the TNM has been changing over time, and we decided to avoid its use, in order to not reduce the overall number of cases available for final analysis. In other studies, stage showed a significant impact on survival [11, 12].

In addition, we inquired the prognostic value of locoregional metastatic lymph nodes and the impact of lymphadenectomy on overall survival. To better understand the role of lymph node metastasis on prognosis, we introduced the concept of lymph node ratio, defined as the ratio between metastatic lymph nodes and total lymph nodes harvested. This was necessary to avoid bias related to the extent of lymphadenectomy. In our series, performing lymphadenectomy did not improve survival (P = 0.904). This could be due to early tumor spread to distant sites, thus overcoming the potential benefits of local control. Sentinel lymph node biopsy has not proven to be useful in anorectal melanoma due to the low rate of positive findings, despite the presence of more distant metastases [13]. Therefore, lymph node spread of anorectal melanoma is far less predictable than, for example, the carcinoma of the breast.

tumors larger than 2 cm in diameter, whereas appendectomy alone is performed for tumors smaller than 1 cm. Patients affected by neuroendocrine tumors with a diameter of 1–2 cm are candidates for hemicolectomy in case of invasion of the cecum or mesoappendix or infiltration of the lymph-vascular system [25]. This treatment algorithm was introduced on the basis of retrospective outcome data provided by Moertel and his colleagues. The disease is usually quite indolent, and

At present, there is no proof of survival benefits of right hemicolectomy compared to appendectomy alone. In one of our studies, we wanted to verify whether

hemicolectomy. The indication for such a procedure in patients with neuroendocrine tumors larger than 2 cm in diameter stands on the augmented risk of visceral lymph node involvement. In fact, tumor size is a predictor of nodal spread [27]. Assuming that there may be a progression from positive lymph nodes to distant metastases, hemicolectomy is recommended to achieve oncologic radicality. It has been argued that a more extended procedure may have a staging value, but not an

Our data showed that the type of surgical procedure did not reach statistical significance (P = 0.513), proving that an extended procedure does not confer a survival advantage. Such findings and the indolent course of the disease suggest that formal right hemicolectomy should be performed in young healthy patients, whereas those burdened with comorbidities can be treated with appendectomy without affecting oncologic outcomes. In other words, tumor size greater than 2 cm

In another study, we focused on the natural history of metastatic lymph nodes and their clinical impact for primary pure and mixed neuroendocrine tumors of the appendix (**Figure 2**). The rationale for the surgical treatment is based on the risk of lymph node spread. However, the role of such an event on the natural history of the disease is not clear. First, the survival curve of our populations showed that pure carcinoids have a better prognosis than those with mixed variants (P < 0.001). After controlling for age, sex, tumor size, surgical intervention, and lymph nodes rate, a Cox proportional hazards model showed that histology was an independent predictor of overall survival (P = 0.004). This suggested that pure and mixed carcinoids differ with respect to their biological aggressiveness. For that reason, we analyzed patients having either pure or mixed carcinoids as two distinct series.

Gender (female) 0.066 Pure 0.154 0.538 0.229–1.263

Tumor size (≤2 cm) 0.017 Pure 0.896 0.937 0.355–2.474

Age <0.001 Pure <0.001 1.083 1.051–1.116

LN rate 0.012 Pure 0.039 5.295 1.089–25.754

**Interaction\* (P value) Group P value Hazard ratio Confidence interval**

0.017 Pure 0.029 0.241 0.067–0.867

Mixed 0.347 1.201 0.820–1.758

Mixed <0.001 0.442 0.286–0.683

Mixed 0.019 1.675 1.088–2.578

Mixed <0.001 1.041 1.026–1.056

Mixed <0.001 17.471 10.4733.382

should not be considered an absolute indication for right hemicolectomy.

2 cm is a good cutoff value for identifying the best candidates for right

overall survival is good [26] (**Table 2**).

*DOI: http://dx.doi.org/10.5772/intechopen.90434*

*Appendiceal Neuroendocrine Tumors and Anorectal Melanoma*

actual impact on survival [28].

Surgical intervention (less than RHC)

*Cox regression models for neuroendocrine tumors.*

**Table 2.**

**107**

Size of the tumor did not affect survival (P = 0.519), although it was previously associated with an increased risk of mesorectal and mesenteric lymph node metastases in anorectal melanoma [14]. Gender (P = 0.707) and age of the patient at time of diagnosis (P = 0.150) did not affect survival as well. Interestingly, ethnicity was found to be an independent predictor of survival (P = 0.019). Specifically, American Indian/Alaskan Native and Asian/Pacific Islander (other) ethnicity showed a worse outcome.

Radical surgery is the best option for cure and should be the goal of treatment [15, 16]. Optimal surgical strategies need to balance the need for radical excision including lymphadenectomy against increasing operative morbidity. Consistently with the recent literature, the type of surgical intervention was not a significant prognostic factor (P = 0.183). The fundamental dilemma regarding the treatment of anorectal melanoma is the choice between abdominoperineal/anterior resection and local wide excision. Previous studies suggested that aggressive treatment could provide better overall results by achieving local oncological control of the disease. More recently, another trend of treatment has been emerging. According to Matsuda et al. [17], no significant differences between the two options of treatment in terms of overall survival were apparent. Abdominoperineal resection has failed to show any advantage in terms of survival, adding a higher morbidity and poorer quality of life. Thus, local excision has now become the standard of treatment. In case of tumor recurrence, abdominoperineal or anterior resection can be performed as a salvage procedure [18, 19].

Radiation therapy did not influence prognosis (P = 0.864), although it has been demonstrated to provide better local control, especially in patients undergoing local excision [20]. The reason stands on the fact that multifocality of the disease and radial microscopic spread make effective radical excision difficult. Targeted or systemic immunotherapy as well as regional chemotherapy has been described to improve overall survival in patients with pelvic recurrences [21–23]. Molecular analysis of recurrence melanoma is an important factor in determining which type of therapy should be adopted [24]. However, better local control is ineffective when distant spread has occurred early in the natural history of the disease.

Interestingly, race resulted to be associated with prognosis. In particular, Spanish people showed a more than double hazard ratio of death as compared to African Americans. Although this result might be intriguing, we do not have sufficient data to discuss it, given the lack of genetic analyses regarding our series. Probably, both genetic and environmental factors may play a role.

#### **3. Appendiceal neuroendocrine tumors**

Current surgical strategy for primary neuroendocrine tumors of the appendix is mostly based on tumor size. Right hemicolectomy is warranted for neuroendocrine

#### *Appendiceal Neuroendocrine Tumors and Anorectal Melanoma DOI: http://dx.doi.org/10.5772/intechopen.90434*

In addition, we inquired the prognostic value of locoregional metastatic lymph nodes and the impact of lymphadenectomy on overall survival. To better understand the role of lymph node metastasis on prognosis, we introduced the concept of lymph node ratio, defined as the ratio between metastatic lymph nodes and total lymph nodes harvested. This was necessary to avoid bias related to the extent of lymphadenectomy. In our series, performing lymphadenectomy did not improve survival (P = 0.904). This could be due to early tumor spread to distant sites, thus overcoming the potential benefits of local control. Sentinel lymph node biopsy has not proven to be useful in anorectal melanoma due to the low rate of positive findings, despite the presence of more distant metastases [13]. Therefore, lymph node spread of anorectal melanoma is

Size of the tumor did not affect survival (P = 0.519), although it was previously associated with an increased risk of mesorectal and mesenteric lymph node metastases in anorectal melanoma [14]. Gender (P = 0.707) and age of the patient at time of diagnosis (P = 0.150) did not affect survival as well. Interestingly, ethnicity was found to be an independent predictor of survival (P = 0.019). Specifically, American Indian/Alaskan Native and Asian/Pacific Islander (other) ethnicity showed a

Radical surgery is the best option for cure and should be the goal of treatment [15, 16]. Optimal surgical strategies need to balance the need for radical excision including lymphadenectomy against increasing operative morbidity. Consistently with the recent literature, the type of surgical intervention was not a significant prognostic factor (P = 0.183). The fundamental dilemma regarding the treatment of anorectal melanoma is the choice between abdominoperineal/anterior resection and local wide excision. Previous studies suggested that aggressive treatment could provide better overall results by achieving local oncological control of the disease. More recently, another trend of treatment has been emerging. According to

Matsuda et al. [17], no significant differences between the two options of treatment in terms of overall survival were apparent. Abdominoperineal resection has failed to show any advantage in terms of survival, adding a higher morbidity and poorer quality of life. Thus, local excision has now become the standard of treatment. In case of tumor recurrence, abdominoperineal or anterior resection can be performed

Radiation therapy did not influence prognosis (P = 0.864), although it has been demonstrated to provide better local control, especially in patients undergoing local excision [20]. The reason stands on the fact that multifocality of the disease and radial microscopic spread make effective radical excision difficult. Targeted or systemic immunotherapy as well as regional chemotherapy has been described to improve overall survival in patients with pelvic recurrences [21–23]. Molecular analysis of recurrence melanoma is an important factor in determining which type of therapy should be adopted [24]. However, better local control is ineffective when

Interestingly, race resulted to be associated with prognosis. In particular, Spanish people showed a more than double hazard ratio of death as compared to African Americans. Although this result might be intriguing, we do not have sufficient data to discuss it, given the lack of genetic analyses regarding our series. Probably, both

Current surgical strategy for primary neuroendocrine tumors of the appendix is mostly based on tumor size. Right hemicolectomy is warranted for neuroendocrine

distant spread has occurred early in the natural history of the disease.

genetic and environmental factors may play a role.

**3. Appendiceal neuroendocrine tumors**

**106**

far less predictable than, for example, the carcinoma of the breast.

worse outcome.

*Tumor Progression and Metastasis*

as a salvage procedure [18, 19].

tumors larger than 2 cm in diameter, whereas appendectomy alone is performed for tumors smaller than 1 cm. Patients affected by neuroendocrine tumors with a diameter of 1–2 cm are candidates for hemicolectomy in case of invasion of the cecum or mesoappendix or infiltration of the lymph-vascular system [25]. This treatment algorithm was introduced on the basis of retrospective outcome data provided by Moertel and his colleagues. The disease is usually quite indolent, and overall survival is good [26] (**Table 2**).

At present, there is no proof of survival benefits of right hemicolectomy compared to appendectomy alone. In one of our studies, we wanted to verify whether 2 cm is a good cutoff value for identifying the best candidates for right hemicolectomy. The indication for such a procedure in patients with neuroendocrine tumors larger than 2 cm in diameter stands on the augmented risk of visceral lymph node involvement. In fact, tumor size is a predictor of nodal spread [27]. Assuming that there may be a progression from positive lymph nodes to distant metastases, hemicolectomy is recommended to achieve oncologic radicality. It has been argued that a more extended procedure may have a staging value, but not an actual impact on survival [28].

Our data showed that the type of surgical procedure did not reach statistical significance (P = 0.513), proving that an extended procedure does not confer a survival advantage. Such findings and the indolent course of the disease suggest that formal right hemicolectomy should be performed in young healthy patients, whereas those burdened with comorbidities can be treated with appendectomy without affecting oncologic outcomes. In other words, tumor size greater than 2 cm should not be considered an absolute indication for right hemicolectomy.

In another study, we focused on the natural history of metastatic lymph nodes and their clinical impact for primary pure and mixed neuroendocrine tumors of the appendix (**Figure 2**). The rationale for the surgical treatment is based on the risk of lymph node spread. However, the role of such an event on the natural history of the disease is not clear. First, the survival curve of our populations showed that pure carcinoids have a better prognosis than those with mixed variants (P < 0.001). After controlling for age, sex, tumor size, surgical intervention, and lymph nodes rate, a Cox proportional hazards model showed that histology was an independent predictor of overall survival (P = 0.004). This suggested that pure and mixed carcinoids differ with respect to their biological aggressiveness. For that reason, we analyzed patients having either pure or mixed carcinoids as two distinct series.


#### **Table 2.**

*Cox regression models for neuroendocrine tumors.*

related to molecular biology. However, these are the best data available, when it is

Tumor growth and spread are complex processes. Rare diseases are the most difficult to analyze, due to controversial issues and lack of data. Moreover, morphologic data retrieved from large databases do not always provide accurate results regarding the biologic aggressiveness and survival. Therefore, molecular biology markers and genetic profiling should be the basis of future investigations.

not feasible to design randomized prospective studies.

*Appendiceal Neuroendocrine Tumors and Anorectal Melanoma*

*DOI: http://dx.doi.org/10.5772/intechopen.90434*

\*, Renato Pietroletti<sup>2</sup>

\*Address all correspondence to: marco.clementi@univaq.it

L'Aquila, San Salvatore Hospital, L'Aquila, Italy

provided the original work is properly cited.

, Andrea Ciarrocchi<sup>2</sup>

1 Department of Biotechnological and Applied Clinical Sciences, University of

2 Surgical Coloproctology University of L'Aquila, Hospital Val Vibrata-Sant'Omero

3 Unit of Pathology Fondazione Universitaria A Gemelli, Catholic University of

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Federica d'Ascanio<sup>2</sup>

,

**4. Conclusion**

**Author details**

Marco Clementi<sup>1</sup>

(TE), Italy

Rome, Italy

**109**

Guido Rindi<sup>3</sup> and Francesco Carlei<sup>1</sup>

**Figure 2.** *Survival curve for patients affected by neuroendocrine tumors, according to lymph node status.*

Age and surgical intervention (less than right hemicolectomy compared to hemicolectomy or more extended procedure) were found to be independent prognostic factors for both pure (P < 0.001 and P < 0.001) and mixed carcinoids (P = 0.029 and P = 0.019). In the latter group, tumor size (P < 0.001) was another independent predictor of survival. It is well established that the biological behavior of mixed neuroendocrine tumors can somewhat resemble that of adenocarcinoma, therefore showing a more aggressive behavior. Lymph node rate was found to have a strong independent negative impact on survival for both pure (P = 0.039) and mixed neuroendocrine tumors (P < 0.001). Metastatic spread to lymph nodes is thus of major importance to both groups. The presence of metastatic nodes largely affects overall survival and represents a reliable clinical hallmark of the aggressiveness of these tumors.

Right hemicolectomy or a more extended procedure exerted a significant protective effect with pure neuroendocrine tumors and a negative effect with mixed neuroendocrine tumors. This controversial result could be related to the higher frequency of distant metastases in the mixed group, although we were unable to test that idea because of the limitations of the SEER database.

Our studies however suffer from several limitations due to their retrospective nature and to well-known shortcomings of the SEER database. Some data were missing, thus limiting the numerosity of the populations. Moreover, the SEER database provides only a certain type of variable and no entries regarding aspects related to molecular biology. However, these are the best data available, when it is not feasible to design randomized prospective studies.

### **4. Conclusion**

Tumor growth and spread are complex processes. Rare diseases are the most difficult to analyze, due to controversial issues and lack of data. Moreover, morphologic data retrieved from large databases do not always provide accurate results regarding the biologic aggressiveness and survival. Therefore, molecular biology markers and genetic profiling should be the basis of future investigations.

#### **Author details**

Age and surgical intervention (less than right hemicolectomy compared to hemicolectomy or more extended procedure) were found to be independent prognostic factors for both pure (P < 0.001 and P < 0.001) and mixed carcinoids (P = 0.029 and P = 0.019). In the latter group, tumor size (P < 0.001) was another independent predictor of survival. It is well established that the biological behavior of mixed neuroendocrine tumors can somewhat resemble that of adenocarcinoma, therefore showing a more aggressive behavior. Lymph node rate was found to have a strong independent negative impact on survival for both pure (P = 0.039) and mixed neuroendocrine tumors (P < 0.001). Metastatic spread to lymph nodes is thus of major importance to both groups. The presence of metastatic nodes largely affects overall survival and represents a reliable clinical hallmark of the aggressive-

*Survival curve for patients affected by neuroendocrine tumors, according to lymph node status.*

Right hemicolectomy or a more extended procedure exerted a significant protective effect with pure neuroendocrine tumors and a negative effect with mixed neuroendocrine tumors. This controversial result could be related to the higher frequency of distant metastases in the mixed group, although we were unable to test

Our studies however suffer from several limitations due to their retrospective nature and to well-known shortcomings of the SEER database. Some data were missing, thus limiting the numerosity of the populations. Moreover, the SEER database provides only a certain type of variable and no entries regarding aspects

that idea because of the limitations of the SEER database.

ness of these tumors.

**108**

**Figure 2.**

*Tumor Progression and Metastasis*

Marco Clementi<sup>1</sup> \*, Renato Pietroletti<sup>2</sup> , Andrea Ciarrocchi<sup>2</sup> , Federica d'Ascanio<sup>2</sup> , Guido Rindi<sup>3</sup> and Francesco Carlei<sup>1</sup>

1 Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, San Salvatore Hospital, L'Aquila, Italy

2 Surgical Coloproctology University of L'Aquila, Hospital Val Vibrata-Sant'Omero (TE), Italy

3 Unit of Pathology Fondazione Universitaria A Gemelli, Catholic University of Rome, Italy

\*Address all correspondence to: marco.clementi@univaq.it

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Ciarrocchi A, Pietroletti R, Carlei F, Amicucci G. Extensive surgery and lymphadenectomy do not improve survival in primary melanoma of the anorectum: Results from analysis of a large database (SEER). Colorectal Diseases. Feb 2016;**19**(2):158-164

[2] Ciarrocchi A, Pietroletti R, Carlei F, Necozione S, Amicucci G. Propensity adjusted appraisal of the surgical strategy for appendiceal carcinoids. Techniques in Coloproctology. Jan 2014; **19**(1):35-41

[3] Ciarrocchi A, Pietroletti R, Carlei F, Amicucci G. Clinical significance of metastatic lymph nodes in the gut of patients with pure and mixed primary appendiceal carcinoids. Diseases of the Colon and Rectum. Jun 2016;**59**(6): 508-512

[4] Ciarrocchi A, Pietroletti R, Carlei F, Amicucci G. Outcome of anal and rectal melanoma: Has site of origin a prognostic value? Analysis of 287 patients. European Surgery. Oct 2015; **47**(5):262-265

[5] Thibault C, Sagar P, Nivatvongs S, Ilstrup DM, Wolff BG. Anorectal melanoma: An incurable disease? Diseases of the Colon and Rectum. 1997; **40**:661-668

[6] Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: A summary of 84,836 cases from the past decade. The American College of Surgeons Commission on cancer and the American Cancer Society. Cancer. 1998; **83**:1664-1678

[7] Lachiewicz AM, Berwick M, Wiggins CL, Thomas NE. Survival differences between patients with scalp or neck melanoma and those with melanoma of other sites in the

surveillance, epidemiology, and end results (SEER) program. Archives of Dermatology. 2008;**144**:515-521

[15] Nilsson PJ, Ragnarsson‐Olding BK. Importance of clear resection margins in anorectal malignant melanoma. The British Journal of Surgery. 2010;**97**:

*DOI: http://dx.doi.org/10.5772/intechopen.90434*

*Appendiceal Neuroendocrine Tumors and Anorectal Melanoma*

[22] Guadagni S, Fiorentini G, Clementi M, Palumbo G, Masedu F, Deraco M, et al. MGMT methylation correlates with melphalan pelvic

[23] Guadagni S, Fiorentini G,

[24] Guadagni S, Fiorentini G, Clementi M, Palumbo G, Palumbo P, Chiominto A, et al. Does locoregional chemotherapy still matter in the treatment of advanced pelvic melanoma? International Journal of Molecular Sciences. 2017;**18**(11):2382

[25] Pape UF, Perren A, Niederle B, Gross D, Gress T, Costa F, et al. ENETS

Neuroendocrinology. 2012;**95**:135-156

Nagorney DM, Dockerty MB. Carcinoid tumor of the appendix: Treatment and prognosis. The New England Journal of

[27] Groth SS, Virnig BA, Al‐Refaie WB, Jarosek SL, Jensen EH, Tuttle TM. Appendiceal carcinoid tumors:

Predictors of lymph node metastasis and the impact of right hemicolectomy on survival. Journal of Surgical Oncology.

[28] Bamboat ZM, Berger DL. Is right hemicolectomy for 2.0-cm appendiceal carcinoids justified? Archives of Surgery. 2006;**142**:349-352

consensus guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and appendix including

[26] Moertel CG, Weiland LH,

Medicine. 1987;**317**:1699-1701

2011;**103**:39-45

goblet cell carcinomas.

2017;**215**:114-124

perfusion survival in stage III melanoma patients: A pilot study. Melanoma Research. 2017;**27**(5):439-447

Clementi M, Palumbo G, Chiominto A, Cappelli S, et al. Melphalan hypoxic perfusion with hemophiltration for melanoma locoregional metastases in the pelvis. Journal of Surgical Research.

[16] Choi BM, Kim HR, Yun HR, Choi SH, Cho YB, Kim HC, et al. Treatment outcomes of anorectal melanoma. Journal of the Korean Society of Coloproctology. 2011;**27**:

[17] Matsuda A, Miyashita M, Matsumoto S, Takahashi G, Matsutani T, Yamada T, et al.

[18] Bullard KM, Tuttle TM, Rothenberger DA, Madoff RD, Baxter NN, Finne CO, et al. Surgical therapy for anorectal melanoma. Journal of the American College of Surgeons.

[19] Belli F, Gallino GF, Vullo SL, Mariani L, Poiasina E, Leo E. Melanoma of the anorectal region: The experience of the National Cancer Institute of Milano. European Journal of Surgical

Meterissian SH, Dunn KB. Anorectal melanoma: Diagnosis and treatment. Diseases of the Colon and Rectum. 2011;

Fiorentini G, Clementi M, Marsili L, Giordano AV, et al. Surgical versus percutaneous isolated pelvic perfusion

Oncology. 2009;**35**:757-762

[20] Meguerditchian AN,

[21] Guadagni S, Palumbo G,

(IPP) for advanced melanoma: Comparison in terms of melphalan pharmacokinetic pelvic bio-availability. BMC Research Notes. 2017;**10**:411

**54**:638-644

**111**

2015;**261**:670-677

2003;**196**:206-211

Abdominoperineal resection provides better local control but equivalent overall survival to local excision of anorectal malignant melanoma: A systematic review. Annals of Surgery.

98-103

27-30

[8] Smyth EC, Flavin M, Barbi A, Bogdatch K, Wolchok JD, Chapman PB, et al. Memorial Sloan-Kettering Cancer Center (MSKCC) single institutional vulvovaginal mucosal melanoma (VVMM) experience from 1995 to 2010. The European Journal of Cancer. 2011; **47**:661

[9] Cagir B, Whiteford MH, Topham A, Rakinic J, Fry RD. Changing epidemiology of anorectal melanoma. Diseases of the Colon and Rectum. 1999; **42**:1203-1208

[10] Bello DM, Smyth E, Perez D, Khan S, Temple LK, Ariyan CE, et al. Anal versus rectal melanoma: Does site of origin predict outcome? Diseases of the Colon and Rectum. 2013;**56**:150-157

[11] Pessaux P, Pocard M, Elias D, Duvillard P, Avril MF, Zimmerman P, et al. Surgical management of primary anorectal melanoma. The British Journal of Surgery. 2004;**244**:1183-1187

[12] Yeh JJ, Shia J, Hwu WJ, Busam KJ, Paty PB, Guillem JG, et al. The role of abdominoperineal resection as surgical therapy for anorectal melanoma. The Annals of Surgery. 2006;**244**:1012-1017

[13] Kelly P, Zagars GK, Cormier JN, Ross MI, Guadagnolo BA. Sphinctersparing local excision and hypofractionated radiation therapy for anorectal melanoma: A 20-year experience. Cancer. 2011;**117**:4747-4755

[14] Wang M, Zhang Z, Zhu J, Sheng W, Lian P, Liu F, et al. Tumour diameter is a predictor of mesorectal and mesenteric lymph node metastases in anorectal melanoma. Colorectal Disease. 2013;**15**:1086-1092

*Appendiceal Neuroendocrine Tumors and Anorectal Melanoma DOI: http://dx.doi.org/10.5772/intechopen.90434*

[15] Nilsson PJ, Ragnarsson‐Olding BK. Importance of clear resection margins in anorectal malignant melanoma. The British Journal of Surgery. 2010;**97**: 98-103

**References**

**19**(1):35-41

508-512

**47**(5):262-265

**40**:661-668

**83**:1664-1678

**110**

[1] Ciarrocchi A, Pietroletti R, Carlei F, Amicucci G. Extensive surgery and lymphadenectomy do not improve survival in primary melanoma of the anorectum: Results from analysis of a large database (SEER). Colorectal Diseases. Feb 2016;**19**(2):158-164

*Tumor Progression and Metastasis*

surveillance, epidemiology, and end results (SEER) program. Archives of Dermatology. 2008;**144**:515-521

[8] Smyth EC, Flavin M, Barbi A, Bogdatch K, Wolchok JD, Chapman PB, et al. Memorial Sloan-Kettering Cancer Center (MSKCC) single institutional vulvovaginal mucosal melanoma

**47**:661

**42**:1203-1208

(VVMM) experience from 1995 to 2010. The European Journal of Cancer. 2011;

[9] Cagir B, Whiteford MH, Topham A,

epidemiology of anorectal melanoma. Diseases of the Colon and Rectum. 1999;

[10] Bello DM, Smyth E, Perez D, Khan S, Temple LK, Ariyan CE, et al. Anal versus rectal melanoma: Does site of origin predict outcome? Diseases of the Colon and Rectum. 2013;**56**:150-157

[11] Pessaux P, Pocard M, Elias D, Duvillard P, Avril MF, Zimmerman P, et al. Surgical management of primary anorectal melanoma. The British Journal

of Surgery. 2004;**244**:1183-1187

[12] Yeh JJ, Shia J, Hwu WJ, Busam KJ, Paty PB, Guillem JG, et al. The role of abdominoperineal resection as surgical therapy for anorectal melanoma. The Annals of Surgery. 2006;**244**:1012-1017

[13] Kelly P, Zagars GK, Cormier JN, Ross MI, Guadagnolo BA. Sphincter-

hypofractionated radiation therapy for anorectal melanoma: A 20-year

experience. Cancer. 2011;**117**:4747-4755

[14] Wang M, Zhang Z, Zhu J, Sheng W, Lian P, Liu F, et al. Tumour diameter is

mesenteric lymph node metastases in anorectal melanoma. Colorectal Disease.

sparing local excision and

a predictor of mesorectal and

2013;**15**:1086-1092

Rakinic J, Fry RD. Changing

[2] Ciarrocchi A, Pietroletti R, Carlei F, Necozione S, Amicucci G. Propensity adjusted appraisal of the surgical strategy for appendiceal carcinoids. Techniques in Coloproctology. Jan 2014;

[3] Ciarrocchi A, Pietroletti R, Carlei F, Amicucci G. Clinical significance of metastatic lymph nodes in the gut of patients with pure and mixed primary appendiceal carcinoids. Diseases of the Colon and Rectum. Jun 2016;**59**(6):

[4] Ciarrocchi A, Pietroletti R, Carlei F, Amicucci G. Outcome of anal and rectal

[5] Thibault C, Sagar P, Nivatvongs S, Ilstrup DM, Wolff BG. Anorectal melanoma: An incurable disease? Diseases of the Colon and Rectum. 1997;

[6] Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: A summary of 84,836 cases from the past decade. The American College of Surgeons Commission on cancer and the

American Cancer Society. Cancer. 1998;

[7] Lachiewicz AM, Berwick M, Wiggins CL, Thomas NE. Survival differences between patients with scalp or neck melanoma and those with melanoma of other sites in the

melanoma: Has site of origin a prognostic value? Analysis of 287 patients. European Surgery. Oct 2015; [16] Choi BM, Kim HR, Yun HR, Choi SH, Cho YB, Kim HC, et al. Treatment outcomes of anorectal melanoma. Journal of the Korean Society of Coloproctology. 2011;**27**: 27-30

[17] Matsuda A, Miyashita M, Matsumoto S, Takahashi G, Matsutani T, Yamada T, et al. Abdominoperineal resection provides better local control but equivalent overall survival to local excision of anorectal malignant melanoma: A systematic review. Annals of Surgery. 2015;**261**:670-677

[18] Bullard KM, Tuttle TM, Rothenberger DA, Madoff RD, Baxter NN, Finne CO, et al. Surgical therapy for anorectal melanoma. Journal of the American College of Surgeons. 2003;**196**:206-211

[19] Belli F, Gallino GF, Vullo SL, Mariani L, Poiasina E, Leo E. Melanoma of the anorectal region: The experience of the National Cancer Institute of Milano. European Journal of Surgical Oncology. 2009;**35**:757-762

[20] Meguerditchian AN, Meterissian SH, Dunn KB. Anorectal melanoma: Diagnosis and treatment. Diseases of the Colon and Rectum. 2011; **54**:638-644

[21] Guadagni S, Palumbo G, Fiorentini G, Clementi M, Marsili L, Giordano AV, et al. Surgical versus percutaneous isolated pelvic perfusion (IPP) for advanced melanoma: Comparison in terms of melphalan pharmacokinetic pelvic bio-availability. BMC Research Notes. 2017;**10**:411

[22] Guadagni S, Fiorentini G, Clementi M, Palumbo G, Masedu F, Deraco M, et al. MGMT methylation correlates with melphalan pelvic perfusion survival in stage III melanoma patients: A pilot study. Melanoma Research. 2017;**27**(5):439-447

[23] Guadagni S, Fiorentini G, Clementi M, Palumbo G, Chiominto A, Cappelli S, et al. Melphalan hypoxic perfusion with hemophiltration for melanoma locoregional metastases in the pelvis. Journal of Surgical Research. 2017;**215**:114-124

[24] Guadagni S, Fiorentini G, Clementi M, Palumbo G, Palumbo P, Chiominto A, et al. Does locoregional chemotherapy still matter in the treatment of advanced pelvic melanoma? International Journal of Molecular Sciences. 2017;**18**(11):2382

[25] Pape UF, Perren A, Niederle B, Gross D, Gress T, Costa F, et al. ENETS consensus guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and appendix including goblet cell carcinomas. Neuroendocrinology. 2012;**95**:135-156

[26] Moertel CG, Weiland LH, Nagorney DM, Dockerty MB. Carcinoid tumor of the appendix: Treatment and prognosis. The New England Journal of Medicine. 1987;**317**:1699-1701

[27] Groth SS, Virnig BA, Al‐Refaie WB, Jarosek SL, Jensen EH, Tuttle TM. Appendiceal carcinoid tumors: Predictors of lymph node metastasis and the impact of right hemicolectomy on survival. Journal of Surgical Oncology. 2011;**103**:39-45

[28] Bamboat ZM, Berger DL. Is right hemicolectomy for 2.0-cm appendiceal carcinoids justified? Archives of Surgery. 2006;**142**:349-352

**113**

**Chapter 6**

**Abstract**

patient prognosis.

neurotransmitters

**1. Introduction**

cancer in their life course [2].

Neuroimmunoendocrine

**Keywords:** neuroimmunoendocrine network, breast cancer,

and Breast Cancer

*Rocío Alejandra Ruiz-Manzano,* 

*and Jorge Morales-Montor*

Interactions in Tumorigenesis

*Tania de Lourdes Ochoa-Mercado, Mariana Segovia-Mendoza,* 

*Karen Elizabeth Nava-Castro, Margarita Isabel Palacios-Arreola* 

Organism homeostasis is regulated through the tri-directional relationships between immune, endocrine, and nervous systems. These relationships are established by a complex network of chemokines, cytokines, hormones (peptide and non-peptide), neurotransmitters, and neurohormones that act onto its target cells, through common receptors. Despite initial attribution of the exclusive action of each molecule group (neurotransmitters, hormones, and cytokines), to the function of one specific system (nervous, endocrine, and immune, respectively), ligand and receptor pleiotropy and redundancy showed the multidirectional communication between systems. Cancer and metabolic and autoimmune diseases get established when homeostasis is disrupted. These interactions act in different disease levels, in cancer, since initial immunosurveillance phase, until immunosubversion and metastasis, in all cases is crucial for tumor development, cancer outcome, and

neuroimmunoregulation, endocrinoimmune regulation, tumor, cytokines, steroids,

Cancer is one of the most common health issues worldwide. According to the World Health Organization (WHO), in 2018 18,078,957 new cases and 9,555,027 related deaths were reported. Breast cancer is the second leading cancer, after lung cancer, but is the first in women incidence and prevalence [1]. An estimation made in 2009 calculated that one out of eight American women could develop breast

There are several risk factors associated with breast cancer. The first and most important is gender; as mentioned before, women get breast cancer more often than males. Other risk factors are early menarche, first terminal pregnancy after 30 years old, late menopause, nulliparity, no breastfeeding, overweight or obesity, family or personal history of breast cancer, alcohol abuse, consumption of hormone oral

#### **Chapter 6**

## Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer

*Rocío Alejandra Ruiz-Manzano,* 

*Tania de Lourdes Ochoa-Mercado, Mariana Segovia-Mendoza, Karen Elizabeth Nava-Castro, Margarita Isabel Palacios-Arreola and Jorge Morales-Montor*

#### **Abstract**

Organism homeostasis is regulated through the tri-directional relationships between immune, endocrine, and nervous systems. These relationships are established by a complex network of chemokines, cytokines, hormones (peptide and non-peptide), neurotransmitters, and neurohormones that act onto its target cells, through common receptors. Despite initial attribution of the exclusive action of each molecule group (neurotransmitters, hormones, and cytokines), to the function of one specific system (nervous, endocrine, and immune, respectively), ligand and receptor pleiotropy and redundancy showed the multidirectional communication between systems. Cancer and metabolic and autoimmune diseases get established when homeostasis is disrupted. These interactions act in different disease levels, in cancer, since initial immunosurveillance phase, until immunosubversion and metastasis, in all cases is crucial for tumor development, cancer outcome, and patient prognosis.

**Keywords:** neuroimmunoendocrine network, breast cancer, neuroimmunoregulation, endocrinoimmune regulation, tumor, cytokines, steroids, neurotransmitters

#### **1. Introduction**

Cancer is one of the most common health issues worldwide. According to the World Health Organization (WHO), in 2018 18,078,957 new cases and 9,555,027 related deaths were reported. Breast cancer is the second leading cancer, after lung cancer, but is the first in women incidence and prevalence [1]. An estimation made in 2009 calculated that one out of eight American women could develop breast cancer in their life course [2].

There are several risk factors associated with breast cancer. The first and most important is gender; as mentioned before, women get breast cancer more often than males. Other risk factors are early menarche, first terminal pregnancy after 30 years old, late menopause, nulliparity, no breastfeeding, overweight or obesity, family or personal history of breast cancer, alcohol abuse, consumption of hormone oral

#### **Figure 1.**

*Nervous regulation during breast tumor growth and metastasis. Sympathetic fibers and blood vessels infiltrate tumor and are responsible for tumor communication with the nervous system. Sympathetic fibers release norepinephrine in tumor, which binds to β2-adrenergic receptor in the tumor cell membrane and activates adenylate cyclase through G-protein-coupled receptor subunit α. AC promotes ATP-cAMP conversion, and cAMP activates protein kinase A and exchange protein activated by adenylyl cyclase. PKA phosphorylates β-adrenergic receptor kinase, CREB, and GATA1 transcription factors. BARK recruits β-arrestin, inhibits β-adrenergic signal, and activates Src kinase, which in turn activates STAT3 and downstream focal adhesion kinase. FAK enhances migration. CREB, GATA1, and STAT3 promote VEGF, IL-6, IL-8, and MMP-9 expression, enhancing angiogenesis, migration, and invasion. In the other pathway activated through cAMP, EPAC also promotes cell migration. Stress stimulates hypothalamic-pituitary-adrenocortical axis, and the hypothalamus secretes corticotropin-releasing factor (CRF) that stimulates the adrenocorticotropic hormone (ACTH) secretion into blood vessels and systemic circulation. ACTH in adrenal gland cortex stimulates cortisol release. In tumor, cortisol binds to glucocorticoid receptor (GCR) in breast cancer cells and promotes the expression of MAPK phosphatase-1 (MKP1) and serine/threonine protein kinase 1 (SGK1) and other genes related to cell survival and apoptosis protection.*

contraceptives or menopausal hormone therapy, and environmental pollution with compounds such as bisphenols and phthalates, among others [3–5].

To classify breast cancer, the actualized TNM anatomical staging system categorizes primary tumor (T), regional lymph node invasion (N), and distant metastases (M), to determine the actual stage group of breast cancer. This classification is very useful, not only for diagnosis and prognosis but also for treatment. In addition to the anatomical staging system, factor-based prognostic stage groups that include tumor grade (histological), hormone receptor status, and a multigene panel status (when is available) were added in the 2017 TNM meeting [2, 3, 6].

Hormone receptor status takes into account the presence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) in tumor mammary cells. There are some characteristics that determine the status of the tumor, such as anatomical localization, tumor grade, hormone receptor status, and, with it, the prognostic and treatment of breast cancer [6].

A normal breast is composed of mammary glands (lobules and ducts), fibrous connective and adipose tissues, blood and lymph vessels, lymph nodes, nerves, and ligaments [7]. Duct branches form each mammary gland epithelium whose caliber is decreased until it forms ductules that flow into lobes [7, 8]. The epithelium is formed by luminal epithelial cells and basal epithelial cells, also known as myoepithelial cells, adjacent to the basement membrane [9]. Proliferation and apoptosis of mammary epithelia are regulated by the extracellular matrix (ECM) signals [10]. Either lobules or ducts can become dysplastic and eventually neoplastic, a phenomenon also regulated by ECM, and adjacent cell interactions, including stromal,

**115**

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

vascular, fibroblasts, and immune cells, may favor the transformation and uncon-

In breast cancer progression, there are three phases: benign disease and noninvasive and invasive cancer (**Figure 1**). By definition, benign disease and noninvasive cancer share the same condition, where transformed cells do not trespass the basal membrane but are differentiated by histological grade. An example of this is the lobular carcinoma in situ, classified as a benign tumor, with associated risk in developing carcinoma [6]. On the other hand, in the invasive cancer, cells migrate through basal membrane to stromal breast and/or adjacent tissues and organs [11]. Several interactions determine different outcomes in tumor development, including the interactions among nervous, immune, and endocrine systems with the tumor. Next, we described the overall function of these systems in breast cancer

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

trolled proliferation of cells in the breast tissue.

and finally the interactions between them.

**2. System interactions in breast cancer**

*2.1.1 Sympathetic nervous system*

immune system [13].

cancer cells [13, 14].

*2.1.2 Adrenergic signaling in tumors*

going to be performed [21].

**2.1 The role of the nervous system on tumor growth and metastasis**

Nervous regulation during cancer is mainly mediated through the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenocortical (HPA) axis [12].

The sympathetic nervous system regulates the organism's vital involuntary functions and is in charge of the "fight-or-flight" response in danger and stressful situations and modulates the connection between the central nervous system and

SNS nerve fibers emerge from the thoracolumbar spinal cord, innervate different tissues, and produce norepinephrine [12, 14]. Nowadays, it is known that sympathetic nerve fibers innervate the bone marrow, thymus (primary lymphoid organs), spleen and lymph nodes (secondary lymphoid organs), and mucosa- (MALT), bronchus- (BALT), and gut- (GALT) associated lymphoid tissues [15–17]. Epinephrine arrives to the target tissue through blood circulation after being produced in the adrenal gland. Both norepinephrine and epinephrine bind with different affinities to adrenergic receptors α (α1/α2) and β (β1/β2/β3) in target cells in different tissues and organs, such as the heart, brain, adipose tissue, mammary gland, ovaries, prostate, lymphoid tissue, bones, and different types of

These adrenergic receptors are expressed differentially. In smooth muscles α1AR and α2AR can be found, although the latter also is expressed in platelets and neurons [14]. Regarding β receptors, of which noradrenaline is the main ligand, β1AR can be found in the adipose tissue and cardiac muscle. And β2-adrenergic receptors (β2ARs) are expressed in tumor and immune cells, in the heart, lung tissue, and smooth muscle. At least, β3AR can be found in the adipose tissue. Either β1AR, β2AR,

or β3AR activates cAMP and in turn stimulates protein kinase A (PKA) [14].

β2AR expression has been detected in breast cancer cell lines, with different densities among them [18], and also in human breast tumor biopsies [19, 20]. Therefore, β2AR expression should be considered if a β2AR agonist treatment is

#### *Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

vascular, fibroblasts, and immune cells, may favor the transformation and uncontrolled proliferation of cells in the breast tissue.

In breast cancer progression, there are three phases: benign disease and noninvasive and invasive cancer (**Figure 1**). By definition, benign disease and noninvasive cancer share the same condition, where transformed cells do not trespass the basal membrane but are differentiated by histological grade. An example of this is the lobular carcinoma in situ, classified as a benign tumor, with associated risk in developing carcinoma [6]. On the other hand, in the invasive cancer, cells migrate through basal membrane to stromal breast and/or adjacent tissues and organs [11].

Several interactions determine different outcomes in tumor development, including the interactions among nervous, immune, and endocrine systems with the tumor. Next, we described the overall function of these systems in breast cancer and finally the interactions between them.

#### **2. System interactions in breast cancer**

#### **2.1 The role of the nervous system on tumor growth and metastasis**

Nervous regulation during cancer is mainly mediated through the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenocortical (HPA) axis [12].

#### *2.1.1 Sympathetic nervous system*

*Tumor Progression and Metastasis*

**Figure 1.**

contraceptives or menopausal hormone therapy, and environmental pollution with

*Nervous regulation during breast tumor growth and metastasis. Sympathetic fibers and blood vessels infiltrate tumor and are responsible for tumor communication with the nervous system. Sympathetic fibers release norepinephrine in tumor, which binds to β2-adrenergic receptor in the tumor cell membrane and activates adenylate cyclase through G-protein-coupled receptor subunit α. AC promotes ATP-cAMP conversion, and cAMP activates protein kinase A and exchange protein activated by adenylyl cyclase. PKA phosphorylates β-adrenergic receptor kinase, CREB, and GATA1 transcription factors. BARK recruits β-arrestin, inhibits β-adrenergic signal, and activates Src kinase, which in turn activates STAT3 and downstream focal adhesion kinase. FAK enhances migration. CREB, GATA1, and STAT3 promote VEGF, IL-6, IL-8, and MMP-9 expression, enhancing angiogenesis, migration, and invasion. In the other pathway activated through cAMP, EPAC also promotes cell migration. Stress stimulates hypothalamic-pituitary-adrenocortical axis, and the hypothalamus secretes corticotropin-releasing factor (CRF) that stimulates the adrenocorticotropic hormone (ACTH) secretion into blood vessels and systemic circulation. ACTH in adrenal gland cortex stimulates cortisol release. In tumor, cortisol binds to glucocorticoid receptor (GCR) in breast cancer cells and promotes the expression of MAPK phosphatase-1 (MKP1) and serine/threonine protein kinase 1 (SGK1) and other genes related to cell survival and apoptosis protection.*

To classify breast cancer, the actualized TNM anatomical staging system categorizes primary tumor (T), regional lymph node invasion (N), and distant metastases (M), to determine the actual stage group of breast cancer. This classification is very useful, not only for diagnosis and prognosis but also for treatment. In addition to the anatomical staging system, factor-based prognostic stage groups that include tumor grade (histological), hormone receptor status, and a multigene panel status

Hormone receptor status takes into account the presence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) in tumor mammary cells. There are some characteristics that determine the status of the tumor, such as anatomical localization, tumor grade, hormone receptor status, and, with it, the prognostic and treatment of breast cancer [6]. A normal breast is composed of mammary glands (lobules and ducts), fibrous connective and adipose tissues, blood and lymph vessels, lymph nodes, nerves, and ligaments [7]. Duct branches form each mammary gland epithelium whose caliber is decreased until it forms ductules that flow into lobes [7, 8]. The epithelium is formed by luminal epithelial cells and basal epithelial cells, also known as myoepithelial cells, adjacent to the basement membrane [9]. Proliferation and apoptosis of mammary epithelia are regulated by the extracellular matrix (ECM) signals [10]. Either lobules or ducts can become dysplastic and eventually neoplastic, a phenomenon also regulated by ECM, and adjacent cell interactions, including stromal,

compounds such as bisphenols and phthalates, among others [3–5].

(when is available) were added in the 2017 TNM meeting [2, 3, 6].

**114**

The sympathetic nervous system regulates the organism's vital involuntary functions and is in charge of the "fight-or-flight" response in danger and stressful situations and modulates the connection between the central nervous system and immune system [13].

SNS nerve fibers emerge from the thoracolumbar spinal cord, innervate different tissues, and produce norepinephrine [12, 14]. Nowadays, it is known that sympathetic nerve fibers innervate the bone marrow, thymus (primary lymphoid organs), spleen and lymph nodes (secondary lymphoid organs), and mucosa- (MALT), bronchus- (BALT), and gut- (GALT) associated lymphoid tissues [15–17]. Epinephrine arrives to the target tissue through blood circulation after being produced in the adrenal gland. Both norepinephrine and epinephrine bind with different affinities to adrenergic receptors α (α1/α2) and β (β1/β2/β3) in target cells in different tissues and organs, such as the heart, brain, adipose tissue, mammary gland, ovaries, prostate, lymphoid tissue, bones, and different types of cancer cells [13, 14].

These adrenergic receptors are expressed differentially. In smooth muscles α1AR and α2AR can be found, although the latter also is expressed in platelets and neurons [14]. Regarding β receptors, of which noradrenaline is the main ligand, β1AR can be found in the adipose tissue and cardiac muscle. And β2-adrenergic receptors (β2ARs) are expressed in tumor and immune cells, in the heart, lung tissue, and smooth muscle. At least, β3AR can be found in the adipose tissue. Either β1AR, β2AR, or β3AR activates cAMP and in turn stimulates protein kinase A (PKA) [14].

#### *2.1.2 Adrenergic signaling in tumors*

β2AR expression has been detected in breast cancer cell lines, with different densities among them [18], and also in human breast tumor biopsies [19, 20]. Therefore, β2AR expression should be considered if a β2AR agonist treatment is going to be performed [21].

It is known that β2AR signaling regulates proliferation and tumor cell invasion; this is evidenced with β2AR blockers and the associated beneficial effect in breast cancer recurrence and bone, lung, and brain metastasis [13, 22]. Interestingly, primary TN tumor cells expressed lesser β2AR mRNA and protein than TN brain metastatic cells from primary breast tumor; these metastatic cells exhibited increased proliferation and migration. In vivo and in vitro, invasive and metastatic potential of these cells was diminished when treated with propranolol [22].

There have been different mechanisms described that regulate invasion and metastasis through β2AR signaling in tumor cells. Norepinephrine, epinephrine, or agonists bind β2AR and activate adenylate cyclase (AC) through G-proteincoupled receptor subunit α (Gαs). AC activation promotes ATP-cAMP conversion (**Figure 1**) and Ca2+ intracellular increase [23]. In highly metastatic breast tumor cells (MDA-MB-231HM), another G-protein subunit, Gβγ, also promotes intracellular Ca2+ augmentation through β2AR signaling. Either through Gβγ or Gαs, cAMP activates effector PKA and exchange protein activated by adenylyl cyclase (EPAC) and inhibits pERK1/pERK2; therefore, cell proliferation is mediated independently by ERK phosphorylation [23]. PKA phosphorylates CREB/ATF, GATA1 transcription factors, and β-adrenergic receptor kinase (BARK). BARK recruits β-arrestin which activates Src kinase, and this activates STAT3 [24]. Focal adhesion kinase (FAK) activated by STAT3 enhances migration and apoptosis resistance. CREB/ATF, GATA1, and STAT3 promote VEGF, IL-6, IL-8, and MMP-9 expression and enhance angiogenesis, migration, and invasion (**Figure 1**) [24]. Meanwhile, in breast tumor cells (MCF-7 and MDA-MB-231) treated with an EPAC inhibitor (ESI-09), migration inhibition was found associated with mislocalization of the A-kinase anchoring protein 9 (AKAP9); therefore, EPAC also promotes cell migration [25].

Another way in which β2AR signaling stimulates tumor growth is through promoting DNA damage and p53-associated apoptosis suppression [26].

#### *2.1.3 Tumor innervation*

During tumor initial innervation, nearby healthy tissue provides sympathetic fibers that infiltrate the periphery of the growing tumor [27], in response to neurotropic factors secreted by tumor cells, such as neurotrophic growth factor (NGF) [28] and brain-derived neurotrophic factor (BDNF) [29]. These factors increase nerve fiber growth and thereby tumor innervation [28]. Tumor innervation is associated with vasculature; therefore, together with nerve fibers, blood vessels go through the tumor mass [30] (**Figure 1**). Sympathetic innervation in tumor is the main catecholamine source [30, 31]; this is evidenced because its local concentration is higher than plasma [31]. In this sense, innervation is a feature of tumor microenvironment associated with tumor aggressiveness [28].

Therefore, β-receptor antagonists could have an important role in the development of new therapies that diminish metastasis risk and promote a slow tumor progression.

#### *2.1.4 HPA axis*

The HPA axis also plays an important role in stress response in mammals. In the hypothalamus, the paraventricular nucleus neurons secrete corticotropin-releasing factor into hypophyseal portal blood. CRF stimulates the release of adrenocorticotropic hormone by the anterior pituitary gland, to the blood vessels and systemic circulation. When ACTH reaches adrenal glands, the cortex stimulates the corticosterone production (in rodents) or cortisol (humans) (**Figure 1**) [32].

**117**

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

and glucocorticoids exert different effects in these cells.

their survival capabilities, favoring tumor growth.

*2.1.5 Stress and tumor growth*

Cortisol and corticosterone (glucocorticoids) exert their effects through glucocorticoid receptor. Different immune and breast cancer cells express this receptor,

GCR in breast cancer cells, especially in triple-negative lines (MDA-MB-231), promotes the expression of genes related to cell survival and apoptosis protection, for example, MAPK phosphatase-1 and serine/threonine protein kinase 1 (**Figure 1**) [33, 34]. In addition, the activation of the GCR induces the expression of genes related to cell survival, adhesion, and EMT in a premalignant breast [35]. Correspondingly, in xenograft MDA-MB-231 breast tumors in mice pre-treated with systemic dexamethasone, the paclitaxel treatment effect was inhibited [36]. Therefore, glucocorticoids protect breast cancer cells from apoptosis and enhance

Stress is largely linked to cancer development. Stressor exposition and SNS activation promote noradrenaline release into the tumor that regulates tumor progression [30]. In animals under social isolation (a stress experimental model), there is an increased tumor size and reduced survival [37]. Also in other stress models,

During metastatic establishment, β2AR overexpression enhances cell proliferation and invasion, to ensure metastatic establishment, and, maybe, that is why in primary tumor resection, the surgery induces stress and releases norepinephrine and epinephrine that enhance tumor metastasis. Thus, the use of treatments that antagonize the effect of these neurotransmitters may reduce metastasis [22]. Thus, nervous control of tumor growth is regulated by the sympathetic and HPA systems. The sympathetic regulation is via tumor innervation with sympathetic fibers and the adrenergic signaling in tumor, through local and peripheral catecholamine (epinephrine and norepinephrine) production and the β2AR expression in tumor and immune cells. Meanwhile, HPA system regulates glucocorticoid production, which enhances tumor cell survival and downmodulates inflammatory

increased tumor progression and metastasis have been observed [38, 39].

response, thus enhancing tumor growth and metastasis (**Figure 1**).

Tumorigenesis usually courses a slow development during years, and the immune response depends on the different stages of the disease and the tumor

Every day, immune cells detect and destroy transformed cells, in a phenomenon called immunosurveillance. But, when transformed cells evade elimination mechanisms (immunoescape), survive and proliferate. At this point, tumor can remain in a state of dormancy, partially by the action of immune cells, but when the balance between stromal, immune, and tumor cells with their secretory products leads to local immunosuppression, the immunosubversion is established, and the tumor

Dendritic cells are antigen-presenting cells (APCs) that recognize, uptake, process, and present antigens to different cells including T cells. In the immunosurveillance

**3. Immune response in mammary tumors**

**3.1 Immune innate cells in mammary tumors**

microenvironment [40].

grows (**Figure 2**) [41, 42].

*3.1.1 Dendritic cells*

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

#### *Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

Cortisol and corticosterone (glucocorticoids) exert their effects through glucocorticoid receptor. Different immune and breast cancer cells express this receptor, and glucocorticoids exert different effects in these cells.

GCR in breast cancer cells, especially in triple-negative lines (MDA-MB-231), promotes the expression of genes related to cell survival and apoptosis protection, for example, MAPK phosphatase-1 and serine/threonine protein kinase 1 (**Figure 1**) [33, 34]. In addition, the activation of the GCR induces the expression of genes related to cell survival, adhesion, and EMT in a premalignant breast [35]. Correspondingly, in xenograft MDA-MB-231 breast tumors in mice pre-treated with systemic dexamethasone, the paclitaxel treatment effect was inhibited [36]. Therefore, glucocorticoids protect breast cancer cells from apoptosis and enhance their survival capabilities, favoring tumor growth.

#### *2.1.5 Stress and tumor growth*

*Tumor Progression and Metastasis*

promotes cell migration [25].

*2.1.3 Tumor innervation*

It is known that β2AR signaling regulates proliferation and tumor cell invasion; this is evidenced with β2AR blockers and the associated beneficial effect in breast cancer recurrence and bone, lung, and brain metastasis [13, 22]. Interestingly, primary TN tumor cells expressed lesser β2AR mRNA and protein than TN brain metastatic cells from primary breast tumor; these metastatic cells exhibited increased proliferation and migration. In vivo and in vitro, invasive and metastatic

There have been different mechanisms described that regulate invasion and metastasis through β2AR signaling in tumor cells. Norepinephrine, epinephrine, or agonists bind β2AR and activate adenylate cyclase (AC) through G-proteincoupled receptor subunit α (Gαs). AC activation promotes ATP-cAMP conversion (**Figure 1**) and Ca2+ intracellular increase [23]. In highly metastatic breast tumor cells (MDA-MB-231HM), another G-protein subunit, Gβγ, also promotes intracellular Ca2+ augmentation through β2AR signaling. Either through Gβγ or Gαs, cAMP activates effector PKA and exchange protein activated by adenylyl cyclase (EPAC) and inhibits pERK1/pERK2; therefore, cell proliferation is mediated independently by ERK phosphorylation [23]. PKA phosphorylates CREB/ATF, GATA1 transcription factors, and β-adrenergic receptor kinase (BARK). BARK recruits β-arrestin which activates Src kinase, and this activates STAT3 [24]. Focal adhesion kinase (FAK) activated by STAT3 enhances migration and apoptosis resistance. CREB/ATF, GATA1, and STAT3 promote VEGF, IL-6, IL-8, and MMP-9 expression and enhance angiogenesis, migration, and invasion (**Figure 1**) [24]. Meanwhile, in breast tumor cells (MCF-7 and MDA-MB-231) treated with an EPAC inhibitor (ESI-09), migration inhibition was found associated with mislocalization of the A-kinase anchoring protein 9 (AKAP9); therefore, EPAC also

Another way in which β2AR signaling stimulates tumor growth is through

During tumor initial innervation, nearby healthy tissue provides sympathetic fibers that infiltrate the periphery of the growing tumor [27], in response to neurotropic factors secreted by tumor cells, such as neurotrophic growth factor (NGF) [28] and brain-derived neurotrophic factor (BDNF) [29]. These factors increase nerve fiber growth and thereby tumor innervation [28]. Tumor innervation is associated with vasculature; therefore, together with nerve fibers, blood vessels go through the tumor mass [30] (**Figure 1**). Sympathetic innervation in tumor is the main catecholamine source [30, 31]; this is evidenced because its local concentration is higher than plasma [31]. In this sense, innervation is a feature of tumor

Therefore, β-receptor antagonists could have an important role in the development of new therapies that diminish metastasis risk and promote a slow tumor

The HPA axis also plays an important role in stress response in mammals. In the hypothalamus, the paraventricular nucleus neurons secrete corticotropin-releasing factor into hypophyseal portal blood. CRF stimulates the release of adrenocorticotropic hormone by the anterior pituitary gland, to the blood vessels and systemic circulation. When ACTH reaches adrenal glands, the cortex stimulates the corticos-

promoting DNA damage and p53-associated apoptosis suppression [26].

microenvironment associated with tumor aggressiveness [28].

terone production (in rodents) or cortisol (humans) (**Figure 1**) [32].

potential of these cells was diminished when treated with propranolol [22].

**116**

progression.

*2.1.4 HPA axis*

Stress is largely linked to cancer development. Stressor exposition and SNS activation promote noradrenaline release into the tumor that regulates tumor progression [30]. In animals under social isolation (a stress experimental model), there is an increased tumor size and reduced survival [37]. Also in other stress models, increased tumor progression and metastasis have been observed [38, 39].

During metastatic establishment, β2AR overexpression enhances cell proliferation and invasion, to ensure metastatic establishment, and, maybe, that is why in primary tumor resection, the surgery induces stress and releases norepinephrine and epinephrine that enhance tumor metastasis. Thus, the use of treatments that antagonize the effect of these neurotransmitters may reduce metastasis [22].

Thus, nervous control of tumor growth is regulated by the sympathetic and HPA systems. The sympathetic regulation is via tumor innervation with sympathetic fibers and the adrenergic signaling in tumor, through local and peripheral catecholamine (epinephrine and norepinephrine) production and the β2AR expression in tumor and immune cells. Meanwhile, HPA system regulates glucocorticoid production, which enhances tumor cell survival and downmodulates inflammatory response, thus enhancing tumor growth and metastasis (**Figure 1**).

#### **3. Immune response in mammary tumors**

Tumorigenesis usually courses a slow development during years, and the immune response depends on the different stages of the disease and the tumor microenvironment [40].

Every day, immune cells detect and destroy transformed cells, in a phenomenon called immunosurveillance. But, when transformed cells evade elimination mechanisms (immunoescape), survive and proliferate. At this point, tumor can remain in a state of dormancy, partially by the action of immune cells, but when the balance between stromal, immune, and tumor cells with their secretory products leads to local immunosuppression, the immunosubversion is established, and the tumor grows (**Figure 2**) [41, 42].

#### **3.1 Immune innate cells in mammary tumors**

#### *3.1.1 Dendritic cells*

Dendritic cells are antigen-presenting cells (APCs) that recognize, uptake, process, and present antigens to different cells including T cells. In the immunosurveillance

#### **Figure 2.**

*Immune response in breast tumor development. (1) In immunosurveillance, breast tissue-resident conventional dendritic cells (cDC) capture antigens released by transformed cell after recognition and destruction by cytotoxic cells (NK cells). cDC migrate to peripheric lymph node and as DC type 1 (DC1) or DC type 2 (DC2) present antigens to CD8<sup>+</sup> T cells or CD4<sup>+</sup> T cells, respectively. In lymph nodes T follicular cells activate B lymphocytes into plasma (antibody producer) or B memory cells. After the activation and subsequent proliferation, CD8<sup>+</sup> T cytotoxic and CD4<sup>+</sup> T helper cells migrate. Cytotoxic cells induce apoptosis to transformed cells, and T helper cells produce cytokines and chemokines to enhance cytotoxic effect. (2) In the equilibrium state, transformed cells evade immune recognition and proliferate to hyperplasia (benign disease) and eventually to ductal carcinoma in situ (DCIS). In these phases immune cells are recluted, and cytotoxic cells (CD8<sup>+</sup> , neutrophils, and eosinophils) may eliminate transformed cells in an equilibrium phase. Indirectly, other cells enhance cytotoxic response, for example, M1 macrophages produce IL-12 that enhances dendritic cell antigen presentation to CD8<sup>+</sup> cells. Also mast cells MHC-I<sup>+</sup> stimulate CD8<sup>+</sup> T-cell proliferation. (3) In immunosubversion and metastasis, when invasive ductal carcinoma is established, tumor dendritic cells (tDC) are induced through IL-10, vascular endothelial factor (VEGF), prostaglandin E2 (PGE2), hypoxia, and lactic acid and by direct contact with tumor CTLA4<sup>+</sup> . tDC produce IL-10, which in turn induces their own expansion as well as T regulatory cell (Tregs) proliferation and the inhibition of effector CD4<sup>+</sup> and CD8<sup>+</sup> T cells, Th1 differentiation, and CD8<sup>+</sup> T cells function. Also, IL-10, D vitamin, and cortisol activate M2. M2 macrophages produce IL-4, IL-10, IL-13 (that feedback M2 generation), NGF, and TGF-β that with IDO inhibit cytotoxic NK function. Mast cells secrete VEGF, tryptase, chymase, and IL-8 that enhance metastasis to different organs (lung and bone). Neutrophils may enhance metastasis because they form premetastatic niches that promote tumor cell migration and metastasis establishment.*

phase, dendritic cells resident in the breast tissue sense and capture different antigens released by transformed cells and then migrate to draining lymph nodes, where, as a mature cell, antigens to naïve T cells are present [43–45]. After the activation and subsequent proliferation, the CD8+ T and CD4+ T cells migrate to the site where transformed neoplastic cells reside. The cytotoxic response is carried out mainly by CD8+ T cells and NK cells, which detect and induce apoptosis to transformed cells; meanwhile, CD4+ T helper cells produce cytokines and chemokines that modulate the immune response and recruit other immune cells (**Figure 2**).

Two lineages of dendritic cells are responsible for T-cell priming. The first are DC1s that express chemokine receptor CXR1 and present antigens through MHC-I

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*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

T cells. The second are the DC2s that express CD172a and

T cells [46]. Meanwhile, DC2s (CD11<sup>+</sup>

as the main subset of DC that can induce a strong cytotoxic response against tumor

unclear why. A possibility is an inadequate process of antigen or the nature of tumor antigen. These DC2s cells can be tolerogenic, because they cannot generate an

Three features lead to the induction of suppressive or tumor phenotype DC. The

There are many tumor microenvironment factors that suppress DC activation in vitro, for example, IL-10, vascular endothelial factor, prostaglandin E2, hypoxia, and lactic acid [47]. Another important interaction is when breast tumor and DC are in contact. Chen et al. showed a decreased expression of CD40, CD80, CD86 (costimulatory molecules), HLA-DR, and CD83 and a reduced production of IFN-γ, TNF-α, IL-1β, IL-2, IL-6, and IL-12, in lipopolysaccharide (LPS)-stimulated

When a transformed cell escapes of the immune recognition and destruction, and starts proliferating, it recruits different immune cells and promotes a protumoral and suppressor microenvironment. Among these tumor-recruited cells are DCs, which migrate to local lymph nodes and present tumor antigens to lymphocytes. Meanwhile some recruited DC go to lymph nodes, and another subset of DC remains in tumor and developed suppressor functions through the direct inhibition

and CD8+

production (IL-10) (**Figure 2**) [43, 49]. These DC may have an important role in lymphocyte priming in tumor, associated with the presence of tertiary lymphoid structures (TLS) in breast tumors, specially placed in stroma and with naïve T cells

Neutrophils are polymorphonuclear (PMN) cells and the most abundant leukocyte in human. These cells are responsible for host defense to bacterial, fungal, and viral infections and support wound healing [52]. Neutrophils can phagocyte, form neutrophil extracellular traps (NETs) to eliminate invasive microorganisms, and synthesize and store in cytoplasmic granules neutrophil elastase, cathepsin G, proteinase 3, neutrophil collagenase (MMP-8), gelatinase B (MMP-9), reactive oxygen species (ROS), and antimicrobial peptides [53–55]. Through chemotactic stimuli, neutrophils arrive to the inflammation site and phagocyte the invading microorganism. Thereafter, cytoplasmic granules in the neutrophil get fused with the phagolysosome where the microorganism is destroyed [52]. Under adverse circumstances, neutrophil can release proteinases through microbursts, to the extracellular space, or produce NETs to fix the microorganisms, stop their migra-

first is the presence of tumor cell neoantigens that leads eventually to immunoescape and the failure of immunosurveillance. The second is the degree of DC maturation, in which immature DC acquire a tolerogenic phenotype and generate regulatory T cells. And the third is related to the immune suppression in the tumor microenvironment mediated by other cells and soluble factors. The balance of stimulatory and suppressive signals determines tumor progression and is related to

T cells [43]. DC1s can be lymphoid-resident DC1s

in mice), being the latter mentioned

breast cancer cells. These suppressive

T cells or through suppressive cytokine

T-cell proliferation, Th1 differentiation, and cytotoxic

T cells in lymph nodes, but it is

in mouse)

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

(CD8α in mice) or migratory DC1s (CD103<sup>+</sup>

adequate activation and stimulation [43].

human DC, when co-cultured with CTLA4+

and CD8+

lymphocyte (CTL) function (**Figure 2**) [48].

in tumors that are activated in situ [50, 51].

tion, and concentrate on toxic factors [56].

of the local activation of CD4+

DC inhibit CD4<sup>+</sup>

*3.1.2 Neutrophils*

seem to fail in tumor antigen presentation to CD4<sup>+</sup>

cell tumor phenotype and the interaction among cells [43].

MHC-II (high), to activate CD4+

through the activation of CD8+

preferentially to CD8<sup>+</sup>

#### *Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

preferentially to CD8<sup>+</sup> T cells. The second are the DC2s that express CD172a and MHC-II (high), to activate CD4+ T cells [43]. DC1s can be lymphoid-resident DC1s (CD8α in mice) or migratory DC1s (CD103<sup>+</sup> in mice), being the latter mentioned as the main subset of DC that can induce a strong cytotoxic response against tumor through the activation of CD8+ T cells [46]. Meanwhile, DC2s (CD11<sup>+</sup> in mouse) seem to fail in tumor antigen presentation to CD4+ T cells in lymph nodes, but it is unclear why. A possibility is an inadequate process of antigen or the nature of tumor antigen. These DC2s cells can be tolerogenic, because they cannot generate an adequate activation and stimulation [43].

Three features lead to the induction of suppressive or tumor phenotype DC. The first is the presence of tumor cell neoantigens that leads eventually to immunoescape and the failure of immunosurveillance. The second is the degree of DC maturation, in which immature DC acquire a tolerogenic phenotype and generate regulatory T cells. And the third is related to the immune suppression in the tumor microenvironment mediated by other cells and soluble factors. The balance of stimulatory and suppressive signals determines tumor progression and is related to cell tumor phenotype and the interaction among cells [43].

There are many tumor microenvironment factors that suppress DC activation in vitro, for example, IL-10, vascular endothelial factor, prostaglandin E2, hypoxia, and lactic acid [47]. Another important interaction is when breast tumor and DC are in contact. Chen et al. showed a decreased expression of CD40, CD80, CD86 (costimulatory molecules), HLA-DR, and CD83 and a reduced production of IFN-γ, TNF-α, IL-1β, IL-2, IL-6, and IL-12, in lipopolysaccharide (LPS)-stimulated human DC, when co-cultured with CTLA4+ breast cancer cells. These suppressive DC inhibit CD4<sup>+</sup> and CD8+ T-cell proliferation, Th1 differentiation, and cytotoxic lymphocyte (CTL) function (**Figure 2**) [48].

When a transformed cell escapes of the immune recognition and destruction, and starts proliferating, it recruits different immune cells and promotes a protumoral and suppressor microenvironment. Among these tumor-recruited cells are DCs, which migrate to local lymph nodes and present tumor antigens to lymphocytes. Meanwhile some recruited DC go to lymph nodes, and another subset of DC remains in tumor and developed suppressor functions through the direct inhibition of the local activation of CD4+ and CD8+ T cells or through suppressive cytokine production (IL-10) (**Figure 2**) [43, 49]. These DC may have an important role in lymphocyte priming in tumor, associated with the presence of tertiary lymphoid structures (TLS) in breast tumors, specially placed in stroma and with naïve T cells in tumors that are activated in situ [50, 51].

#### *3.1.2 Neutrophils*

*Tumor Progression and Metastasis*

**118**

CD4+

**Figure 2.**

*stimulate CD8<sup>+</sup>*

*CTLA4<sup>+</sup>*

subsequent proliferation, the CD8+

*migration and metastasis establishment.*

*or DC type 2 (DC2) present antigens to CD8<sup>+</sup>*

*activation and subsequent proliferation, CD8<sup>+</sup>*

*cells are recluted, and cytotoxic cells (CD8<sup>+</sup>*

*produce IL-12 that enhances dendritic cell antigen presentation to CD8<sup>+</sup>*

*(Tregs) proliferation and the inhibition of effector CD4<sup>+</sup>*

response and recruit other immune cells (**Figure 2**).

phase, dendritic cells resident in the breast tissue sense and capture different antigens released by transformed cells and then migrate to draining lymph nodes, where, as a mature cell, antigens to naïve T cells are present [43–45]. After the activation and

T cells migrate to the site where trans-

 *T cells, respectively. In lymph nodes T* 

*, neutrophils, and eosinophils) may eliminate transformed cells* 

 *T helper cells migrate. Cytotoxic* 

 *cells. Also mast cells MHC-I<sup>+</sup>*

 *T cells, Th1 differentiation, and CD8<sup>+</sup>*

T

T and CD4+

*Immune response in breast tumor development. (1) In immunosurveillance, breast tissue-resident conventional dendritic cells (cDC) capture antigens released by transformed cell after recognition and destruction by cytotoxic cells (NK cells). cDC migrate to peripheric lymph node and as DC type 1 (DC1)* 

*follicular cells activate B lymphocytes into plasma (antibody producer) or B memory cells. After the* 

 *T cells or CD4<sup>+</sup>*

*cells induce apoptosis to transformed cells, and T helper cells produce cytokines and chemokines to enhance cytotoxic effect. (2) In the equilibrium state, transformed cells evade immune recognition and proliferate to hyperplasia (benign disease) and eventually to ductal carcinoma in situ (DCIS). In these phases immune* 

*in an equilibrium phase. Indirectly, other cells enhance cytotoxic response, for example, M1 macrophages* 

*carcinoma is established, tumor dendritic cells (tDC) are induced through IL-10, vascular endothelial factor (VEGF), prostaglandin E2 (PGE2), hypoxia, and lactic acid and by direct contact with tumor* 

*. tDC produce IL-10, which in turn induces their own expansion as well as T regulatory cell* 

*T cells function. Also, IL-10, D vitamin, and cortisol activate M2. M2 macrophages produce IL-4, IL-10, IL-13 (that feedback M2 generation), NGF, and TGF-β that with IDO inhibit cytotoxic NK function. Mast cells secrete VEGF, tryptase, chymase, and IL-8 that enhance metastasis to different organs (lung and bone). Neutrophils may enhance metastasis because they form premetastatic niches that promote tumor cell* 

 *T cytotoxic and CD4<sup>+</sup>*

 *T-cell proliferation. (3) In immunosubversion and metastasis, when invasive ductal* 

 *and CD8<sup>+</sup>*

formed neoplastic cells reside. The cytotoxic response is carried out mainly by CD8+

cells and NK cells, which detect and induce apoptosis to transformed cells; meanwhile,

T helper cells produce cytokines and chemokines that modulate the immune

Two lineages of dendritic cells are responsible for T-cell priming. The first are DC1s that express chemokine receptor CXR1 and present antigens through MHC-I

Neutrophils are polymorphonuclear (PMN) cells and the most abundant leukocyte in human. These cells are responsible for host defense to bacterial, fungal, and viral infections and support wound healing [52]. Neutrophils can phagocyte, form neutrophil extracellular traps (NETs) to eliminate invasive microorganisms, and synthesize and store in cytoplasmic granules neutrophil elastase, cathepsin G, proteinase 3, neutrophil collagenase (MMP-8), gelatinase B (MMP-9), reactive oxygen species (ROS), and antimicrobial peptides [53–55]. Through chemotactic stimuli, neutrophils arrive to the inflammation site and phagocyte the invading microorganism. Thereafter, cytoplasmic granules in the neutrophil get fused with the phagolysosome where the microorganism is destroyed [52]. Under adverse circumstances, neutrophil can release proteinases through microbursts, to the extracellular space, or produce NETs to fix the microorganisms, stop their migration, and concentrate on toxic factors [56].

Some authors mentioned a neutrophil polarization similar to classical activated macrophages (M1) and alternative activated macrophages (M2), named N1 and N2; also, neutrophils present different degrees of activation, and according to it, there are four types of PMN: naïve circulating, mildly activated, activated (acute inflammation), and highly activated (sepsis, unsuccessful phagocytosis). Among mildly activated neutrophils are tumor-associated neutrophils (TANs) that in mice express CD11b+ and Ly-6Ghi markers [52, 57].

Cellular cytotoxic role in cancer is traditionally associated with cytotoxic T cells, NK cells, and macrophages, and little attention is focused on neutrophils, but nowadays, reports are linking neutrophils to different stages of cancer [56]. Naïve neutrophils are recruited to the tumor, mainly by macrophages, and display the same repertory to kill a microorganism for the destruction of a tumor cell, and eventually a pro-host or pro-tumoral effect in situ is developed (**Figure 2**) [52].

The presence or absence and quantity of neutrophils within the tumor, associated with tumor type, determine the prognostic of the disease [57]. In an orthotopic murine model of breast cancer with 4T1 (metastatic cells) and 4T07 (nonmetastatic cells), more neutrophils within 4T1 tumors in comparison to 4T07 tumors were detected. Also in 4T1 tumors, higher mRNA expression of CXCL1, a neutrophil-recruiting chemokine, was detected [58]. For example, a pre-metastatic niche has been reported in remote organs, where neutrophils come together and shape a microenvironment that favored the migration of tumor cells (**Figure 2**) [59]. One of the mechanisms that shape a pre-metastatic niche could be mediated by NETs, as has been demonstrated in an experiment where neutrophils were co-cultured with 4T1 cells in a transwell chamber assay and produced more NETs than neutrophils co-cultured with 4T07 cells. In the same report, authors proved the presence of NET structures located next to 4T1 cells, which was assumed to contribute to support metastasis [58].

#### *3.1.3 Eosinophils*

Eosinophils are granulocyte cells that can be found in the spleen, lymph nodes, thymus, and gastrointestinal tract [60] and are able to phagocyte and act as antigen-presenting cell in lymph nodes, through the expression of major compatibility complex and costimulatory molecules (CD40, CD80, CD86) [61]. Furthermore, eosinophils produce cytokines, chemokines, growth factors, lipid mediators, and cytotoxic granules (**Table 1**).

Eosinophils are usually related to parasitic infections, especially helminthiases, in which eosinophilia is a characteristic feature. But recently their role in cancer has become relevant. Depending on its cytokine profile production, a new classification of eosinophils has been proposed; the eosinophils that secrete Th1 cytokines (IL-8, TNF-α, and IFN-γ) are called E1, and the ones that produce Th2 cytokines (IL-4, IL-5, and IL-13) are E2. Despite this classification, in breast cancer it is unknown if the eosinophils secrete any of those cytokines, although blood eosinophilia is related to a good or poor prognostic of the disease, depending on the cancer type [79]. Related to eosinophil infiltration into the breast cancer tumor, the presence of eosinophils is one indicator of increased survival, maybe because these cells participate in host-tumor interactions and because of their cytotoxic activity [83].

#### *3.1.4 Mast cells*

Mast cells originate in bone marrow, then circulate and migrate to tissues, and in nearby blood vessels mature into effector cells, in which along with DC and macrophages, are the first cells to recognize and interact with pathogens or allergens [84, 85]. Inside mast cells there are granules with preformed substances that included histamine

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*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

Cytokines IL-8 Supports endothelial cell

TNF-α Pro-inflammatory

IL-4 Promotes a Th2 profile,

IL-5 Stimulates proliferation,

IL-13 Regulates IgE synthesis

TGF-β Regulates cellular

**General functions Cancer-related features**

Breast cancer tissue expresses higher concentrations of IL-8 than normal tissue[63]

Chronic expression sustains breast tumor growth [64]

A higher tumor stage correlates with higher serum levels and lymph node metastasis

Recruitment of eosinophils to tumor

cells to tumor

growth [69]

angiogenesis

cancer [70]

Recruitment of immune

tissue, overexpression of TGF-α induces hyperplasia and proliferation [68]

In early stages suppresses tumor progression but in late stages favors tumor

pancreatic, and prostate

Promotes tumor growth in breast cancer Is associated with poor prognosis [72]

associated with poor prognosis in urothelial

cancer [73]

polarization of B regulatory cells [74]

[67]

proliferation and survival

B-cell differentiation, and IgE isotype switch

differentiation, recruitment, and activation of eosinophils

and mucus production

Chemoattractant for eosinophils

Chemokines secreted by eosinophils to recruit other immune cells

TGF-α In mammary mouse

differentiation, proliferation, apoptosis, and migration [69]

VEGF Promotes angiogenesis Promotes tumor

Leukotrienes Pro-inflammatory Elevated levels in colon,

Shifts Th2 response and downregulates CD8+ T-cell activity and tumor cell antigen presentation

Thromboxanes Overexpression is

Lipoxins (lipoxin A4) Suppressing the

[71]

[65]

[66]

[62]

cytokine

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

Chemokines CCL3, CCL5, CCL11,

Growth factors

Lipid mediators CCL24; CXCL8, CCL7

CCL3, CCL5, CCL11, CCL17, CCL22, CCL23; CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11

Prostaglandin

E2


*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

*Tumor Progression and Metastasis*

and Ly-6Ghi markers [52, 57].

CD11b+

*3.1.3 Eosinophils*

cytotoxic granules (**Table 1**).

Some authors mentioned a neutrophil polarization similar to classical activated macrophages (M1) and alternative activated macrophages (M2), named N1 and N2; also, neutrophils present different degrees of activation, and according to it, there are four types of PMN: naïve circulating, mildly activated, activated (acute inflammation), and highly activated (sepsis, unsuccessful phagocytosis). Among mildly activated neutrophils are tumor-associated neutrophils (TANs) that in mice express

Cellular cytotoxic role in cancer is traditionally associated with cytotoxic T cells, NK cells, and macrophages, and little attention is focused on neutrophils, but nowadays, reports are linking neutrophils to different stages of cancer [56]. Naïve neutrophils are recruited to the tumor, mainly by macrophages, and display the same repertory to kill a microorganism for the destruction of a tumor cell, and eventually a pro-host or pro-tumoral effect in situ is developed (**Figure 2**) [52]. The presence or absence and quantity of neutrophils within the tumor, associated with tumor type, determine the prognostic of the disease [57]. In an orthotopic murine model of breast cancer with 4T1 (metastatic cells) and 4T07 (nonmetastatic cells), more neutrophils within 4T1 tumors in comparison to 4T07 tumors were detected. Also in 4T1 tumors, higher mRNA expression of CXCL1, a neutrophil-recruiting chemokine, was detected [58]. For example, a pre-metastatic niche has been reported in remote organs, where neutrophils come together and shape a microenvironment that favored the migration of tumor cells (**Figure 2**) [59]. One of the mechanisms that shape a pre-metastatic niche could be mediated by NETs, as has been demonstrated in an experiment where neutrophils were co-cultured with 4T1 cells in a transwell chamber assay and produced more NETs than neutrophils co-cultured with 4T07 cells. In the same report, authors proved the presence of NET structures located next to 4T1

cells, which was assumed to contribute to support metastasis [58].

Eosinophils are granulocyte cells that can be found in the spleen, lymph nodes, thymus, and gastrointestinal tract [60] and are able to phagocyte and act as antigen-presenting cell in lymph nodes, through the expression of major compatibility complex and costimulatory molecules (CD40, CD80, CD86) [61]. Furthermore, eosinophils produce cytokines, chemokines, growth factors, lipid mediators, and

Eosinophils are usually related to parasitic infections, especially helminthiases, in which eosinophilia is a characteristic feature. But recently their role in cancer has become relevant. Depending on its cytokine profile production, a new classification of eosinophils has been proposed; the eosinophils that secrete Th1 cytokines (IL-8, TNF-α, and IFN-γ) are called E1, and the ones that produce Th2 cytokines (IL-4, IL-5, and IL-13) are E2. Despite this classification, in breast cancer it is unknown if the eosinophils secrete any of those cytokines, although blood eosinophilia is related to a good or poor prognostic of the disease, depending on the cancer type [79]. Related to eosinophil infiltration into the breast cancer tumor, the presence of eosinophils is one indicator of increased survival, maybe because these cells partici-

pate in host-tumor interactions and because of their cytotoxic activity [83].

Mast cells originate in bone marrow, then circulate and migrate to tissues, and in nearby blood vessels mature into effector cells, in which along with DC and macrophages, are the first cells to recognize and interact with pathogens or allergens [84, 85]. Inside mast cells there are granules with preformed substances that included histamine

**120**

*3.1.4 Mast cells*


*CCL5 or RANTES, regulated on activation normal T expressed and secreted; CCL3 or MIP-1α, macrophage inflammatory protein; CCL7 or MCP-3, monocyte-specific chemokine protein; TGF-α, transforming growth factor α; TGF-β, transforming growth factor β; VEGF, vascular endothelial cell growth factor; GM-CSF, granulocyte macrophage colony-stimulating factor*

#### **Table 1.**

*Functions and related cancer features of cytokines and chemokines.*

(vasodilator), heparin (anticoagulant), serotonin, dopamine, tryptase, and chymase. The mast cell activation stimulates the production of leukotrienes and cytokines (e.g., TNF-α) and the cell degranulation [86].

Mast cells may perform both immunosuppressive and inflammatory functions depending on the interaction with the effector or regulatory immune cells [85]. For example, the expression of MHC-II in mast cells can be induced by the exposure of LPS and IFN-γ, and the interaction of MHC-II-expressing mast cells with effector T cells induces the expansion of Treg cells; meanwhile, mast cells expressing MHC-I can enhance the proliferation of CD8+ T cells [87, 88]. Besides direct contact with T cell, an alternative activation mechanism could be the mast cell production of IFN. This cytokine enhances the proliferation of T cells, depending on the number of mast cells within the microenvironment, for example, at low numbers proliferation is enhanced, but in higher numbers proliferation is inhibited, in a mechanism mediated by the H1 histamine receptor [89, 90].

On the other hand, for naïve B-cell survival and activation and for plasma cell proliferation and differentiation, mast cells interact with B cell through superficial CD40L. Also for the B-cell synthesis of IgE, the secretion of IL-4 and IL-13, among others, by mast cells is necessary [85].

Despite mast cells releasing angiogenic factors, as VEGF, chymase, tryptase, heparin, fibroblast growth factor-2 (FGF-2), IL-8, TGF-β, and nerve growth factor, the inhibition of mast cell degranulation did not change the mammary tumor vascularization, but that does not mean that degranulation may enhance angiogenesis [91]. In this regard, a study informed that tryptase did not stimulate the proliferation of MDA-MB-231 breast cancer cells but indeed enhances its migration and invasion [92]. In malignant breast carcinomas, there are more tryptasecontaining mast cells detected through immunohistochemistry assay than that in benign lesions [93]. Given the prominent angiogenic character of mast cells, to date, their presence has not been strongly associated with the enhancement of the tumor

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*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

mast cells may improve tumor vascularization and metastasis.

vascularization, and it is not clear if comorbidities favoring increased quantities of

Macrophages are mononuclear phagocytic cells that according to environment signals turn into different phenotypes. One of these phenotypes is the classically activated macrophages or M1, induced by Toll-like receptors (TLR) and IFN-γ. These cells are characterized by the expression of IL-12, the major histocompatibility complex class II (MHC-II) and TNF-α, and ROS and nitric oxide (NO) production and are associated with microorganisms and cell destruction [94]. The second phenotype is the "alternatively or selectively" activated macrophages, which are characterized by the secretion of IL-4, IL-10, IL-13, and TGF-β and the expression of arginase-1 and VEGF and are related to wound healing and humoral response [94, 95].

Macrophages, monocytes, and DC can be found in tumor microenvironment,

TAMs are related to immunosuppressive features, for example, low antigenpresenting capability, low tissue remodeling activity, and low toxicity functions that promote tumor growth and metastasis [97]. These immunosuppressive TAMs function as M2 macrophages and are activated by IL-4, IL-10, IL-13, glucocorti-

The innate immune system recognizes and kills infected and transformed cells; NK cells are responsible for this task, through granzyme b-perforin system, TNFrelated apoptosis-inducing ligand (TRAIL), and the expression of CD95 ligand [99]. NK cells produce IFN-γ, granulocyte/macrophage colony-stimulating factor (GM-CSF), and TNF [100] and are one of the main cells in antitumoral response. Depending on the signals that NK cells receive, activation or inhibition receptors

NK cell cytotoxicity is activated by different ligands upregulated during cellular stress, also with the recognition of antibodies in the antibody-dependent cellular toxicity (ADCC) through the expression of CD16 (Fc immunoglobulin fragment low-affinity receptor) and with the detection of cells that underexpressed HLAclass I molecules [101, 103]. In immunosurveillance, tumor cells are detected and destroyed by NK cells, through these mechanisms (**Figure 2**). In immunosubversion, tumor cells evade NK cell recognition, and tumor microenvironment leads to NK cell impairment, through the inhibition of surface-activating receptor expression, such as NKp46 and NKG2D or NKp30 and NKG2D mediated by indoleamine 2,3-dioxygenase (IDO) and TGF-β1, respectively (**Figure 2**) [101, 104, 105].

In breast cancer patients, tumor NK cells possess a more prominent inhibitory phenotype than peripheral NK cells. Also depending on disease progression, for example, in late stages, NK cells lose their cytotoxic activity and express inhibitory

being the macrophages the most abundant phagocytic population. Tumorassociated macrophages (TAMs) are characterized by the cell surface expression of CD68 and have been related to invasion and migration of cancer cells, being a prognostic factor in cancer [95, 96]. Some reports have shown that the density of TAMs in breast cancer samples is related to hormone receptor status, lymph node metastasis, stage, and prognosis. Higher concentrations of TAMs are associated with a poor prognosis, and the worse prognostic group is the one with a high

proportion of CD163 and CD206 (M2 markers) [95].

coids, and vitamin D3 [98].

or coreceptors are expressed [101, 102].

*3.1.6 NK cells*

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

*3.1.5 Macrophages*

vascularization, and it is not clear if comorbidities favoring increased quantities of mast cells may improve tumor vascularization and metastasis.

#### *3.1.5 Macrophages*

*Tumor Progression and Metastasis*

Cytotoxic granules

TNF-α) and the cell degranulation [86].

*Functions and related cancer features of cytokines and chemokines.*

*macrophage colony-stimulating factor*

**Table 1.**

Eosinophil-derived neurotoxin

can enhance the proliferation of CD8+

others, by mast cells is necessary [85].

mediated by the H1 histamine receptor [89, 90].

(vasodilator), heparin (anticoagulant), serotonin, dopamine, tryptase, and chymase. The mast cell activation stimulates the production of leukotrienes and cytokines (e.g.,

Eosinophil cationic protein Tissue remodeling,

Eosinophil peroxidase Related to inflammatory

*CCL5 or RANTES, regulated on activation normal T expressed and secreted; CCL3 or MIP-1α, macrophage inflammatory protein; CCL7 or MCP-3, monocyte-specific chemokine protein; TGF-α, transforming growth factor α; TGF-β, transforming growth factor β; VEGF, vascular endothelial cell growth factor; GM-CSF, granulocyte* 

suppression of T-cell proliferation, mast cell degranulation, and secretion of airway mucus [75]

Major basic protein Tissue damage Cytotoxic effect in human

Cytotoxic activity and chemoattractant of DC, monocytes, neutrophils, mast cells, and T cells [79]

tissue injury [81]

Mast cells may perform both immunosuppressive and inflammatory functions depending on the interaction with the effector or regulatory immune cells [85]. For example, the expression of MHC-II in mast cells can be induced by the exposure of LPS and IFN-γ, and the interaction of MHC-II-expressing mast cells with effector T cells induces the expansion of Treg cells; meanwhile, mast cells expressing MHC-I

T cell, an alternative activation mechanism could be the mast cell production of IFN. This cytokine enhances the proliferation of T cells, depending on the number of mast cells within the microenvironment, for example, at low numbers proliferation is enhanced, but in higher numbers proliferation is inhibited, in a mechanism

On the other hand, for naïve B-cell survival and activation and for plasma cell proliferation and differentiation, mast cells interact with B cell through superficial CD40L. Also for the B-cell synthesis of IgE, the secretion of IL-4 and IL-13, among

Despite mast cells releasing angiogenic factors, as VEGF, chymase, tryptase, heparin, fibroblast growth factor-2 (FGF-2), IL-8, TGF-β, and nerve growth factor, the inhibition of mast cell degranulation did not change the mammary tumor vascularization, but that does not mean that degranulation may enhance angiogenesis [91]. In this regard, a study informed that tryptase did not stimulate the proliferation of MDA-MB-231 breast cancer cells but indeed enhances its migration and invasion [92]. In malignant breast carcinomas, there are more tryptasecontaining mast cells detected through immunohistochemistry assay than that in benign lesions [93]. Given the prominent angiogenic character of mast cells, to date, their presence has not been strongly associated with the enhancement of the tumor

T cells [87, 88]. Besides direct contact with

**General functions Cancer-related features**

Proliferation inhibition in colorectal carcinoma and oral squamous cell carcinoma cell lines, via osmotic lysis [76, 77]

cancer cell lines [78]

Cytotoxic activity in colorectal carcinoma cell

Absent in normal breast tissue but present in breast cancer tumor stroma [82]

line [80]

**122**

Macrophages are mononuclear phagocytic cells that according to environment signals turn into different phenotypes. One of these phenotypes is the classically activated macrophages or M1, induced by Toll-like receptors (TLR) and IFN-γ. These cells are characterized by the expression of IL-12, the major histocompatibility complex class II (MHC-II) and TNF-α, and ROS and nitric oxide (NO) production and are associated with microorganisms and cell destruction [94]. The second phenotype is the "alternatively or selectively" activated macrophages, which are characterized by the secretion of IL-4, IL-10, IL-13, and TGF-β and the expression of arginase-1 and VEGF and are related to wound healing and humoral response [94, 95].

Macrophages, monocytes, and DC can be found in tumor microenvironment, being the macrophages the most abundant phagocytic population. Tumorassociated macrophages (TAMs) are characterized by the cell surface expression of CD68 and have been related to invasion and migration of cancer cells, being a prognostic factor in cancer [95, 96]. Some reports have shown that the density of TAMs in breast cancer samples is related to hormone receptor status, lymph node metastasis, stage, and prognosis. Higher concentrations of TAMs are associated with a poor prognosis, and the worse prognostic group is the one with a high proportion of CD163 and CD206 (M2 markers) [95].

TAMs are related to immunosuppressive features, for example, low antigenpresenting capability, low tissue remodeling activity, and low toxicity functions that promote tumor growth and metastasis [97]. These immunosuppressive TAMs function as M2 macrophages and are activated by IL-4, IL-10, IL-13, glucocorticoids, and vitamin D3 [98].

#### *3.1.6 NK cells*

The innate immune system recognizes and kills infected and transformed cells; NK cells are responsible for this task, through granzyme b-perforin system, TNFrelated apoptosis-inducing ligand (TRAIL), and the expression of CD95 ligand [99]. NK cells produce IFN-γ, granulocyte/macrophage colony-stimulating factor (GM-CSF), and TNF [100] and are one of the main cells in antitumoral response.

Depending on the signals that NK cells receive, activation or inhibition receptors or coreceptors are expressed [101, 102].

NK cell cytotoxicity is activated by different ligands upregulated during cellular stress, also with the recognition of antibodies in the antibody-dependent cellular toxicity (ADCC) through the expression of CD16 (Fc immunoglobulin fragment low-affinity receptor) and with the detection of cells that underexpressed HLAclass I molecules [101, 103]. In immunosurveillance, tumor cells are detected and destroyed by NK cells, through these mechanisms (**Figure 2**). In immunosubversion, tumor cells evade NK cell recognition, and tumor microenvironment leads to NK cell impairment, through the inhibition of surface-activating receptor expression, such as NKp46 and NKG2D or NKp30 and NKG2D mediated by indoleamine 2,3-dioxygenase (IDO) and TGF-β1, respectively (**Figure 2**) [101, 104, 105].

In breast cancer patients, tumor NK cells possess a more prominent inhibitory phenotype than peripheral NK cells. Also depending on disease progression, for example, in late stages, NK cells lose their cytotoxic activity and express inhibitory receptors (NKG2A); meanwhile, in early stages NK cells express activating receptors (NKp30, NKG2D, DNAM-1, and CD16). One of the stroma-derived suppressor factors that induced NK cell function impairment is TGF-β1 [101].

#### **3.2 Immune adaptive cells in mammary tumors**

#### *3.2.1 T lymphocytes*

T lymphocytes are one of the most important cell populations in cancer. The activation of T cells is performed, firstly, through TCR stimulation with its specific antigen, presented in the context of MHC, by a dendritic cell or another professional antigen-presenting cell; secondly, with the binding of "costimulatory" molecules in the dendritic cell; and, thirdly, by the cytokine milieu and soluble factors [106, 107]. In addition, antigen presentation is performed by immature DCs, resulting in a non-responsive or anergic T cells [108]. In breast cancer tertiary lymphoid structures and germinal centers were detected next to tumor in extensively infiltrated tumors. This TLS possesses a similar structure to lymph node, including a T-cell zone with CD3+ /CD4+ T cells and a germinal center with B cells and T follicular helper (Tfh) cells [109].

#### *3.2.2 T helper cells*

Different factors such as the expression of transcription factors, chemokine receptors, signal transduction activators, and the chemokine and cytokine secretion regulate the effector phenotype and function of these cells [107]. Regarding human breast cancer, different effector phenotypes have been reported, for example, through flow cytometry of invasive breast tumors, Tfh, Th1, Th2, Th17, and Tregs were found [109].

#### *3.2.3 T follicular helper (Tfh) cell*

The effector phenotype Tfh cell stays in the lymph node and induces activation and differentiation of affine B cells into plasma or memory cells [110]. But, in advanced stages of invasive breast cancer, CD4+ Tfh cells were detected in the T-cell zone and germinal centers of TLS. This localization is may be due to their function in tumor, because Tfh cells were localized near to B cells [111].

#### *3.2.4 T helper 1 (Th1)*

CD4<sup>+</sup> T helper 1 (Th1) cell differentiation and IFN-γ production are modulated by IL-12 produced by APCs (monocytes/macrophages, DCs, and even NK cells) and IFN-γ (**Figure 2**) [112–114]. Th1 cells express the transcription factor T-bet; secrete IFN-γ, TNF-α, and IL-2; and function as regulators of monocyte activation and T lymphocyte differentiation induction [115, 116]. Th1 cells are associated with early tumor phases, because of their IFN-γ production that activates CD8+ cytotoxic T cells (**Figure 2**) [117]. Therefore, there is an association between improving survival and the infiltration of Th1 and CD8<sup>+</sup> T cells in breast tumors [118].

#### *3.2.5 T helper 2 (Th2)*

A T helper subset related to immunosubversion and tumor progression is the CD4+ T helper 2 (Th2) cells, characterized by the expression of transcription factor GATA3 and the secretion of IL-4, IL-5, IL-10, and IL-13 [121]. Th2 cells are related to

**125**

CD8+

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

nematode response, tissue repair, and antibody production. In breast cancer, Th2 cells have been found in human mammary tumors [109], and IL-13 is reported to be present

Th17 (T helper 17) cells are related to autoimmunity, tissue inflamma-

Tregs are a subset of T helper cells that express Foxp3 transcription factor and have an important role in controlling inflammation and autoimmunity in mouse and man [123]. These cells normally are residents in the secondary lymphoid organs, lung, peripheral blood, gastrointestinal tract, liver, and skin and can be recruited to other tissues, under inflammatory conditions [124]. Tregs are

different mechanisms, for example, the production of tolerogenic cytokines (IL-10, IL-35, and TGF-β), the induction of arginine depletion that leads to T-cell dysfunction, the expression of suppressive molecules (CTLA-4, CD80/CD86), and the direct cytolysis through granzyme b-perforin system and through local consumption of IL-2 (with the constitutive expression of high-affinity receptor

IL-10 is a suppressive cytokine secreted by macrophages, NK cells, NKT cells, B

 cytotoxic T lymphocytes play an important role in adaptive antitumor response; therefore, when tumor immunosubversion is stablished, the cytotoxicity

T cells gets compromised (**Figure 2**). During immunosurveillance, in secondary lymphoid organs (lymph nodes and spleen), APCs present tumor-associated antigens and tumor neoantigens to CTLs, which in the presence of costimulatory and cytokine signals, such as IL-12 (produced by DCs) and IFN-γ (produced by Th1 cells), undergo activation, maturation, and clonal expansion [117, 130]. After, CTLs migrate through the body, search for specific antigen, and kill the tumor antigenspecific cell through IFN-γ release and perforin and granzyme system (**Figure 2**) [117, 131, 132]. Also, through the activation of its receptor, IL-12 promotes the differentiation of effector CD8 cells and inhibits at the same time the development of memory CD8 cells [133, 134]. When effector CTL cells failed in killing target cell and are exposed to persistent antigen stimulation (in chronic infectious diseases or in tumors), CTL express inhibitory cell surface receptors, PD-1, LAG3, TIM3, TIGIT,

T cell exhausted profile is generated; therefore, cytolysis or IFN-γ secretion


prevent autoimmune diseases, and enhance tumor growth (**Figure 2**) [127–129].

T cell (specially Treg cells), that suppress inflammatory responses,

and exert immune suppression through

T cells. During tumor immunosubversion

T cells is IL-2, which is described


tion, and host defense against bacteria, fungi, viruses, and protozoa and play an important role in mucosal immunity [120]. Th17 cells produce IL-17 and IL-22 and express transcription factor RORγt [121]. Regarding Th17 cells in tumor, it is not recognized if they could be induced in tumor or be recruited from other places, but their presence has been detected in breast tumors [109]. Th17 cell tumor infiltration

also in human breast tumors, promoting tumor development (**Figure 2**) [119].

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

mediates an inflammatory microenvironment [122].

, CD127low, CD25hi, and also CTLA+

*3.2.6 T helper 17 (Th17)*

*3.2.7 Regulatory T cells (Tregs)*

CD4<sup>+</sup>

CD4<sup>+</sup>

CD25) [125, 126].

cells, DCs, and CD4+

CD8+

of CD8+

*3.2.8 T cytotoxic lymphocytes (CTLs)*

and CTLA-4, and became exhausted CD8+

not only as a growth factor, secreted by CD4+

mediated through CTLs is inhibited (**Figure 2**) [135]. Another important cytokine related to CD8+

nematode response, tissue repair, and antibody production. In breast cancer, Th2 cells have been found in human mammary tumors [109], and IL-13 is reported to be present also in human breast tumors, promoting tumor development (**Figure 2**) [119].

#### *3.2.6 T helper 17 (Th17)*

*Tumor Progression and Metastasis*

*3.2.1 T lymphocytes*

CD3+

cells [109].

/CD4+

*3.2.2 T helper cells*

were found [109].

*3.2.4 T helper 1 (Th1)*

*3.2.5 T helper 2 (Th2)*

CD4<sup>+</sup>

*3.2.3 T follicular helper (Tfh) cell*

and the infiltration of Th1 and CD8<sup>+</sup>

advanced stages of invasive breast cancer, CD4+

in tumor, because Tfh cells were localized near to B cells [111].

tumor phases, because of their IFN-γ production that activates CD8+

receptors (NKG2A); meanwhile, in early stages NK cells express activating receptors (NKp30, NKG2D, DNAM-1, and CD16). One of the stroma-derived suppressor

T lymphocytes are one of the most important cell populations in cancer. The activation of T cells is performed, firstly, through TCR stimulation with its specific antigen, presented in the context of MHC, by a dendritic cell or another professional antigen-presenting cell; secondly, with the binding of "costimulatory" molecules in the dendritic cell; and, thirdly, by the cytokine milieu and soluble factors [106, 107]. In addition, antigen presentation is performed by immature DCs, resulting in a non-responsive or anergic T cells [108]. In breast cancer tertiary lymphoid structures and germinal centers were detected next to tumor in extensively infiltrated tumors. This TLS possesses a similar structure to lymph node, including a T-cell zone with

T cells and a germinal center with B cells and T follicular helper (Tfh)

Different factors such as the expression of transcription factors, chemokine receptors, signal transduction activators, and the chemokine and cytokine secretion regulate the effector phenotype and function of these cells [107]. Regarding human breast cancer, different effector phenotypes have been reported, for example, through flow cytometry of invasive breast tumors, Tfh, Th1, Th2, Th17, and Tregs

The effector phenotype Tfh cell stays in the lymph node and induces activation and differentiation of affine B cells into plasma or memory cells [110]. But, in

zone and germinal centers of TLS. This localization is may be due to their function

 T helper 1 (Th1) cell differentiation and IFN-γ production are modulated by IL-12 produced by APCs (monocytes/macrophages, DCs, and even NK cells) and IFN-γ (**Figure 2**) [112–114]. Th1 cells express the transcription factor T-bet; secrete IFN-γ, TNF-α, and IL-2; and function as regulators of monocyte activation and T lymphocyte differentiation induction [115, 116]. Th1 cells are associated with early

T cells in breast tumors [118].

cells (**Figure 2**) [117]. Therefore, there is an association between improving survival

A T helper subset related to immunosubversion and tumor progression is the

 T helper 2 (Th2) cells, characterized by the expression of transcription factor GATA3 and the secretion of IL-4, IL-5, IL-10, and IL-13 [121]. Th2 cells are related to

Tfh cells were detected in the T-cell

cytotoxic T

factors that induced NK cell function impairment is TGF-β1 [101].

**3.2 Immune adaptive cells in mammary tumors**

**124**

CD4+

CD4<sup>+</sup> Th17 (T helper 17) cells are related to autoimmunity, tissue inflammation, and host defense against bacteria, fungi, viruses, and protozoa and play an important role in mucosal immunity [120]. Th17 cells produce IL-17 and IL-22 and express transcription factor RORγt [121]. Regarding Th17 cells in tumor, it is not recognized if they could be induced in tumor or be recruited from other places, but their presence has been detected in breast tumors [109]. Th17 cell tumor infiltration mediates an inflammatory microenvironment [122].

#### *3.2.7 Regulatory T cells (Tregs)*

Tregs are a subset of T helper cells that express Foxp3 transcription factor and have an important role in controlling inflammation and autoimmunity in mouse and man [123]. These cells normally are residents in the secondary lymphoid organs, lung, peripheral blood, gastrointestinal tract, liver, and skin and can be recruited to other tissues, under inflammatory conditions [124]. Tregs are CD4<sup>+</sup> , CD127low, CD25hi, and also CTLA+ and exert immune suppression through different mechanisms, for example, the production of tolerogenic cytokines (IL-10, IL-35, and TGF-β), the induction of arginine depletion that leads to T-cell dysfunction, the expression of suppressive molecules (CTLA-4, CD80/CD86), and the direct cytolysis through granzyme b-perforin system and through local consumption of IL-2 (with the constitutive expression of high-affinity receptor CD25) [125, 126].

IL-10 is a suppressive cytokine secreted by macrophages, NK cells, NKT cells, B cells, DCs, and CD4+ T cell (specially Treg cells), that suppress inflammatory responses, prevent autoimmune diseases, and enhance tumor growth (**Figure 2**) [127–129].

#### *3.2.8 T cytotoxic lymphocytes (CTLs)*

CD8+ cytotoxic T lymphocytes play an important role in adaptive antitumor response; therefore, when tumor immunosubversion is stablished, the cytotoxicity of CD8+ T cells gets compromised (**Figure 2**). During immunosurveillance, in secondary lymphoid organs (lymph nodes and spleen), APCs present tumor-associated antigens and tumor neoantigens to CTLs, which in the presence of costimulatory and cytokine signals, such as IL-12 (produced by DCs) and IFN-γ (produced by Th1 cells), undergo activation, maturation, and clonal expansion [117, 130]. After, CTLs migrate through the body, search for specific antigen, and kill the tumor antigenspecific cell through IFN-γ release and perforin and granzyme system (**Figure 2**) [117, 131, 132]. Also, through the activation of its receptor, IL-12 promotes the differentiation of effector CD8 cells and inhibits at the same time the development of memory CD8 cells [133, 134]. When effector CTL cells failed in killing target cell and are exposed to persistent antigen stimulation (in chronic infectious diseases or in tumors), CTL express inhibitory cell surface receptors, PD-1, LAG3, TIM3, TIGIT, and CTLA-4, and became exhausted CD8+ T cells. During tumor immunosubversion CD8+ T cell exhausted profile is generated; therefore, cytolysis or IFN-γ secretion mediated through CTLs is inhibited (**Figure 2**) [135].

Another important cytokine related to CD8+ T cells is IL-2, which is described not only as a growth factor, secreted by CD4+ - and CD8+ -activated T cells, but also as a differentiation inducer for CD8<sup>+</sup> effector cells [115]. CD8<sup>+</sup> T cells cultured with IL-2 presented an upregulation in perforin (Prf1) transcription and a suppressed expression of Bcl6 and IL-7Rα (memory CD8+ markers). Meanwhile, in CD8<sup>+</sup> T cells with deficiency of IL-2 receptor (IL-2Rα or CD25), cell differentiation impairment was shown in vivo, demonstrated with granzyme B and perforin diminished expression and a poor ex vivo cytotoxicity [136].

In regard to CD8<sup>+</sup> T cell antitumor activity, an experiment in tumor from four T1 mammary gland tumor cells in syngeneic mice showed that in mice injected with IL-12, tumor growth was suppressed through an increased CD8+ cell infiltration and production of IFN-γ and the induction of apoptosis of tumor cells [137]. This effect correlates with good prognosis in CD8<sup>+</sup> T cell infiltration in breast tumors in women [138]. With the time, CTLs lose their cytotoxic phenotype and acquired an exhausted phenotype that needs further characterization in breast tumors but is likely to be associated with late stages (triple-negative breast cancer).

#### **4. Endocrine factors related to the development of breast cancer**

Mammary gland epithelium is highly dynamic, characterized by proliferation, differentiation, and apoptosis cycles, regulated in part by hormones. Breast cancer is associated with an abnormal proliferation of epithelial cells, related to genetic mutations and epigenetic modifications in suppressor and DNA repair genes and oncogenes [139].

#### **4.1 Estrogens and progesterone**

During life, the mammary gland development is divided by different stages and modulated by hormones such as estrogens (17β estradiol) and progesterone. These stages are related to sexual development and includes embryonic and prepuberal phase, puberty, pregnancy, lactation, and involution. Epidermal growth factor (EGF) and estrogens that arrive through the breast stroma during puberty induce ductal elongation and branching. Meanwhile, the lobes formed by secretory epithelial cells organized in alveoli develop during gestation and probably in lactation, through the placental lactogens, progesterone, and prolactin signaling [140]. In lactation, milk secretion is promoted by the contraction of rounding epithelium smooth muscle cells mediated by oxytocin [8].

Estrogen effects are regulated through alpha and beta estrogen receptors (ERα and ERβ), both expressed in mammary normal tissue [141]. ERα signaling is responsible for ductal elongation in puberty and the stromal invasion in normal breast tissue [142].

The sharing ERα-ERβ distribution suggests that ERβ may be related to a negative ERα regulation, through antiestrogen or non-habitual effects [143]. The ERα or ERβ receptor dimerization is induced by ligand-receptor union and leads to the formation of homodimers (ERα/α, Erβ/β) or heterodimers (ERα/β). Recently, it was described that the dimer conformation is associated with their function. ERα/α is linked with proliferation induced by estrogen, and ERβ/β homodimer is linked with antiproliferative and pro-apoptotic functions; meanwhile, ERα/β effects are not elucidated as well (**Figure 3**) [144].

Proliferation in breast tumor cells is ligand-dependent in early stages and ligand-independent in late stages. In the estrogen-dependent pathway, cell proliferation is activated through cytoplasmic or membrane estrogen receptors. Intracellular signaling begins with estrogen-receptor union, their consequent translocation to nuclei, where the estrogen-receptor complex binds to specific

**127**

**Figure 3.**

MAPK pathways [145, 147].

factors to promote nearby cell proliferation [148].

prognostic, as well as ERβ tumor expression [150].

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

estrogen-response elements in estrogen-responsive genes or to other transcription factors, such as AP1 or Sp1, in a non-ERE way, functioning as gene transcription co-regulator [145, 146]. Furthermore, estrogen-membrane ER signals through GPR30 and Erk to elicit proliferation (**Figure 3**) [145]. Meanwhile, the estrogenindependent pathway is mediated through ligand binding and activation of growth factor receptors (GFRs), such as epithelial growth factor receptor (EGFR), insulin-like growth factor receptor (IGF), and HER-2, among others. This activation promotes ER phosphorylation and activation through PI3K/AKT and Ras/Raf/

*Endocrine interactions in breast cancer. In the estrogen-dependent pathway, cell proliferation is activated through cytoplasmic or membrane estrogen receptors. Intracellular signaling begins with estrogen-receptor union, their consequent translocation to nuclei, where the estrogen-receptor complex binds to specific estrogenresponse elements (ERE) in estrogen-responsive genes, in a non-ERE way, functioning as gene transcription co-regulator. Furthermore, estrogen-membrane ER signals through GPR30 and Erk to elicit proliferation. Estrogen sources to breast tumor cell are intracrine, endocrine (blood supply), and paracrine (stromal adjacent* 

*cells). Dehydroepiandrosterone (DHEA) and other androstenes inhibit tumor cell proliferation.*

On the other hand, progesterone exerts its action through two receptors (PRA and PRB), both signaling and activating gene transcription [148]. ERα and PR are co-expressed in the mammary gland in 15–30% of epithelial cells [149]. Meanwhile, estradiol and progesterone drive epithelial mammary gland proliferation directly through the hormone-receptor union and have been proposing a second control mechanism in which epithelial cells sense hormone concentrations through their estrogen and progesterone receptors and, in consequence, secrete or not growth

In breast cancer staging, ER and/or PR expression loss is associated with more aggressive tumors, with self-sufficiency of growth signals independently of estrogen or progesterone receptors. Additionally, positive ERα tumor is related to a better

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

#### **Figure 3.**

*Tumor Progression and Metastasis*

In regard to CD8<sup>+</sup>

oncogenes [139].

breast tissue [142].

**4.1 Estrogens and progesterone**

smooth muscle cells mediated by oxytocin [8].

elucidated as well (**Figure 3**) [144].

as a differentiation inducer for CD8<sup>+</sup>

expression of Bcl6 and IL-7Rα (memory CD8+

expression and a poor ex vivo cytotoxicity [136].

effect correlates with good prognosis in CD8<sup>+</sup>

effector cells [115]. CD8<sup>+</sup>

T cell antitumor activity, an experiment in tumor from four T1

IL-2 presented an upregulation in perforin (Prf1) transcription and a suppressed

cells with deficiency of IL-2 receptor (IL-2Rα or CD25), cell differentiation impairment was shown in vivo, demonstrated with granzyme B and perforin diminished

mammary gland tumor cells in syngeneic mice showed that in mice injected with

and production of IFN-γ and the induction of apoptosis of tumor cells [137]. This

women [138]. With the time, CTLs lose their cytotoxic phenotype and acquired an exhausted phenotype that needs further characterization in breast tumors but is

Mammary gland epithelium is highly dynamic, characterized by proliferation, differentiation, and apoptosis cycles, regulated in part by hormones. Breast cancer is associated with an abnormal proliferation of epithelial cells, related to genetic mutations and epigenetic modifications in suppressor and DNA repair genes and

During life, the mammary gland development is divided by different stages and modulated by hormones such as estrogens (17β estradiol) and progesterone. These stages are related to sexual development and includes embryonic and prepuberal phase, puberty, pregnancy, lactation, and involution. Epidermal growth factor (EGF) and estrogens that arrive through the breast stroma during puberty induce ductal elongation and branching. Meanwhile, the lobes formed by secretory epithelial cells organized in alveoli develop during gestation and probably in lactation, through the placental lactogens, progesterone, and prolactin signaling [140]. In lactation, milk secretion is promoted by the contraction of rounding epithelium

Estrogen effects are regulated through alpha and beta estrogen receptors (ERα

The sharing ERα-ERβ distribution suggests that ERβ may be related to a negative ERα regulation, through antiestrogen or non-habitual effects [143]. The ERα or ERβ receptor dimerization is induced by ligand-receptor union and leads to the formation of homodimers (ERα/α, Erβ/β) or heterodimers (ERα/β). Recently, it was described that the dimer conformation is associated with their function. ERα/α is linked with proliferation induced by estrogen, and ERβ/β homodimer is linked with antiproliferative and pro-apoptotic functions; meanwhile, ERα/β effects are not

Proliferation in breast tumor cells is ligand-dependent in early stages and ligand-independent in late stages. In the estrogen-dependent pathway, cell proliferation is activated through cytoplasmic or membrane estrogen receptors. Intracellular signaling begins with estrogen-receptor union, their consequent translocation to nuclei, where the estrogen-receptor complex binds to specific

and ERβ), both expressed in mammary normal tissue [141]. ERα signaling is responsible for ductal elongation in puberty and the stromal invasion in normal

IL-12, tumor growth was suppressed through an increased CD8+

likely to be associated with late stages (triple-negative breast cancer).

**4. Endocrine factors related to the development of breast cancer**

T cells cultured with

cell infiltration

T

markers). Meanwhile, in CD8<sup>+</sup>

T cell infiltration in breast tumors in

**126**

*Endocrine interactions in breast cancer. In the estrogen-dependent pathway, cell proliferation is activated through cytoplasmic or membrane estrogen receptors. Intracellular signaling begins with estrogen-receptor union, their consequent translocation to nuclei, where the estrogen-receptor complex binds to specific estrogenresponse elements (ERE) in estrogen-responsive genes, in a non-ERE way, functioning as gene transcription co-regulator. Furthermore, estrogen-membrane ER signals through GPR30 and Erk to elicit proliferation. Estrogen sources to breast tumor cell are intracrine, endocrine (blood supply), and paracrine (stromal adjacent cells). Dehydroepiandrosterone (DHEA) and other androstenes inhibit tumor cell proliferation.*

estrogen-response elements in estrogen-responsive genes or to other transcription factors, such as AP1 or Sp1, in a non-ERE way, functioning as gene transcription co-regulator [145, 146]. Furthermore, estrogen-membrane ER signals through GPR30 and Erk to elicit proliferation (**Figure 3**) [145]. Meanwhile, the estrogenindependent pathway is mediated through ligand binding and activation of growth factor receptors (GFRs), such as epithelial growth factor receptor (EGFR), insulin-like growth factor receptor (IGF), and HER-2, among others. This activation promotes ER phosphorylation and activation through PI3K/AKT and Ras/Raf/ MAPK pathways [145, 147].

On the other hand, progesterone exerts its action through two receptors (PRA and PRB), both signaling and activating gene transcription [148]. ERα and PR are co-expressed in the mammary gland in 15–30% of epithelial cells [149]. Meanwhile, estradiol and progesterone drive epithelial mammary gland proliferation directly through the hormone-receptor union and have been proposing a second control mechanism in which epithelial cells sense hormone concentrations through their estrogen and progesterone receptors and, in consequence, secrete or not growth factors to promote nearby cell proliferation [148].

In breast cancer staging, ER and/or PR expression loss is associated with more aggressive tumors, with self-sufficiency of growth signals independently of estrogen or progesterone receptors. Additionally, positive ERα tumor is related to a better prognostic, as well as ERβ tumor expression [150].

Besides the receptor's presence in tumor cells, another important issue to consider is the hormone levels within the tumor. Intratumoral estradiol concentration in normal breast tissue was lower than in ductal carcinoma in situ and invasive ductal carcinoma [151].

In this regard, aromatase is an important enzyme responsible for the production of estrogens, estrone, and estradiol, through the aromatization and conversion of androstenedione and testosterone [152]. Invasive ductal carcinoma expresses a higher amount of aromatase mRNA than DCIS and normal breast tissue, and both epithelial and stromal cells expressed aromatase mRNA [151]. Therefore, tumor cells have different sources of estrogen, called endocrine (ovary), intracrine, and paracrine, which enhance cell proliferation of tumor target cells.

#### **4.2 Androgens**

Meanwhile estrogens stimulate mammary gland development, and androgens inhibit it. For example, estrogen treatment in prostate cancer patients promotes mammary gland growth and ingestion of androgens by athletes or transsexuals and produces mammary gland atrophy [153].

Androgens as testosterone (T) and dihydrotestosterone (DHT) exert their effects through the union to their androgen receptor (AR). This receptor has been colocalized with ER and PR in mammary gland epithelia, but not in adjacent stromal cells; therefore, androgen-mediated proliferation is regulated in the mammary epithelium [154]. The androgen receptor (AR) has been reported to be present in 80% of primary breast tumors, and its presence is associated with a favorable response to endocrine treatment and a better prognostic, especially if ER is also present [155].

In this sense, the union of BRCA1 gene product with AR activates AR functions; therefore, the mutation of this BRCA1 may interfere with AR antiproliferative functions and allow cell proliferation [156].

#### **4.3 Adrenal steroids**

Dehydroepiandrosterone, an estrogen and testosterone precursor [157], is an adrenal steroid which is metabolized into active metabolites, such as Δ5-androstene-3β, 17β-diol (17β-androstenediol), Δ5-androstene-3β17α-diol (17α-androstenediol), and Δ5-androstene-3β,7β,17β-triol (17β-androstenetriol) [158]. DHEA is able to activate ERα, ERβ, AR, and glucocorticoid receptor (GR); meanwhile, its metabolites showed a weaker activation [159]. All of androstene hormones (DHEA, 17β-androstenediol, 17α-androstenediol, and 17β-androstenetriol) have been shown to have an antiproliferative effect in cellular lines, including breast cancer (**Figure 3**) [160]. Only DHEA presented a protective effect in vivo, but the other androstenes have not been tested in vitro [160]; therefore, there is a promising search field around androstenes and the development of breast cancer.

#### **5. Tumor development and neuroimmunoendocrine interactions**

The relation between nervous and immune systems is importantly transduced through β2AR and GCR localized in immune cells, such as B lymphocytes, T lymphocytes, NK cells, and macrophages, which regulate cytokine production, molecule expression, development, survival, proliferation, circulation, and cell recruitment [161]. Meanwhile, interactions among endocrine and immune or nervous systems are regulated through the hormone receptor expression (ER, PR, and AR) and the effects driving in immune and/or nervous cells (**Figure 4**).

**129**

CD4+

**Figure 4.**

CD4+

of these cells [165, 166].

TNF-α production, in LPS-activated DCs [169].

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

In mice treated with selective β2AR agonists, such as clenbuterol or salbutamol,

*Neuroimmunoendocrine interactions in breast cancer. Bidirectional interactions among nervous, immune, and* 

cytes, and antigen-primed T cells and B cells is retarded and is associated with lymphopenia. This lymphocyte retention is mediated through CXC chemokine receptor 4 (CXCR4) in T cells and B cells and is thought to explain the reduction of T-cell-mediated inflammation and lymphopenia [161]. CXCR4 is also expressed in monocytes and dendritic cells. CXCR4 ligand is the stromal cell-derived factor 12 (CXCL12), and both are linked to breast cancer metastasis. CXCR4-CXCL12 union

In lymph nodes with breast cancer metastasis, an increased level of CXCR4 transcript was detected compared to nonmetastatic lymph nodes. Also, a higher mRNA expression was found in breast cancer tumor stages III–IV than in stages I–II. Interestingly, in tumor tissues with HER-2 expression, CXCR4 transcription levels are also more elevated than in HER-2-negative tumors; therefore, there is a positive correlation between CXCR4 and HER-2 expression in breast tumors [163]. This phenomenon is explained because HER-2 enhances and impedes CXCR4 degradation [164]. CXCR4-CXCL12 axis is evolved in organ-directed metastasis, mainly associated with a higher CXCL12 expression in lymph nodes and lung, liver, and bone tissues where breast cancer metastasis is very common. CXCL12 acts as a chemoattractant for breast cancer cells that express CXCR4, promoting the arrival

Another group of immune cells, in which β2AR produces an inhibitory effect, is the DCs. The stimulation of β2AR with salbutamol inhibited the NF-κB transcription [167]. This transcription factor is required for DC antigen presentation; for the expression of CD80, CD86, and CD40 (costimulatory molecules); and for IL-12 secretion [168]. Also, salmeterol (β2AR agonist) diminishes the IL-1, IL-6, and

On the other hand, in human monocytes primed during 16 hours with IFN-γ and stimulated with LPS, the addition of salbutamol diminished the IL-12 and TNF-α secretion, but not the IL-1α, IL-1β, or IL-10 production. Also, in neonatal

lymphocytes, the Th1 cell differentiation in vitro was inhibited; instead, these

T cells, stimulated with β2AR agonists, produce IL-4 (Th2 cytokine), but not

, CD8+

T lympho-

to stimulate these receptors, the lymph node egress of CD4<sup>+</sup>

*endocrine systems are stablished by soluble factors and receptors in cells of the three systems.*

promotes cell migration and adhesion and angiogenesis [162].

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

**Figure 4.**

*Tumor Progression and Metastasis*

ductal carcinoma [151].

**4.2 Androgens**

produces mammary gland atrophy [153].

tions and allow cell proliferation [156].

**4.3 Adrenal steroids**

Besides the receptor's presence in tumor cells, another important issue to consider is the hormone levels within the tumor. Intratumoral estradiol concentration in normal breast tissue was lower than in ductal carcinoma in situ and invasive

of estrogens, estrone, and estradiol, through the aromatization and conversion of androstenedione and testosterone [152]. Invasive ductal carcinoma expresses a higher amount of aromatase mRNA than DCIS and normal breast tissue, and both epithelial and stromal cells expressed aromatase mRNA [151]. Therefore, tumor cells have different sources of estrogen, called endocrine (ovary), intracrine, and

paracrine, which enhance cell proliferation of tumor target cells.

In this regard, aromatase is an important enzyme responsible for the production

Meanwhile estrogens stimulate mammary gland development, and androgens inhibit it. For example, estrogen treatment in prostate cancer patients promotes mammary gland growth and ingestion of androgens by athletes or transsexuals and

Androgens as testosterone (T) and dihydrotestosterone (DHT) exert their effects through the union to their androgen receptor (AR). This receptor has been colocalized with ER and PR in mammary gland epithelia, but not in adjacent stromal cells; therefore, androgen-mediated proliferation is regulated in the mammary epithelium [154]. The androgen receptor (AR) has been reported to be present in 80% of primary breast tumors, and its presence is associated with a favorable response to endocrine treatment and a better prognostic, especially if ER is also present [155]. In this sense, the union of BRCA1 gene product with AR activates AR functions; therefore, the mutation of this BRCA1 may interfere with AR antiproliferative func-

Dehydroepiandrosterone, an estrogen and testosterone precursor [157], is an adrenal steroid which is metabolized into active metabolites, such as Δ5-androstene-3β, 17β-diol (17β-androstenediol), Δ5-androstene-3β17α-diol (17α-androstenediol), and Δ5-androstene-3β,7β,17β-triol (17β-androstenetriol) [158]. DHEA is able to activate ERα, ERβ, AR, and glucocorticoid receptor (GR); meanwhile, its metabolites showed a weaker activation [159]. All of androstene hormones (DHEA, 17β-androstenediol, 17α-androstenediol, and 17β-androstenetriol) have been shown to have an antiproliferative effect in cellular lines, including breast cancer (**Figure 3**) [160]. Only DHEA presented a protective effect in vivo, but the other androstenes have not been tested in vitro [160]; therefore, there is a promis-

ing search field around androstenes and the development of breast cancer.

**5. Tumor development and neuroimmunoendocrine interactions**

through β2AR and GCR localized in immune cells, such as B lymphocytes, T lymphocytes, NK cells, and macrophages, which regulate cytokine production, molecule expression, development, survival, proliferation, circulation, and cell recruitment [161]. Meanwhile, interactions among endocrine and immune or nervous systems are regulated through the hormone receptor expression (ER, PR, and AR) and the effects driving in immune and/or nervous cells (**Figure 4**).

The relation between nervous and immune systems is importantly transduced

**128**

*Neuroimmunoendocrine interactions in breast cancer. Bidirectional interactions among nervous, immune, and endocrine systems are stablished by soluble factors and receptors in cells of the three systems.*

In mice treated with selective β2AR agonists, such as clenbuterol or salbutamol, to stimulate these receptors, the lymph node egress of CD4<sup>+</sup> , CD8+ T lymphocytes, and antigen-primed T cells and B cells is retarded and is associated with lymphopenia. This lymphocyte retention is mediated through CXC chemokine receptor 4 (CXCR4) in T cells and B cells and is thought to explain the reduction of T-cell-mediated inflammation and lymphopenia [161]. CXCR4 is also expressed in monocytes and dendritic cells. CXCR4 ligand is the stromal cell-derived factor 12 (CXCL12), and both are linked to breast cancer metastasis. CXCR4-CXCL12 union promotes cell migration and adhesion and angiogenesis [162].

In lymph nodes with breast cancer metastasis, an increased level of CXCR4 transcript was detected compared to nonmetastatic lymph nodes. Also, a higher mRNA expression was found in breast cancer tumor stages III–IV than in stages I–II. Interestingly, in tumor tissues with HER-2 expression, CXCR4 transcription levels are also more elevated than in HER-2-negative tumors; therefore, there is a positive correlation between CXCR4 and HER-2 expression in breast tumors [163]. This phenomenon is explained because HER-2 enhances and impedes CXCR4 degradation [164]. CXCR4-CXCL12 axis is evolved in organ-directed metastasis, mainly associated with a higher CXCL12 expression in lymph nodes and lung, liver, and bone tissues where breast cancer metastasis is very common. CXCL12 acts as a chemoattractant for breast cancer cells that express CXCR4, promoting the arrival of these cells [165, 166].

Another group of immune cells, in which β2AR produces an inhibitory effect, is the DCs. The stimulation of β2AR with salbutamol inhibited the NF-κB transcription [167]. This transcription factor is required for DC antigen presentation; for the expression of CD80, CD86, and CD40 (costimulatory molecules); and for IL-12 secretion [168]. Also, salmeterol (β2AR agonist) diminishes the IL-1, IL-6, and TNF-α production, in LPS-activated DCs [169].

On the other hand, in human monocytes primed during 16 hours with IFN-γ and stimulated with LPS, the addition of salbutamol diminished the IL-12 and TNF-α secretion, but not the IL-1α, IL-1β, or IL-10 production. Also, in neonatal CD4+ lymphocytes, the Th1 cell differentiation in vitro was inhibited; instead, these CD4+ T cells, stimulated with β2AR agonists, produce IL-4 (Th2 cytokine), but not

IFN-γ (Th1 cytokine) [168]. Meanwhile in rats, adrenaline or metaproterenol (β2AR agonist) in physiologic doses inhibited NK cell activation [170].

Either by directly action on tumor or immune cells, sympathetic signals regulate tumor progression. In this regard, as mentioned before, immune cell recruitment is a crucial step in immunosurveillance and immunosubversion. Sympathetic innervation in distant organs such as bone marrow promotes noradrenaline secretion that activates bone marrow-resident cells and promotes immune cell development and trafficking [171] and the posterior cell recruitment to tumor microenvironment mediated through tumor chemokine release and chemokine receptor expression in immune cells [166]. In this sense, tumor primary macrophage recruitment [39] and tumor cells increasing cytokine pro-inflammatory expression [21] are β2AR mediated and influencing tumor progression [37, 39].

Despite the differences in β2AR breast tumor cell expression that as an example in MB-231 cell line is higher than in MB-231BR cell line, the treatment with a β2AR agonist (terbutaline or norepinephrine) modulates VEGF secretion through cAMP-PKA pathway, which is diminished in MB-231 cell line and augmented in MB-231BR cell line (metastatic to mouse brain). Meanwhile, IL-6 production in both cell lines was increased, in a cAMP-dependent and PKA-independent pathway [21]. These differences in VEGF secretion are maybe associated with the brain metastatic potential of MB-231BR cell line, because VEGF enhances blood vessel neoformation for tumor growth.

As mentioned before, immunosuppressive TAM works as M2 macrophages and, in this sense, has been found that epinephrine induces M2 macrophage polarization, in RAW 264.7 cells. This polarization is regulated through β2AR. Also, in breast tumors co-expression of CD163+ (M2 macrophages human marker) and β2AR cell has been demonstrated; thus, macrophages in tumor microenvironment are influenced by adrenergic signals [37]. The relationship between M1 or M2 macrophages and hormone receptor status in breast cancer is due to the development of the disease. Hollmen et al. reported that when a cell line positive for the estrogen receptor (ER) is co-cultured with human monocytes, they acquire an M1 phenotype; meanwhile, the co-culture of them with ER- breast cancer cell line induced an M2 phenotype. The above indicates that ER governs the changes of the macrophages phenotype [172]. ER<sup>+</sup> breast cancer is related with an "early" development and a better prognostic, maybe associated with a M1 acute phase inflammatory response that effectively controls tumor progression. Meanwhile, TNBC usually presents a worse prognosis, and the presence of M2 exerts an immunosuppressive intratumoral effect that allows breast tumor growth and metastasis. Therefore, the macrophage phenotype is due to microenvironmental conditions and is associated consequently with tumor staging and prognosis.

Overexpression of HER-2 is correlated with β2AR expression levels in breast tumor samples. In this sense, in MCF-7 cells overexpressing HER-2 (MCF-7/ HER-2), β2AR expression was also elevated, in an autocrine way through MCF-7/ HER-2 epinephrine secretion. Interestingly, β2AR activation with epinephrine, with norepinephrine, or with β2AR agonists (isoproterenol and salmeterol) induces HER-2 expression in MCF-7 breast cancer cells. These findings are important because in HER-2<sup>+</sup> breast cancer cells, the activation of this surface tyrosine kinase may improve epinephrine secretion, through ERK signaling. Epinephrine may upregulate either β2AR expression or HER-2 [173].

Concerning to breast cancer, in more aggressive tumors (TNBC), an increased amount of Foxp3+ lymphocytes can be found in than less aggressive tumors (ER+ or HER+ tumors); this higher Treg tumor infiltration is also related to an increased risk of recurrence and a poor prognosis [174].

**131**

UNAM.

**Conflict of interest**

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

/HER+

more effective therapies against breast cancer.

and HER+

tumor was associated with a reduction (28%) of mortality risk, but if these cells were in the tumor stroma, the risk reduction was lower (21%). A similar risk reduction

is associated then with the induction of tumor cell apoptosis that improve the prognosis and in some point is still acting as an effector-killing cell rather than a memory cell.

In breast cancer development, tumor cell proliferation is extensively studied, and almost all the treatments are encouraged to diminish it. Tumor cell interactions with other immune, nervous, tumor, and stromal cells, through the production of soluble factors and the expression of receptors, are the drivers of this proliferation. These relations may be driven inside the tumor or across the organism in distant places that respond to tumor signals. Therefore, elucidating not only molecular mechanisms but interactions among cells may enhance the development of new and

The authors are grateful for the financial support received from the following agencies: Grant IN-209719 from Programa de Apoyo a Proyectos de Innovación Tecnológica (PAPIIT), Dirección General de Asuntos del Personal Académico (DGAPA), and Universidad Nacional Autónoma de México (UNAM) and Grant 2125 from Fronteras en la Ciencia, Consejo Nacional de Ciencia y Tecnología

(CONACYT), both to J. Morales-Montor. Grant IA-202919 from Programa de Apoyo a Proyectos de Innovación Tecnológica (PAPIIT), Dirección General de Asuntos del Personal Académico (DGAPA), and Universidad Nacional Autónoma de México (UNAM) to KE. Nava-Castro. Rocío Alejandra Ruiz-Manzano is a PhD student at Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, and received a fellowship from CONACyT. Mariana Segovia-Mendoza and Margarita Isabel Palacios-Arreola are postdoctoral fellows from DGAPA,

The authors declare that there is no conflict of interest.

breast tumors [138]. The CD8+

breast tumors, CD8+

cell infiltration in

T-cell presence in tumor

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

Ali et al. reported that in ER<sup>−</sup>

(27%) was found in ER+

**Acknowledgements**

**6. Conclusion**

Ali et al. reported that in ER<sup>−</sup> and HER+ breast tumors, CD8+ cell infiltration in tumor was associated with a reduction (28%) of mortality risk, but if these cells were in the tumor stroma, the risk reduction was lower (21%). A similar risk reduction (27%) was found in ER+ /HER+ breast tumors [138]. The CD8+ T-cell presence in tumor is associated then with the induction of tumor cell apoptosis that improve the prognosis and in some point is still acting as an effector-killing cell rather than a memory cell.

### **6. Conclusion**

*Tumor Progression and Metastasis*

IFN-γ (Th1 cytokine) [168]. Meanwhile in rats, adrenaline or metaproterenol (β2AR

Either by directly action on tumor or immune cells, sympathetic signals regulate tumor progression. In this regard, as mentioned before, immune cell recruitment is a crucial step in immunosurveillance and immunosubversion. Sympathetic innervation in distant organs such as bone marrow promotes noradrenaline secretion that activates bone marrow-resident cells and promotes immune cell development and trafficking [171] and the posterior cell recruitment to tumor microenvironment mediated through tumor chemokine release and chemokine receptor expression in immune cells [166]. In this sense, tumor primary macrophage recruitment [39] and tumor cells increasing cytokine pro-inflammatory expression [21] are β2AR medi-

Despite the differences in β2AR breast tumor cell expression that as an example

As mentioned before, immunosuppressive TAM works as M2 macrophages and, in this sense, has been found that epinephrine induces M2 macrophage polarization, in RAW 264.7 cells. This polarization is regulated through β2AR. Also, in breast

cell has been demonstrated; thus, macrophages in tumor microenvironment are influenced by adrenergic signals [37]. The relationship between M1 or M2 macrophages and hormone receptor status in breast cancer is due to the development of the disease. Hollmen et al. reported that when a cell line positive for the estrogen receptor (ER) is co-cultured with human monocytes, they acquire an M1 phenotype; meanwhile, the co-culture of them with ER- breast cancer cell line induced an M2 phenotype. The above indicates that ER governs the changes of the macro-

and a better prognostic, maybe associated with a M1 acute phase inflammatory response that effectively controls tumor progression. Meanwhile, TNBC usually presents a worse prognosis, and the presence of M2 exerts an immunosuppressive intratumoral effect that allows breast tumor growth and metastasis. Therefore, the macrophage phenotype is due to microenvironmental conditions and is associated

Overexpression of HER-2 is correlated with β2AR expression levels in breast tumor samples. In this sense, in MCF-7 cells overexpressing HER-2 (MCF-7/ HER-2), β2AR expression was also elevated, in an autocrine way through MCF-7/ HER-2 epinephrine secretion. Interestingly, β2AR activation with epinephrine, with norepinephrine, or with β2AR agonists (isoproterenol and salmeterol) induces HER-2 expression in MCF-7 breast cancer cells. These findings are important

may improve epinephrine secretion, through ERK signaling. Epinephrine may

Concerning to breast cancer, in more aggressive tumors (TNBC), an increased

tumors); this higher Treg tumor infiltration is also related to an increased risk

(M2 macrophages human marker) and β2AR

breast cancer is related with an "early" development

breast cancer cells, the activation of this surface tyrosine kinase

lymphocytes can be found in than less aggressive tumors (ER+

or

in MB-231 cell line is higher than in MB-231BR cell line, the treatment with a β2AR agonist (terbutaline or norepinephrine) modulates VEGF secretion through cAMP-PKA pathway, which is diminished in MB-231 cell line and augmented in MB-231BR cell line (metastatic to mouse brain). Meanwhile, IL-6 production in both cell lines was increased, in a cAMP-dependent and PKA-independent pathway [21]. These differences in VEGF secretion are maybe associated with the brain metastatic potential of MB-231BR cell line, because VEGF enhances blood vessel

agonist) in physiologic doses inhibited NK cell activation [170].

ated and influencing tumor progression [37, 39].

neoformation for tumor growth.

tumors co-expression of CD163+

phages phenotype [172]. ER<sup>+</sup>

because in HER-2<sup>+</sup>

amount of Foxp3+

consequently with tumor staging and prognosis.

upregulate either β2AR expression or HER-2 [173].

of recurrence and a poor prognosis [174].

**130**

HER+

In breast cancer development, tumor cell proliferation is extensively studied, and almost all the treatments are encouraged to diminish it. Tumor cell interactions with other immune, nervous, tumor, and stromal cells, through the production of soluble factors and the expression of receptors, are the drivers of this proliferation. These relations may be driven inside the tumor or across the organism in distant places that respond to tumor signals. Therefore, elucidating not only molecular mechanisms but interactions among cells may enhance the development of new and more effective therapies against breast cancer.

### **Acknowledgements**

The authors are grateful for the financial support received from the following agencies: Grant IN-209719 from Programa de Apoyo a Proyectos de Innovación Tecnológica (PAPIIT), Dirección General de Asuntos del Personal Académico (DGAPA), and Universidad Nacional Autónoma de México (UNAM) and Grant 2125 from Fronteras en la Ciencia, Consejo Nacional de Ciencia y Tecnología (CONACYT), both to J. Morales-Montor. Grant IA-202919 from Programa de Apoyo a Proyectos de Innovación Tecnológica (PAPIIT), Dirección General de Asuntos del Personal Académico (DGAPA), and Universidad Nacional Autónoma de México (UNAM) to KE. Nava-Castro. Rocío Alejandra Ruiz-Manzano is a PhD student at Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, and received a fellowship from CONACyT. Mariana Segovia-Mendoza and Margarita Isabel Palacios-Arreola are postdoctoral fellows from DGAPA, UNAM.

### **Conflict of interest**

The authors declare that there is no conflict of interest.

*Tumor Progression and Metastasis*

#### **Author details**

Rocío Alejandra Ruiz-Manzano1 , Tania de Lourdes Ochoa-Mercado1 , Mariana Segovia-Mendoza1 , Karen Elizabeth Nava-Castro2 , Margarita Isabel Palacios-Arreola2 and Jorge Morales-Montor1 \*

1 Immunology Department, Biomedical Research Institute, National Autonomous University of Mexico, Mexico City, Mexico

2 Ambiental Genotoxicity and Mutagenesis Laboratory, Environmental Sciences Department, Atmospheric Sciences Center, National Autonomous University of Mexico, Mexico City, Mexico

\*Address all correspondence to: jmontor66@biomedicas.unam.mx; jmontor66@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**133**

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

[9] Gusterson BA, Warburton MJ, Mitchell D, Ellison M, Munro Neville A,

[10] Barcellos-Hoff MH, Aggeler J, Ram TG, Bissell MJ. Functional differentiation and alveolar morphogenesis of primary

mammary cultures on reconstituted basement membrane. Development.

[12] Hanoun M, Maryanovich M, Arnal-Estapé A, Frenette PS. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron. 2015;**86**(2):360-373

[13] Elefteriou F. Chronic stress, sympathetic activation and skeletal metastasis of breast cancer cells. BoneKEy Reports. 2015;**4**:693

[14] Cole SW, Nagaraja AS, Lutgendorf SK, Green PA, Sood AK. Sympathetic nervous system regulation of the tumour microenvironment. Nature Reviews.

[15] Bellinger DL, Lorton D. Autonomic regulation of cellular immune function. Autonomic Neuroscience: Basic & Clinical.

[16] Bellinger DL, Millar BA, Perez S, Carter J, Wood C, Thyagarajan S, et al. Sympathetic modulation of

immunity: Relevance to disease. Cellular Immunology. 2008;**252**(1-2):27-56

Cancer. 2015;**15**:563

2014;**182**:15-41

[11] Hanahan D, Coussens LM. Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell.

Rudland PS. Distribution of myoepithelial cells and basement membrane proteins in the normal breast and in benign and malignant breast diseases. Cancer Research.

1982;**42**(11):4763-4770

1989;**105**(2):223-235

2012;**21**(3):309-322

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

[1] Globocan W. Breast Cancer Fact Sheet Lyon [updated]. France: WHO; 2018 Available from: http://gco.iarc.fr/

[2] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA: A Cancer Journal for Clinicians.

Tamimi RM. Established breast cancer risk factors and risk of intrinsic tumor subtypes. BBA Reviews on Cancer.

[4] Nava-Castro KE, Morales-Montor J, Ortega-Hernando A, Camacho-Arroyo I. Diethylstilbestrol exposure in neonatal mice induces changes in the adulthood in the immune response to taenia crassiceps without modifications of parasite loads. BioMed Research International.

[5] Palacios-Arreola MI, Nava-Castro KE, Rio-Araiza VHD, Perez-Sanchez NY, Morales-Montor J. A single neonatal administration of bisphenol a induces higher tumour weight associated to changes in tumour microenvironment in the adulthood. Scientific Reports.

[6] Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast cancer-major changes in the American joint committee on cancer eighth edition cancer staging manual. CA: A Cancer Journal for Clinicians.

[7] Macias H, Hinck L. Mammary gland development. WIREs Developmental

[8] Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Developmental Cell.

today/fact-sheets-cancers

[3] Barnard ME, Boeke CE,

2009;**59**(4):225-249

2015;**1856**(1):73-85

2014;**2014**:498681

2017;**7**(1):10573

2017;**67**(4):291-303

2001;**1**(4):467-475

Biology. 2012;**1**(4):533-557

**References**

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

#### **References**

*Tumor Progression and Metastasis*

**132**

**Author details**

Rocío Alejandra Ruiz-Manzano1

Margarita Isabel Palacios-Arreola2

University of Mexico, Mexico City, Mexico

provided the original work is properly cited.

Mariana Segovia-Mendoza1

Mexico, Mexico City, Mexico

jmontor66@hotmail.com

, Tania de Lourdes Ochoa-Mercado1

and Jorge Morales-Montor1

, Karen Elizabeth Nava-Castro2

1 Immunology Department, Biomedical Research Institute, National Autonomous

2 Ambiental Genotoxicity and Mutagenesis Laboratory, Environmental Sciences Department, Atmospheric Sciences Center, National Autonomous University of

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: jmontor66@biomedicas.unam.mx;

,

,

\*

[1] Globocan W. Breast Cancer Fact Sheet Lyon [updated]. France: WHO; 2018 Available from: http://gco.iarc.fr/ today/fact-sheets-cancers

[2] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA: A Cancer Journal for Clinicians. 2009;**59**(4):225-249

[3] Barnard ME, Boeke CE, Tamimi RM. Established breast cancer risk factors and risk of intrinsic tumor subtypes. BBA Reviews on Cancer. 2015;**1856**(1):73-85

[4] Nava-Castro KE, Morales-Montor J, Ortega-Hernando A, Camacho-Arroyo I. Diethylstilbestrol exposure in neonatal mice induces changes in the adulthood in the immune response to taenia crassiceps without modifications of parasite loads. BioMed Research International. 2014;**2014**:498681

[5] Palacios-Arreola MI, Nava-Castro KE, Rio-Araiza VHD, Perez-Sanchez NY, Morales-Montor J. A single neonatal administration of bisphenol a induces higher tumour weight associated to changes in tumour microenvironment in the adulthood. Scientific Reports. 2017;**7**(1):10573

[6] Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast cancer-major changes in the American joint committee on cancer eighth edition cancer staging manual. CA: A Cancer Journal for Clinicians. 2017;**67**(4):291-303

[7] Macias H, Hinck L. Mammary gland development. WIREs Developmental Biology. 2012;**1**(4):533-557

[8] Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Developmental Cell. 2001;**1**(4):467-475

[9] Gusterson BA, Warburton MJ, Mitchell D, Ellison M, Munro Neville A, Rudland PS. Distribution of myoepithelial cells and basement membrane proteins in the normal breast and in benign and malignant breast diseases. Cancer Research. 1982;**42**(11):4763-4770

[10] Barcellos-Hoff MH, Aggeler J, Ram TG, Bissell MJ. Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane. Development. 1989;**105**(2):223-235

[11] Hanahan D, Coussens LM. Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;**21**(3):309-322

[12] Hanoun M, Maryanovich M, Arnal-Estapé A, Frenette PS. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron. 2015;**86**(2):360-373

[13] Elefteriou F. Chronic stress, sympathetic activation and skeletal metastasis of breast cancer cells. BoneKEy Reports. 2015;**4**:693

[14] Cole SW, Nagaraja AS, Lutgendorf SK, Green PA, Sood AK. Sympathetic nervous system regulation of the tumour microenvironment. Nature Reviews. Cancer. 2015;**15**:563

[15] Bellinger DL, Lorton D. Autonomic regulation of cellular immune function. Autonomic Neuroscience: Basic & Clinical. 2014;**182**:15-41

[16] Bellinger DL, Millar BA, Perez S, Carter J, Wood C, Thyagarajan S, et al. Sympathetic modulation of immunity: Relevance to disease. Cellular Immunology. 2008;**252**(1-2):27-56

[17] Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987-2007). Brain, Behavior, and Immunity. 2007;**21**(6):736-745

[18] Madden KS. Sympathetic neural-immune interactions regulate hematopoiesis, thermoregulation and inflammation in mammals. Developmental and Comparative Immunology. 2017;**66**:92-97

[19] Du YY, Zhou LH, Wang YH, Yan TT, Jiang YW, Shao ZM, et al. Association of alpha2a and beta2 adrenoceptor expression with clinical outcome in breast cancer. Current Medical Research and Opinion. 2014;**30**(7):1337-1344

[20] Powe DG, Voss MJ, Habashy HO, Zanker KS, Green AR, Ellis IO, et al. Alpha- and beta-adrenergic receptor (AR) protein expression is associated with poor clinical outcome in breast cancer: An immunohistochemical study. Breast Cancer Research and Treatment. 2011;**130**(2):457-463

[21] Madden KS, Szpunar MJ, Brown EB. Beta-adrenergic receptors (beta-AR) regulate VEGF and IL-6 production by divergent pathways in high beta-AR-expressing breast cancer cell lines. Breast Cancer Research and Treatment. 2011;**130**(3):747-758

[22] Choy C, Raytis JL, Smith DD, Duenas M, Neman J, Jandial R, et al. Inhibition of beta2-adrenergic receptor reduces triple-negative breast cancer brain metastases: The potential benefit of perioperative beta-blockade. Oncology Reports. 2016;**35**(6):3135-3142

[23] Pon CK, Lane JR, Sloan EK, Halls ML. The beta2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion. The FASEB Journal. 2016;**30**(3):1144-1154

[24] Cole SW, Sood AK. Molecular pathways: Beta-adrenergic signaling in cancer. Clinical Cancer Research. 2012;**18**(5):1201-1206

[25] Kumar N, Gupta S, Dabral S, Singh S, Sehrawat S. Role of exchange protein directly activated by cAMP (EPAC1) in breast cancer cell migration and apoptosis. Molecular and Cellular Biochemistry. 2017;**430**(1-2):115-125

[26] Hara MR, Kovacs JJ, Whalen EJ, Rajagopal S, Strachan RT, Grant W, et al. A stress response pathway regulates DNA damage through beta (2)-adrenoreceptors and beta-arrestin-1. Nature. 2011;**477**(7364):349-U129

[27] Ayala GE, Dai H, Powell M, Li R, Ding Y, Wheeler TM, et al. Cancerrelated axonogenesis and neurogenesis in prostate cancer. Clinical Cancer Research. 2008;**14**(23):7593-7603

[28] Pundavela J, Roselli S, Faulkner S, Attia J, Scott RJ, Thorne RF, et al. Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer. Molecular Oncology. 2015;**9**(8):1626-1635

[29] Kowalski PJ, Paulino AFG. Perineural invasion in adenoid cystic carcinoma: Its causation/ promotion by brain-derived neurotrophic factor. Human Pathology. 2002;**33**(9):933-936

[30] Szpunar MJ, Belcher EK, Dawes RP, Madden KS. Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer. Brain, Behavior, and Immunity. 2016;**53**:223-233

[31] Lutgendorf SK, DeGeest K, Dahmoush L, Farley D, Penedo F, Bender D, et al. Social isolation is associated with elevated tumor

**135**

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

progression. Brain, Behavior, and Immunity. 2013;**30**(Suppl):S19-S25

[39] Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Research.

[40] Zou W, Restifo NP. T(H)17 cells in tumour immunity and immunotherapy.

[41] Emens LA, Silverstein SC, Khleif S,

[42] Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance:

immunosubversion. Nature Reviews. Immunology. 2006;**6**(10):715-727

[43] Gardner A, Ruffell B. Dendritic cells and cancer immunity. Trends in Immunology. 2016;**37**(12):855-865

[44] Steinman RM. Decisions about dendritic cells: Past, present, and future. Annual Review of Immunology.

[45] Steinman RM, Inaba K, Turley S, Pierre P, Mellman I. Antigen capture, processing, and presentation by dendritic cells: Recent cell biological studies. Human Immunology. 1999;**60**(7):562-567

[46] Segura E, Amigorena S. Crosspresentation in mouse and human dendritic cells. Advances in Immunology. 2015;**127**:1-31

[47] Gottfried E, Kreutz M, Mackensen A. Tumor-induced modulation of dendritic cell function. Cytokine & Growth Factor Reviews.

2008;**19**(1):65-77

Nature Reviews. Immunology.

Marincola FM, Galon J. Toward integrative cancer immunotherapy: Targeting the tumor microenvironment. Journal of Translational Medicine.

2010;**70**(18):7042-7052

2010;**10**(4):248-256

2012;**10**(1):70

2012;**30**:1-22

Immunoselection and

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

norepinephrine in ovarian carcinoma

[32] Stephens MA, Wand G. Stress and the HPA axis: Role of glucocorticoids in alcohol dependence. Alcohol Research: Current Reviews.

[33] Melhem A, Yamada SD, Fleming GF, Delgado B, Brickley DR, Wu W, et al. Administration of glucocorticoids to ovarian cancer patients is associated with expression of the anti-apoptotic genes SGK1 and MKP1/DUSP1 in ovarian tissues. Clinical Cancer Research. 2009;**15**(9):3196-3204

patients. Brain, Behavior, and Immunity. 2011;**25**(2):250-255

[34] Mikosz CA, Brickley DR,

[35] Pan D, Kocherginsky M, Conzen SD. Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen

receptor-negative breast cancer. Cancer Research. 2011;**71**(20):6360-6370

[36] Pang D, Kocherginsky M, Krausz T, Kim SY, Conzen SD. Dexamethasone decreases xenograft response to paclitaxel through inhibition of tumor cell apoptosis. Cancer Biology & Therapy. 2006;**5**(8):933-940

[37] Qin JF, Jin FJ, Li N, Guan HT, Lan L,

Ni H, et al. Adrenergic receptor beta2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. BMB Reports.

[38] Armaiz-Pena GN, Cole SW, Lutgendorf SK, Sood AK.

Neuroendocrine influences on cancer

2015;**48**(5):295-300

Sharkey MS, Moran TW, Conzen SD. Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. The Journal of Biological Chemistry. 2001;**276**(20):16649-16654

2012;**34**(4):468-483

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

norepinephrine in ovarian carcinoma patients. Brain, Behavior, and Immunity. 2011;**25**(2):250-255

*Tumor Progression and Metastasis*

innervation and regulation of the immune system (1987-2007). Brain, Behavior, and Immunity.

[18] Madden KS. Sympathetic

neural-immune interactions regulate hematopoiesis, thermoregulation and inflammation in mammals. Developmental and Comparative Immunology. 2017;**66**:92-97

[19] Du YY, Zhou LH, Wang YH, Yan TT, Jiang YW, Shao ZM, et al. Association of alpha2a and beta2 adrenoceptor expression with clinical outcome in breast cancer. Current Medical Research and Opinion.

[20] Powe DG, Voss MJ, Habashy HO, Zanker KS, Green AR, Ellis IO, et al. Alpha- and beta-adrenergic receptor (AR) protein expression is associated with poor clinical outcome in breast cancer: An immunohistochemical study. Breast Cancer Research and Treatment.

[21] Madden KS, Szpunar MJ, Brown EB. Beta-adrenergic receptors (beta-AR) regulate VEGF and IL-6 production by divergent pathways in high beta-AR-expressing breast cancer cell lines. Breast Cancer Research and Treatment.

[22] Choy C, Raytis JL, Smith DD, Duenas M, Neman J, Jandial R, et al. Inhibition of beta2-adrenergic receptor reduces triple-negative breast cancer brain metastases: The potential benefit of perioperative beta-blockade. Oncology Reports.

[23] Pon CK, Lane JR, Sloan EK, Halls ML. The beta2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion. The FASEB Journal.

2014;**30**(7):1337-1344

2011;**130**(2):457-463

2011;**130**(3):747-758

2016;**35**(6):3135-3142

2016;**30**(3):1144-1154

2007;**21**(6):736-745

[17] Nance DM, Sanders VM. Autonomic

[24] Cole SW, Sood AK. Molecular pathways: Beta-adrenergic signaling in cancer. Clinical Cancer Research.

[25] Kumar N, Gupta S, Dabral S, Singh S, Sehrawat S. Role of exchange protein directly activated by cAMP (EPAC1) in breast cancer cell migration and apoptosis. Molecular and Cellular Biochemistry. 2017;**430**(1-2):115-125

[26] Hara MR, Kovacs JJ, Whalen EJ, Rajagopal S, Strachan RT, Grant W, et al. A stress response pathway regulates DNA damage through beta (2)-adrenoreceptors and beta-arrestin-1. Nature. 2011;**477**(7364):349-U129

[27] Ayala GE, Dai H, Powell M, Li R, Ding Y, Wheeler TM, et al. Cancerrelated axonogenesis and neurogenesis in prostate cancer. Clinical Cancer Research. 2008;**14**(23):7593-7603

[28] Pundavela J, Roselli S, Faulkner S, Attia J, Scott RJ, Thorne RF, et al. Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer. Molecular Oncology.

2015;**9**(8):1626-1635

2002;**33**(9):933-936

2016;**53**:223-233

[29] Kowalski PJ, Paulino AFG. Perineural invasion in adenoid cystic carcinoma: Its causation/ promotion by brain-derived

norepinephrine content, and

[31] Lutgendorf SK, DeGeest K, Dahmoush L, Farley D, Penedo F, Bender D, et al. Social isolation is associated with elevated tumor

neurotrophic factor. Human Pathology.

[30] Szpunar MJ, Belcher EK, Dawes RP, Madden KS. Sympathetic innervation,

norepinephrine turnover in orthotopic and spontaneous models of breast cancer. Brain, Behavior, and Immunity.

2012;**18**(5):1201-1206

**134**

[32] Stephens MA, Wand G. Stress and the HPA axis: Role of glucocorticoids in alcohol dependence. Alcohol Research: Current Reviews. 2012;**34**(4):468-483

[33] Melhem A, Yamada SD, Fleming GF, Delgado B, Brickley DR, Wu W, et al. Administration of glucocorticoids to ovarian cancer patients is associated with expression of the anti-apoptotic genes SGK1 and MKP1/DUSP1 in ovarian tissues. Clinical Cancer Research. 2009;**15**(9):3196-3204

[34] Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD. Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. The Journal of Biological Chemistry. 2001;**276**(20):16649-16654

[35] Pan D, Kocherginsky M, Conzen SD. Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Cancer Research. 2011;**71**(20):6360-6370

[36] Pang D, Kocherginsky M, Krausz T, Kim SY, Conzen SD. Dexamethasone decreases xenograft response to paclitaxel through inhibition of tumor cell apoptosis. Cancer Biology & Therapy. 2006;**5**(8):933-940

[37] Qin JF, Jin FJ, Li N, Guan HT, Lan L, Ni H, et al. Adrenergic receptor beta2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. BMB Reports. 2015;**48**(5):295-300

[38] Armaiz-Pena GN, Cole SW, Lutgendorf SK, Sood AK. Neuroendocrine influences on cancer progression. Brain, Behavior, and Immunity. 2013;**30**(Suppl):S19-S25

[39] Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Research. 2010;**70**(18):7042-7052

[40] Zou W, Restifo NP. T(H)17 cells in tumour immunity and immunotherapy. Nature Reviews. Immunology. 2010;**10**(4):248-256

[41] Emens LA, Silverstein SC, Khleif S, Marincola FM, Galon J. Toward integrative cancer immunotherapy: Targeting the tumor microenvironment. Journal of Translational Medicine. 2012;**10**(1):70

[42] Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: Immunoselection and immunosubversion. Nature Reviews. Immunology. 2006;**6**(10):715-727

[43] Gardner A, Ruffell B. Dendritic cells and cancer immunity. Trends in Immunology. 2016;**37**(12):855-865

[44] Steinman RM. Decisions about dendritic cells: Past, present, and future. Annual Review of Immunology. 2012;**30**:1-22

[45] Steinman RM, Inaba K, Turley S, Pierre P, Mellman I. Antigen capture, processing, and presentation by dendritic cells: Recent cell biological studies. Human Immunology. 1999;**60**(7):562-567

[46] Segura E, Amigorena S. Crosspresentation in mouse and human dendritic cells. Advances in Immunology. 2015;**127**:1-31

[47] Gottfried E, Kreutz M, Mackensen A. Tumor-induced modulation of dendritic cell function. Cytokine & Growth Factor Reviews. 2008;**19**(1):65-77

[48] Chen X, Shao Q, Hao S, Zhao Z, Wang Y, Guo X, et al. CTLA-4 positive breast cancer cells suppress dendritic cells maturation and function. Oncotarget. 2017;**8**(8):13703-13715

[49] Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CMT, Pryer N, et al. Macrophage IL-10 blocks CD8(+) T cell-dependent responses to chemotherapy by suppressing IL-12 expression in Intratumoral dendritic cells. Cancer Cell. 2014;**26**(5):623-637

[50] Buisseret L, Desmedt C, Garaud S, Fornili M, Wang X, Van den Eyden G, et al. Reliability of tumor-infiltrating lymphocyte and tertiary lymphoid structure assessment in human breast cancer. Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 2017;**30**(9):1204-1212

[51] Thompson ED, Enriquez HL, Fu YX, Engelhard VH. Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. The Journal of Experimental Medicine. 2010;**207**(8):1791-1804

[52] Houghton AM. The paradox of tumor-associated neutrophils fueling tumor growth with cytotoxic substances. Cell Cycle. 2010;**9**(9):1732-1737

[53] Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;**303**(5663):1532-1535

[54] Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nature Reviews. Immunology. 2013;**13**(3):159-175

[55] Pham CTN. Neutrophil serine proteases: Specific regulators of inflammation. Nature Reviews. Immunology. 2006;**6**(7):541-550

[56] Garley M, Jablonska E, Dabrowska D. NETs in cancer. Tumor Biology. 2016;**37**(11):14355-14361

[57] Treffers LW, Hiemstra IH, Kuijpers TW, van den Berg TK, Matlung HL. Neutrophils in cancer. Immunological Reviews. 2016;**273**(1):312-328

[58] Park J, Wysocki RW, Amoozgar Z, Maiorino L, Fein MR, Jorns J, et al. Cancer cells induce metastasissupporting neutrophil extracellular DNA traps. Science Translational Medicine. 2016;**8**(361):1-21

[59] Wels J, Kaplan RN, Rafii S, Lyden D. Migratory neighbors and distant invaders: Tumor-associated niche cells. Genes & Development. 2008;**22**(5):559-574

[60] Kato M, Kephart GM, Talley NJ, Wagner JM, Sarr MG, Bonno M, et al. Eosinophil infiltration and degranulation in normal human tissue. The Anatomical Record. 1998;**252**(3):418-425

[61] Akuthota P, Wang HB, Weller PF. Eosinophils as antigen-presenting cells in allergic upper airway disease. Current Opinion in Allergy and Clinical Immunology. 2010;**10**(1):14-19

[62] Hamed EA, Zakhary MM, Maximous DW. Apoptosis, angiogenesis, inflammation, and oxidative stress: Basic interactions in patients with early and metastatic breast cancer. Journal of Cancer Research and Clinical Oncology. 2012;**138**(6):999-1009

[63] Snoussia K, Mahfoudha W, Bouaouinaac N, Ahmedd SB, Helalb AN, Chouchane L. Genetic variation in IL-8 associated with increased risk and poor prognosis of breast carcinoma. Human Immunology. 2006;**67**(1-2):13-21

**137**

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

[73] Sobolesky PM, Halushka PV, Garrett-Mayer E, Smith MT, Moussa O. Regulation of the tumor suppressor FOXO3 by the thromboxane-A2 receptors in urothelial cancer. PLoS

[74] Wang Z, Cheng Q, Tang K, Sun Y, Zhang K, Zhang Y, et al. Lipid mediator lipoxin A4 inhibits tumor growth by targeting IL-10-producing regulatory

B (Breg) cells. Cancer Letters.

[75] Rothenberg ME, Hogan SP. The eosinophil. The Annual Review of Immunology. 2006;**24**:147-174

[76] Gatault S, Legrand F, Delbeke M, Loiseau S, Capron M. Involvement of eosinophils in the anti-tumor response. Cancer Immunology, Immunotherapy.

[77] De Lima PO, Dos Santos FV, Oliveira DT, De Figueredo RC, Pereira MC. Effect of eosinophil cationic protein on human oral squamous carcinoma cell viability. Molecular and Clinical Oncology. 2015;**3**(2):353-356

[78] Kubo H, Loegering DA, Adolphson CR, Gleich GJ. Cytotoxic properties of eosinophil granule major basic protein for tumor cells. International Archives of Allergy and Immunology.

[79] Sakkal S, Miller S, Apostolopoulos V,

[81] Wu W, Samoszuk MK, Comhair SA, Thomassen MJ, Farver CF, Dweik RA, et al. Eosinophils generate brominating oxidants in allergen-induced asthma. The Journal of Clinical Investigation.

Nurgali K. Eosinophils in cancer: Favourable or unfavourable? Current Medicinal Chemistry. 2016;**23**(7):650-666

[80] Davis BP, Rothenberg ME. Eosinophils and cancer. Cancer Immunology Research. 2014;**2**(1):1-8

2000;**105**(10):1455-1463

One. 2014;**9**(9):e107530

2015;**364**(2):118-124

2012;**61**(9):1527-1534

1999;**118**(2-4):426-428

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

El-Merzebany M, Kilic G, Veenstra T, Saeed M et al. Effect of tumour necrosis factor-alpha on estrogen metabolic pathways in breast cancer cells. Journal

[64] Kamel M, Shouman S,

of Cancer. 2012;**3**:310-321

1992;**79**(12):3101-3109

2004;**26**(1):51-60

2015;**35**(1):1-16

2002;**161**(2):421-428

2010;**10**(3):181-193

[72] Wang D, Dubois RN.

2004;**31**(1 Suppl 3):64-73

[65] Sanderson CJ. Interleukin-5, eosinophils, and disease. Blood.

[66] Grencis RK, Bancroft AJ. Interleukin-13—A key mediator in resistance to gastrointestinaldwelling nematode parasites. Clinical Reviews in Allergy and Immunology.

[67] Srabovic N, Mujagic Z, Mujanovic-Mustedanagic J, Muminovic Z, Softic A, Begic L. Interleukin 13 expression in the primary breast cancer tumour tissue. Biochemia Medica. 2011;**21**(2):131-138

[68] Humphreys RC, Hennighausen L. Transforming growth factor alpha and mouse models of human breast cancer. Oncogene. 2000;**19**(8):1085-1091

[69] Esquivel-Velazquez M, Ostoa-Saloma P, Palacios-Arreola MI, Nava-Castro KE, Castro JI, Morales-Montor J. The role of cytokines in breast cancer development and progression. Journal of Interferon and Cytokine Research.

[70] Hennig R, Ding XZ, Tong WG, Schneider MB, Standop J, Friess H et al. 5-Lipoxygenase and leukotriene B(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. The American Journal of Pathology.

[71] Wang D, Dubois RN. Eicosanoids and cancer. Nature Reviews Cancer.

Cyclooxygenase-2: A potential target in breast cancer. Seminars in Oncology. *Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

[64] Kamel M, Shouman S, El-Merzebany M, Kilic G, Veenstra T, Saeed M et al. Effect of tumour necrosis factor-alpha on estrogen metabolic pathways in breast cancer cells. Journal of Cancer. 2012;**3**:310-321

[65] Sanderson CJ. Interleukin-5, eosinophils, and disease. Blood. 1992;**79**(12):3101-3109

*Tumor Progression and Metastasis*

[48] Chen X, Shao Q, Hao S, Zhao Z, Wang Y, Guo X, et al. CTLA-4 positive breast cancer cells suppress dendritic cells maturation and function. Oncotarget. 2017;**8**(8):13703-13715

[56] Garley M, Jablonska E, Dabrowska D.

[58] Park J, Wysocki RW, Amoozgar Z, Maiorino L, Fein MR, Jorns J, et al. Cancer cells induce metastasissupporting neutrophil extracellular DNA traps. Science Translational Medicine. 2016;**8**(361):1-21

NETs in cancer. Tumor Biology. 2016;**37**(11):14355-14361

[57] Treffers LW, Hiemstra IH, Kuijpers TW, van den Berg TK, Matlung HL. Neutrophils in cancer. Immunological Reviews.

[59] Wels J, Kaplan RN, Rafii S, Lyden D. Migratory neighbors and distant invaders: Tumor-associated niche cells. Genes & Development.

[60] Kato M, Kephart GM, Talley NJ, Wagner JM, Sarr MG, Bonno M, et al. Eosinophil infiltration and degranulation in normal human tissue. The Anatomical Record.

[61] Akuthota P, Wang HB, Weller PF. Eosinophils as antigen-presenting cells in allergic upper airway disease. Current Opinion in Allergy and Clinical

Immunology. 2010;**10**(1):14-19

[62] Hamed EA, Zakhary MM, Maximous DW. Apoptosis, angiogenesis, inflammation, and oxidative stress: Basic interactions in patients with early and metastatic breast cancer. Journal of Cancer Research and Clinical Oncology.

[63] Snoussia K, Mahfoudha W, Bouaouinaac N, Ahmedd SB, Helalb AN, Chouchane L. Genetic variation in IL-8 associated with increased risk and poor prognosis of breast carcinoma. Human Immunology.

2012;**138**(6):999-1009

2006;**67**(1-2):13-21

2016;**273**(1):312-328

2008;**22**(5):559-574

1998;**252**(3):418-425

[49] Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CMT, Pryer N, et al. Macrophage IL-10 blocks CD8(+) T cell-dependent responses to chemotherapy by suppressing IL-12 expression in Intratumoral dendritic cells. Cancer Cell. 2014;**26**(5):623-637

[50] Buisseret L, Desmedt C, Garaud S, Fornili M, Wang X, Van den Eyden G, et al. Reliability of tumor-infiltrating lymphocyte and tertiary lymphoid structure assessment in human breast cancer. Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc.

[51] Thompson ED, Enriquez HL, Fu YX, Engelhard VH. Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. The Journal of Experimental Medicine.

2017;**30**(9):1204-1212

2010;**207**(8):1791-1804

2010;**9**(9):1732-1737

[52] Houghton AM. The paradox of tumor-associated neutrophils fueling tumor growth with cytotoxic substances. Cell Cycle.

[53] Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y,

extracellular traps kill bacteria. Science.

Weiss DS, et al. Neutrophil

2004;**303**(5663):1532-1535

[54] Kolaczkowska E, Kubes P. Neutrophil recruitment and function

in health and inflammation. Nature Reviews. Immunology.

[55] Pham CTN. Neutrophil serine proteases: Specific regulators of inflammation. Nature Reviews. Immunology. 2006;**6**(7):541-550

2013;**13**(3):159-175

**136**

[66] Grencis RK, Bancroft AJ. Interleukin-13—A key mediator in resistance to gastrointestinaldwelling nematode parasites. Clinical Reviews in Allergy and Immunology. 2004;**26**(1):51-60

[67] Srabovic N, Mujagic Z, Mujanovic-Mustedanagic J, Muminovic Z, Softic A, Begic L. Interleukin 13 expression in the primary breast cancer tumour tissue. Biochemia Medica. 2011;**21**(2):131-138

[68] Humphreys RC, Hennighausen L. Transforming growth factor alpha and mouse models of human breast cancer. Oncogene. 2000;**19**(8):1085-1091

[69] Esquivel-Velazquez M, Ostoa-Saloma P, Palacios-Arreola MI, Nava-Castro KE, Castro JI, Morales-Montor J. The role of cytokines in breast cancer development and progression. Journal of Interferon and Cytokine Research. 2015;**35**(1):1-16

[70] Hennig R, Ding XZ, Tong WG, Schneider MB, Standop J, Friess H et al. 5-Lipoxygenase and leukotriene B(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. The American Journal of Pathology. 2002;**161**(2):421-428

[71] Wang D, Dubois RN. Eicosanoids and cancer. Nature Reviews Cancer. 2010;**10**(3):181-193

[72] Wang D, Dubois RN. Cyclooxygenase-2: A potential target in breast cancer. Seminars in Oncology. 2004;**31**(1 Suppl 3):64-73

[73] Sobolesky PM, Halushka PV, Garrett-Mayer E, Smith MT, Moussa O. Regulation of the tumor suppressor FOXO3 by the thromboxane-A2 receptors in urothelial cancer. PLoS One. 2014;**9**(9):e107530

[74] Wang Z, Cheng Q, Tang K, Sun Y, Zhang K, Zhang Y, et al. Lipid mediator lipoxin A4 inhibits tumor growth by targeting IL-10-producing regulatory B (Breg) cells. Cancer Letters. 2015;**364**(2):118-124

[75] Rothenberg ME, Hogan SP. The eosinophil. The Annual Review of Immunology. 2006;**24**:147-174

[76] Gatault S, Legrand F, Delbeke M, Loiseau S, Capron M. Involvement of eosinophils in the anti-tumor response. Cancer Immunology, Immunotherapy. 2012;**61**(9):1527-1534

[77] De Lima PO, Dos Santos FV, Oliveira DT, De Figueredo RC, Pereira MC. Effect of eosinophil cationic protein on human oral squamous carcinoma cell viability. Molecular and Clinical Oncology. 2015;**3**(2):353-356

[78] Kubo H, Loegering DA, Adolphson CR, Gleich GJ. Cytotoxic properties of eosinophil granule major basic protein for tumor cells. International Archives of Allergy and Immunology. 1999;**118**(2-4):426-428

[79] Sakkal S, Miller S, Apostolopoulos V, Nurgali K. Eosinophils in cancer: Favourable or unfavourable? Current Medicinal Chemistry. 2016;**23**(7):650-666

[80] Davis BP, Rothenberg ME. Eosinophils and cancer. Cancer Immunology Research. 2014;**2**(1):1-8

[81] Wu W, Samoszuk MK, Comhair SA, Thomassen MJ, Farver CF, Dweik RA, et al. Eosinophils generate brominating oxidants in allergen-induced asthma. The Journal of Clinical Investigation. 2000;**105**(10):1455-1463

[82] Samoszuk M, Sholly S, Epstein AL. Eosinophil peroxidase is detectable with a monoclonal antibody in collagen bands of nodular sclerosis Hodgkin's disease. Laboratory Investigation. 1987;**56**(4):394-400

[83] Gouon-Evans V, Lin EY, Pollard JW. Requirement of macrophages and eosinophils and their cytokines/ chemokines for mammary gland development. Breast Cancer Research. 2002;**4**(4):155-164

[84] Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: Macrophages, mast cells and neutrophils. Nature Immunology. 2011;**12**(11):1035-1044

[85] Mekori YA, Hershko AY, Frossi B, Mion F, Pucillo CE. Integrating innate and adaptive immune cells: Mast cells as crossroads between regulatory and effector B and T cells. European Journal of Pharmacology. 2016;**778**:84-89

[86] Della Rovere F, Granata A, Monaco M, Basile G. Phagocytosis of cancer cells by mast cells in breast Cancer. Anticancer Research. 2009;**29**(8):3157-3161

[87] Kambayashi T, Allenspach EJ, Chang JT, Zou T, Shoag JE, Reiner SL, et al. Inducible MHC class II expression by mast cells supports effector and regulatory T cell activation. Journal of Immunology. 2009;**182**(8):4686-4695

[88] Stelekati E, Bahri R, D'Orlando O, Orinska Z, Mittrucker HW, Langenhaun R, et al. Mast cell-mediated antigen presentation regulates CD8(+) T cell effector functions. Immunity. 2009;**31**(4):665-676

[89] Khan MM, Strober S, Melmon KL. Regulatory effects of mast-cells on lymphoid-cells—The role of histamine Type-1 receptors in the interaction between mast-cells, helper T-cells

and natural suppressor cells. Cellular Immunology. 1986;**103**(1):41-53

[90] Nakae S, Suto H, Kakurai M, Sedgwick JD, Tsai M, Galli SJ. Mast cells enhance T cell activation: Importance of mast cell-derived TNF. Proceedings of the National Academy of Sciences of The United States of America. 2005;**102**(18):6467-6472

[91] Faustino-Rocha AI, Gama A, Oliveira PA, Katrien VE, Saunders JH, Pires MJ, et al. Modulation of mammary tumor vascularization by mast cells: Ultrasonographic and histopathological approaches. Life Sciences. 2017;**176**:35-41

[92] Xiang M, Gu Y, Zhao F, Lu H, Chen S, Yin L. Mast cell tryptase promotes breast cancer migration and invasion. Oncology Reports. 2010;**23**(3):615-619

[93] Kankkunen JP, HArvima IT, Naukkarinen A. Quantitative analysis of tryptase and chymase containing mast cells in benign and malignant breast lesions. International Journal of Cancer. 1997;**72**(3):385-388

[94] Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;**141**(1):39-51

[95] Zhao X, Qu J, Sun Y, Wang J, Liu X, Wang F, et al. Prognostic significance of tumor-associated macrophages in breast cancer: A meta-analysis of the literature. Oncotarget. 2017;**8**(18):30576-30586

[96] Wu P, Wu D, Zhao L, Huang L, Chen G, Shen G, et al. Inverse role of distinct subsets and distribution of macrophage in lung cancer prognosis: A meta-analysis. Oncotarget. 2016;**7**(26):40451-40460

[97] Noy R, Pollard JW. Tumor-associated macrophages: From mechanisms to therapy. Immunity. 2014;**41**(1):49-61

**139**

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood.

[106] Curtsinger JM, Mescher MF. Inflammatory cytokines as a third signal for T cell activation. Current Opinion in Immunology.

[107] Kohlhapp FJ, Zloza A. CD4<sup>+</sup>

cells. In: Marshall JL, editor. Cancer Therapeutic Targets. New York, NY: Springer, New York; 2017. pp. 117-129

[108] Mescher MF, Agarwal P, Casey KA, Hammerbeck CD, Xiao Z, Curtsinger JM. Molecular basis for checkpoints in the CD8 T cell response: Tolerance versus activation. Seminars in Immunology.

[109] Gu-Trantien C, Willard-Gallo K. Tumor-infiltrating follicular helper T cells: The new kids on the block. Oncoimmunology. 2013;**2**(10):e26066

[110] Tangye SG, Ma CS, Brink R, Deenick EK. The good, the bad and the ugly—TFH cells in human health and disease. Nature Reviews Immunology.

[111] Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A et al.

predicts breast cancer survival. The Journal of Clinical Investigation.

[112] Gollob JA, Ritz J. CD2-CD58 interaction and the control of T-cell interleukin-12 responsiveness. Adhesion molecules link innate and acquired immunity. Annals of the New York Academy of Sciences. 1996;**795**:71-81

[113] Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G, et al. Natural killer cell stimulatory factor (interleukin 12

follicular helper T cell infiltration

T

2006;**108**(13):4118-4125

2010;**22**(3):333-340

2007;**19**(3):153-161

2013;**13**(6):412-426

2013;**123**(7):2873-2892

CD4+

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

[98] Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. The Journal of Pathology.

[99] Lodoen MB, Lanier LL. Natural killer cells as an initial defense against pathogens. Current Opinion in Immunology. 2006;**18**(4):391-398

[100] Arase H, Arase N, Saito T. Interferon gamma production by natural killer (NK) cells and NK1.1(+) T cells upon NKR-P1 cross-linking. The Journal of Experimental Medicine.

1996;**183**(5):2391-2396

2011;**121**(9):3609-3622

2005;**117**(2):248-255

2003;**100**(7):4120-4125

[104] Castriconi R, Cantoni C,

[102] Moretta L, Moretta A. Unravelling natural killer cell function: Triggering and inhibitory human NK receptors. The EMBO Journal. 2004;**23**(2):255-259

[103] Madjd Z, Spendlove I, Pinder SE, Ellis IO, Durrant LG. Total loss of MHC class I is an independent indicator of good prognosis in breast cancer. International Journal of Cancer.

Della Chiesa M, Vitale M, Marcenaro E, Conte R, et al. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: Consequences for the NK-mediated killing of dendritic cells. Proceedings of the National Academy of Sciences of the United States of America.

[105] Della Chiesa M, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, et al. The tryptophan

[101] Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R, et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. The Journal of Clinical Investigation.

2013;**229**(2):176-185

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

[98] Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. The Journal of Pathology. 2013;**229**(2):176-185

*Tumor Progression and Metastasis*

1987;**56**(4):394-400

2002;**4**(4):155-164

[82] Samoszuk M, Sholly S, Epstein AL. Eosinophil peroxidase is detectable with a monoclonal antibody in collagen bands of nodular sclerosis Hodgkin's disease. Laboratory Investigation.

and natural suppressor cells. Cellular Immunology. 1986;**103**(1):41-53

[90] Nakae S, Suto H, Kakurai M, Sedgwick JD, Tsai M, Galli SJ. Mast cells enhance T cell activation: Importance of mast cell-derived TNF. Proceedings of the National Academy of Sciences of The United States of America.

[91] Faustino-Rocha AI, Gama A, Oliveira PA, Katrien VE, Saunders JH, Pires MJ, et al. Modulation of mammary tumor vascularization by mast cells: Ultrasonographic and histopathological

[92] Xiang M, Gu Y, Zhao F, Lu H, Chen S, Yin L. Mast cell tryptase promotes breast cancer migration and invasion. Oncology Reports.

[93] Kankkunen JP, HArvima IT,

Naukkarinen A. Quantitative analysis of tryptase and chymase containing mast cells in benign and malignant breast lesions. International Journal of Cancer.

[94] Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;**141**(1):39-51

[95] Zhao X, Qu J, Sun Y, Wang J, Liu X, Wang F, et al. Prognostic significance of tumor-associated macrophages in breast cancer: A meta-analysis of the literature. Oncotarget. 2017;**8**(18):30576-30586

[96] Wu P, Wu D, Zhao L, Huang L, Chen G, Shen G, et al. Inverse role of distinct subsets and distribution of macrophage in lung cancer prognosis:

[97] Noy R, Pollard JW. Tumor-associated macrophages: From mechanisms to therapy. Immunity. 2014;**41**(1):49-61

A meta-analysis. Oncotarget. 2016;**7**(26):40451-40460

2005;**102**(18):6467-6472

approaches. Life Sciences.

2017;**176**:35-41

2010;**23**(3):615-619

1997;**72**(3):385-388

[83] Gouon-Evans V, Lin EY, Pollard JW. Requirement of macrophages and eosinophils and their cytokines/ chemokines for mammary gland development. Breast Cancer Research.

[84] Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: Macrophages, mast cells and neutrophils. Nature Immunology. 2011;**12**(11):1035-1044

[85] Mekori YA, Hershko AY, Frossi B, Mion F, Pucillo CE. Integrating innate and adaptive immune cells: Mast cells as crossroads between regulatory and effector B and T cells. European Journal of Pharmacology. 2016;**778**:84-89

[86] Della Rovere F, Granata A, Monaco M, Basile G. Phagocytosis of cancer cells by mast cells in breast Cancer. Anticancer Research.

[87] Kambayashi T, Allenspach EJ, Chang JT, Zou T, Shoag JE, Reiner SL, et al. Inducible MHC class II expression by mast cells supports effector and regulatory T cell activation. Journal of Immunology. 2009;**182**(8):4686-4695

[88] Stelekati E, Bahri R, D'Orlando O, Orinska Z, Mittrucker HW, Langenhaun R, et al. Mast cell-mediated antigen presentation regulates CD8(+) T cell effector functions. Immunity.

[89] Khan MM, Strober S, Melmon KL. Regulatory effects of mast-cells on lymphoid-cells—The role of histamine Type-1 receptors in the interaction between mast-cells, helper T-cells

2009;**29**(8):3157-3161

2009;**31**(4):665-676

**138**

[99] Lodoen MB, Lanier LL. Natural killer cells as an initial defense against pathogens. Current Opinion in Immunology. 2006;**18**(4):391-398

[100] Arase H, Arase N, Saito T. Interferon gamma production by natural killer (NK) cells and NK1.1(+) T cells upon NKR-P1 cross-linking. The Journal of Experimental Medicine. 1996;**183**(5):2391-2396

[101] Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R, et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. The Journal of Clinical Investigation. 2011;**121**(9):3609-3622

[102] Moretta L, Moretta A. Unravelling natural killer cell function: Triggering and inhibitory human NK receptors. The EMBO Journal. 2004;**23**(2):255-259

[103] Madjd Z, Spendlove I, Pinder SE, Ellis IO, Durrant LG. Total loss of MHC class I is an independent indicator of good prognosis in breast cancer. International Journal of Cancer. 2005;**117**(2):248-255

[104] Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, et al. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: Consequences for the NK-mediated killing of dendritic cells. Proceedings of the National Academy of Sciences of the United States of America. 2003;**100**(7):4120-4125

[105] Della Chiesa M, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, et al. The tryptophan

catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood. 2006;**108**(13):4118-4125

[106] Curtsinger JM, Mescher MF. Inflammatory cytokines as a third signal for T cell activation. Current Opinion in Immunology. 2010;**22**(3):333-340

[107] Kohlhapp FJ, Zloza A. CD4<sup>+</sup> T cells. In: Marshall JL, editor. Cancer Therapeutic Targets. New York, NY: Springer, New York; 2017. pp. 117-129

[108] Mescher MF, Agarwal P, Casey KA, Hammerbeck CD, Xiao Z, Curtsinger JM. Molecular basis for checkpoints in the CD8 T cell response: Tolerance versus activation. Seminars in Immunology. 2007;**19**(3):153-161

[109] Gu-Trantien C, Willard-Gallo K. Tumor-infiltrating follicular helper T cells: The new kids on the block. Oncoimmunology. 2013;**2**(10):e26066

[110] Tangye SG, Ma CS, Brink R, Deenick EK. The good, the bad and the ugly—TFH cells in human health and disease. Nature Reviews Immunology. 2013;**13**(6):412-426

[111] Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A et al. CD4+ follicular helper T cell infiltration predicts breast cancer survival. The Journal of Clinical Investigation. 2013;**123**(7):2873-2892

[112] Gollob JA, Ritz J. CD2-CD58 interaction and the control of T-cell interleukin-12 responsiveness. Adhesion molecules link innate and acquired immunity. Annals of the New York Academy of Sciences. 1996;**795**:71-81

[113] Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G, et al. Natural killer cell stimulatory factor (interleukin 12

[IL-12]) induces T helper type 1 (Th1) specific immune responses and inhibits the development of IL-4-producing Th cells. The Journal of Experimental Medicine. 1993;**177**(4):1199-1204

[114] Trinchieri G. Interleukin-12: A cytokine produced by antigenpresenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994;**84**(12):4008-4027

[115] Malek TR, Castro I. Interleukin-2 receptor signaling: At the interface between tolerance and immunity. Immunity. 2010;**33**(2):153-165

[116] Mosmann TR, Coffman RL. TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology. 1989;**7**:145-173

[117] Pruneri G, Vingiani A, Denkert C. Tumor infiltrating lymphocytes in early breast cancer. Breast (Edinburgh, Scotland). 2018;**37**:207-214

[118] Mahmoud S, Lee A, Ellis I, Green A. CD8(+) T lymphocytes infiltrating breast cancer: A promising new prognostic marker? Oncoimmunology. 2012;**1**(3):364-365

[119] Aspord C, Pedroza-Gonzalez A, Gallegos M, Tindle S, Burton EC, Su D, et al. Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4<sup>−</sup> T cells that facilitate tumor development. The Journal of Experimental Medicine. 2007;**204**(5):1037-1047

[120] Guglani L, Khader SA. Th17 cytokines in mucosal immunity and inflammation. Current Opinion in HIV and AIDS. 2010;**5**(2):120-127

[121] Zhu J, Paul WE. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunological Reviews. 2010;**238**(1):247-262

[122] Ye J, Livergood RS, Peng G. The role and regulation of human Th17 cells in tumor immunity. The American Journal of Pathology. 2013;**182**(1):10-20

[123] Josefowicz SZ, Lu L-F, Rudensky AY. Regulatory T cells: Mechanisms of differentiation and function. Annual Review of Immunology. 2012;**30**:531-564

[124] Sather BD, Treuting P, Perdue N, Miazgowicz M, Fontenot JD, Rudensky AY, et al. Altering the distribution of Foxp3(+) regulatory T cells results in tissue-specific inflammatory disease. The Journal of Experimental Medicine. 2007;**204**(6):1335-1347

[125] Khor B, Regulatory T. Cells: Central concepts from ontogeny to therapy. Transfusion Medicine Reviews. 2017;**31**(1):36-44

[126] Vignali DAA, Collison LW, Workman CJ. How regulatory T cells work. Nature Reviews. Immunology. 2008;**8**(7):523-532

[127] Hamidullah CB, Konwar R. Role of interleukin-10 in breast cancer. Breast Cancer Research and Treatment. 2012;**133**(1):11-21

[128] Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nature Reviews. Immunology. 2010;**10**(3):170-181

[129] Trandem K, Zhao J, Fleming E, Perlman S. Highly activated cytotoxic CD8 T cells express protective IL-10 at the peak of coronavirus-induced encephalitis. Journal of Immunology. 2011;**186**(6):3642-3652

[130] Curtsinger JM, Lins DC, Mescher MF. Signal 3 determines tolerance versus full activation of naive

**141**

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

Official Journal of the European Society for Medical Oncology.

[139] Nava-Castro KE, Palacios-Arreola MI, Ostoa-Saloma P, Muñiz-Hernández S, Cerbón MA, Gomez-Icazbalceta G, et al. The immunoendocrine network in breast cancer. Advances in Neuroimmune

[140] Brisken C, Park S, Vass T, Lydon JP,

2014;**25**(8):1536-1543

Biology. 2014;**5**(2):109-131

1998;**95**(9):5076-5081

[141] Pelletier G, El-Alfy M.

Immunocytochemical localization of estrogen receptors alpha and beta in the human reproductive organs. The Journal of Clinical Endocrinology and Metabolism. 2000;**85**(12):4835-4840

[142] Mallepell S, Krust A, Chambon P, Brisken C. Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**(7):2196-2201

[143] Hall JM, McDonnell DP. The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology. 1999;**140**(12):5566-5578

[144] Coriano CG, Liu F, Sievers CK, Liang M, Wang Y, Lim Y, et al. A computational-based approach to identify estrogen receptor alpha/beta heterodimer selective ligands. Molecular Pharmacology. 2018;**93**(3):197-207

O'Malley BW, Weinberg RA. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proceedings of the National Academy of Sciences of the United States of America.

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

CD8 T cells: Dissociating proliferation and development of effector function. The Journal of Experimental Medicine.

[131] Varn FS, Mullins DW, Arias-Pulido H, Fiering S, Cheng C. Adaptive immunity programmes in breast cancer.

Immunology. 2017;**150**(1):25-34

[132] Zhang N, Bevan MJ. CD8(+) T cells: Foot soldiers of the immune system. Immunity. 2011;**35**(2):161-168

[133] Maimela NR, Liu S, Zhang Y.

microenvironment. Computational and Structural Biotechnology Journal.

[134] Tugues S, Burkhard SH, Ohs I, Vrohlings M, Nussbaum K, Vom Berg J, et al. New insights into IL-12-mediated tumor suppression. Cell Death and Differentiation. 2015;**22**(2):237-246

[135] Schietinger A, Greenberg PD. Tolerance and exhaustion: Defining mechanisms of T cell dysfunction. Trends in Immunology. 2014;**35**(2):51-60

[136] Pipkin ME, Sacks JA, Cruz-Guilloty F, Lichtenheld MG, Bevan MJ, Rao A. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity.

[137] Yang SX, Wei WS, Ouyan QW, Jiang QH, Zou YF, Qu W, et al.

Interleukin-12 activated CD8(+) T cells induces apoptosis in breast cancer cells and reduces tumor growth. Biomedicine & pharmacotherapy = Biomedecine & Pharmacotherapie. 2016;**84**:1466-1471

[138] Ali HR, Provenzano E, Dawson SJ,

infiltration and breast cancer survival in 12,439 patients. Annals of Oncology:

T-cell

Blows FM, Liu B, Shah M, et al. Association between CD8<sup>+</sup>

T cells in tumor

Fates of CD8<sup>+</sup>

2019;**17**:1-13

2010;**32**(1):79-90

2003;**197**(9):1141-1151

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

CD8 T cells: Dissociating proliferation and development of effector function. The Journal of Experimental Medicine. 2003;**197**(9):1141-1151

*Tumor Progression and Metastasis*

[IL-12]) induces T helper type 1 (Th1) specific immune responses and inhibits the development of IL-4-producing Th cells. The Journal of Experimental Medicine. 1993;**177**(4):1199-1204

factors. Immunological Reviews.

[122] Ye J, Livergood RS, Peng G. The role and regulation of human Th17 cells in tumor immunity. The American Journal of Pathology. 2013;**182**(1):10-20

[123] Josefowicz SZ, Lu L-F, Rudensky AY.

[124] Sather BD, Treuting P, Perdue N, Miazgowicz M, Fontenot JD, Rudensky AY, et al. Altering the distribution of Foxp3(+) regulatory T cells results in tissue-specific inflammatory disease. The Journal of Experimental Medicine.

Regulatory T cells: Mechanisms of differentiation and function. Annual Review of Immunology.

2010;**238**(1):247-262

2012;**30**:531-564

2007;**204**(6):1335-1347

2017;**31**(1):36-44

2008;**8**(7):523-532

2012;**133**(1):11-21

2011;**186**(6):3642-3652

[130] Curtsinger JM, Lins DC, Mescher MF. Signal 3 determines tolerance versus full activation of naive

[125] Khor B, Regulatory T. Cells: Central concepts from ontogeny to therapy. Transfusion Medicine Reviews.

[126] Vignali DAA, Collison LW, Workman CJ. How regulatory T cells work. Nature Reviews. Immunology.

[127] Hamidullah CB, Konwar R. Role of interleukin-10 in breast cancer. Breast Cancer Research and Treatment.

[128] Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nature Reviews. Immunology. 2010;**10**(3):170-181

[129] Trandem K, Zhao J, Fleming E, Perlman S. Highly activated cytotoxic CD8 T cells express protective IL-10 at the peak of coronavirus-induced encephalitis. Journal of Immunology.

[114] Trinchieri G. Interleukin-12: A cytokine produced by antigen-

Blood. 1994;**84**(12):4008-4027

presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes.

[115] Malek TR, Castro I. Interleukin-2 receptor signaling: At the interface between tolerance and immunity. Immunity. 2010;**33**(2):153-165

[116] Mosmann TR, Coffman RL. TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties. Annual Review of

[117] Pruneri G, Vingiani A, Denkert C. Tumor infiltrating lymphocytes in early breast cancer. Breast (Edinburgh,

Immunology. 1989;**7**:145-173

Scotland). 2018;**37**:207-214

2007;**204**(5):1037-1047

[120] Guglani L, Khader SA. Th17 cytokines in mucosal immunity and inflammation. Current Opinion in HIV

[121] Zhu J, Paul WE. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription

and AIDS. 2010;**5**(2):120-127

[118] Mahmoud S, Lee A, Ellis I, Green A. CD8(+) T lymphocytes infiltrating breast cancer: A promising new prognostic marker? Oncoimmunology. 2012;**1**(3):364-365

[119] Aspord C, Pedroza-Gonzalez A, Gallegos M, Tindle S, Burton EC, Su D, et al. Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4<sup>−</sup> T cells that facilitate tumor development. The Journal of Experimental Medicine.

**140**

[131] Varn FS, Mullins DW, Arias-Pulido H, Fiering S, Cheng C. Adaptive immunity programmes in breast cancer. Immunology. 2017;**150**(1):25-34

[132] Zhang N, Bevan MJ. CD8(+) T cells: Foot soldiers of the immune system. Immunity. 2011;**35**(2):161-168

[133] Maimela NR, Liu S, Zhang Y. Fates of CD8<sup>+</sup> T cells in tumor microenvironment. Computational and Structural Biotechnology Journal. 2019;**17**:1-13

[134] Tugues S, Burkhard SH, Ohs I, Vrohlings M, Nussbaum K, Vom Berg J, et al. New insights into IL-12-mediated tumor suppression. Cell Death and Differentiation. 2015;**22**(2):237-246

[135] Schietinger A, Greenberg PD. Tolerance and exhaustion: Defining mechanisms of T cell dysfunction. Trends in Immunology. 2014;**35**(2):51-60

[136] Pipkin ME, Sacks JA, Cruz-Guilloty F, Lichtenheld MG, Bevan MJ, Rao A. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity. 2010;**32**(1):79-90

[137] Yang SX, Wei WS, Ouyan QW, Jiang QH, Zou YF, Qu W, et al. Interleukin-12 activated CD8(+) T cells induces apoptosis in breast cancer cells and reduces tumor growth. Biomedicine & pharmacotherapy = Biomedecine & Pharmacotherapie. 2016;**84**:1466-1471

[138] Ali HR, Provenzano E, Dawson SJ, Blows FM, Liu B, Shah M, et al. Association between CD8<sup>+</sup> T-cell infiltration and breast cancer survival in 12,439 patients. Annals of Oncology: Official Journal of the European Society for Medical Oncology. 2014;**25**(8):1536-1543

[139] Nava-Castro KE, Palacios-Arreola MI, Ostoa-Saloma P, Muñiz-Hernández S, Cerbón MA, Gomez-Icazbalceta G, et al. The immunoendocrine network in breast cancer. Advances in Neuroimmune Biology. 2014;**5**(2):109-131

[140] Brisken C, Park S, Vass T, Lydon JP, O'Malley BW, Weinberg RA. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proceedings of the National Academy of Sciences of the United States of America. 1998;**95**(9):5076-5081

[141] Pelletier G, El-Alfy M. Immunocytochemical localization of estrogen receptors alpha and beta in the human reproductive organs. The Journal of Clinical Endocrinology and Metabolism. 2000;**85**(12):4835-4840

[142] Mallepell S, Krust A, Chambon P, Brisken C. Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**(7):2196-2201

[143] Hall JM, McDonnell DP. The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology. 1999;**140**(12):5566-5578

[144] Coriano CG, Liu F, Sievers CK, Liang M, Wang Y, Lim Y, et al. A computational-based approach to identify estrogen receptor alpha/beta heterodimer selective ligands. Molecular Pharmacology. 2018;**93**(3):197-207

[145] Khan D, Ansar AS. The immune system is a natural target for estrogen action: Opposing effects of estrogen in two prototypical autoimmune diseases. Frontiers in Immunology. 2015;**6**:635

[146] Osborne CK, Schiff R, Fuqua SA, Shou J. Estrogen receptor: Current understanding of its activation and modulation. Clinical Cancer Research. 2001;**7**(12 Suppl):4338s-4342s; discussion 411s-412s

[147] Nemere I, Pietras RJ, Blackmore PF. Membrane receptors for steroid hormones: Signal transduction and physiological significance. Journal of Cellular Biochemistry. 2003;**88**(3):438-445

[148] Scarpin KM, Graham JD, Mote PA, Clarke CL. Progesterone action in human tissues: Regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression. Nuclear Receptor Signaling. 2009;**7**:e009-e

[149] Clarke RB, Spence K, Anderson E, Howell A, Okano H, Potten CS. A putative human breast stem cell population is enriched for steroid receptor-positive cells. Developmental Biology. 2005;**277**(2):443-456

[150] Fox EM, Davis RJ, Shupnik MA. ERbeta in breast cancer—Onlooker, passive player, or active protector? Steroids. 2008;**73**(11):1039-1051

[151] Shibuya R, Suzuki T, Miki Y, Yoshida K, Moriya T, Ono K, et al. Intratumoral concentration of sex steroids and expression of sex steroidproducing enzymes in ductal carcinoma in situ of human breast. Endocrine-Related Cancer. 2008;**15**(1):113-124

[152] Sasano H, Harada N. Intratumoral aromatase in human breast, endometrial, and ovarian malignancies. Endocrine Reviews. 1998;**19**(5):593-607

[153] Dimitrakakis C, Bondy C. Androgens and the breast. Breast Cancer Research: BCR. 2009;**11**(5):212

[154] Yeh S, Hu YC, Wang PH, Xie C, Xu Q, Tsai MY, et al. Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor. The Journal of Experimental Medicine. 2003;**198**(12):1899-1908

[155] Vera-Badillo FE, Templeton AJ, de Gouveia P, Diaz-Padilla I, Bedard PL, Al-Mubarak M, et al. Androgen receptor expression and outcomes in early breast cancer: A systematic review and metaanalysis. Journal of the National Cancer Institute. 2014;**106**(1):djt319

[156] Spurdle AB, Antoniou AC, Duffy DL, Pandeya N, Kelemen L, Chen X, et al. The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Research. 2005;**7**(2):R176-R183

[157] Labrie F, Belanger A, Luu-The V, Labrie C, Simard J, Cusan L, et al. DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: Its role during aging. Steroids. 1998;**63**(5-6):322-328

[158] Oberbeck R, Kobbe P. Dehydroepiandrosterone (DHEA): A steroid with multiple effects. Is there any possible option in the treatment of critical illness? Current Medicinal Chemistry. 2010;**17**(11):1039-1047

[159] Shaak TL, Wijesinghe DS, Chalfant CE, Diegelmann RF, Ward KR, Loria RM. Structural stereochemistry of androstene hormones determines interactions with human androgen, estrogen, and glucocorticoid receptors. International Journal of Medicinal Chemistry. 2013;**2013**:203606

**143**

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer*

Fabbri L, et al. Beta2-agonists prevent Th1 development by selective inhibition of interleukin 12. The Journal of Clinical Investigation. 1997;**100**(6):1513-1519

[169] Abdi K, Singh NJ, Matzinger P. Lipopolysaccharide-activated dendritic cells: "exhausted" or alert and waiting? Journal of immunology (Baltimore, MD:

1950). 2012;**188**(12):5981-5989

[170] Ben-Eliyahu S, Shakhar G, Shakhar K, Melamed R. Timing within the oestrous cycle modulates adrenergic

suppression of NK activity and

[171] Scanzano A, Cosentino M. Adrenergic regulation of innate immunity: A review. Frontiers in Pharmacology. 2015;**6**:171

[172] Hollmen M, Karaman S,

2016;**83**(5):373-374

2011;**125**(2):351-362

[173] Shi M, Liu D, Duan H, Qian L, Wang L, Niu L, et al. The beta2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Research and Treatment.

[174] Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva EV, et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity. 2016;**45**(5):1122-1134

2000;**83**(12):1747-1754

resistance to metastasis: Possible clinical implications. British Journal of Cancer.

Schwager S, Lisibach A, Christiansen A, Maksimow M, et al. G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer.

Scandinavian Journal of Immunology.

*DOI: http://dx.doi.org/10.5772/intechopen.88128*

proliferation, migration, and death of breast cancer cells. European Journal of Pharmacology. 2011;**660**(2-3):268-274

[161] Nakai A, Hayano Y, Furuta F, Noda M, Suzuki K. Control of

lymphocyte egress from lymph nodes through beta2-adrenergic receptors. The Journal of Experimental Medicine.

[162] Luker KE, Luker GD. Functions of CXCL12 and CXCR4 in breast cancer. Cancer Letters. 2006;**238**(1):30-41

[163] Dayer R, Babashah S, Jamshidi S, Sadeghizadeh M. Upregulation of CXC chemokine receptor 4-CXC chemokine ligand 12 axis ininvasive breast carcinoma: A potent biomarker predicting lymph node metastasis. Journal of Cancer Research and Therapeutics. 2018;**14**(2):345-350

[164] Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M, et al. Upregulation of CXCR4 is essential for HER2-mediated

[165] Mukherjee D, Zhao J. The role of chemokine receptor CXCR4 in breast cancer metastasis. American Journal of Cancer Research. 2013;**3**(1):46-57

Nava-Castro KE, Castro JI, Garcia-Zepeda E, Carrero JC, Morales-Montor J. The role of chemokines in breast cancer pathology and its possible use as therapeutic targets. Journal of Immunology Research.

[167] Herve J, Dubreil L, Tardif V, Terme M, Pogu S, Anegon I, et al. beta2-Adrenoreceptor agonist

inhibits antigen cross-presentation by dendritic cells. Journal of Immunology.

[168] Panina-Bordignon P, Mazzeo D, Lucia PD, D'Ambrosio D, Lang R,

tumor metastasis. Cancer Cell.

[166] Palacios-Arreola MI,

2014;**2014**:849720

2013;**190**(7):3163-3171

2004;6(5):459-469

dehydroepiandrosterone on

2014;**211**(13):2583-2598

[160] Lopez-Marure R, Contreras PG, Dillon JS. Effects of

*Neuroimmunoendocrine Interactions in Tumorigenesis and Breast Cancer DOI: http://dx.doi.org/10.5772/intechopen.88128*

dehydroepiandrosterone on proliferation, migration, and death of breast cancer cells. European Journal of Pharmacology. 2011;**660**(2-3):268-274

*Tumor Progression and Metastasis*

[145] Khan D, Ansar AS. The immune system is a natural target for estrogen action: Opposing effects of estrogen in two prototypical autoimmune diseases. Frontiers in Immunology. 2015;**6**:635

[153] Dimitrakakis C, Bondy C. Androgens and the breast. Breast Cancer Research: BCR. 2009;**11**(5):212

2003;**198**(12):1899-1908

Institute. 2014;**106**(1):djt319

Research. 2005;**7**(2):R176-R183

[158] Oberbeck R, Kobbe P.

[159] Shaak TL, Wijesinghe DS,

[160] Lopez-Marure R, Contreras

PG, Dillon JS. Effects of

Chalfant CE, Diegelmann RF, Ward KR, Loria RM. Structural stereochemistry of androstene hormones determines interactions with human androgen, estrogen, and glucocorticoid receptors. International Journal of Medicinal Chemistry. 2013;**2013**:203606

[157] Labrie F, Belanger A, Luu-The V, Labrie C, Simard J, Cusan L, et al. DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: Its role during aging. Steroids. 1998;**63**(5-6):322-328

Dehydroepiandrosterone (DHEA): A steroid with multiple effects. Is there any possible option in the treatment of critical illness? Current Medicinal Chemistry. 2010;**17**(11):1039-1047

[154] Yeh S, Hu YC, Wang PH, Xie C, Xu Q, Tsai MY, et al. Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor. The Journal of Experimental Medicine.

[155] Vera-Badillo FE, Templeton AJ, de Gouveia P, Diaz-Padilla I, Bedard PL, Al-Mubarak M, et al. Androgen receptor expression and outcomes in early breast cancer: A systematic review and metaanalysis. Journal of the National Cancer

[156] Spurdle AB, Antoniou AC, Duffy DL, Pandeya N, Kelemen L, Chen X, et al. The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer

[146] Osborne CK, Schiff R, Fuqua SA, Shou J. Estrogen receptor: Current understanding of its activation and modulation. Clinical Cancer Research.

[147] Nemere I, Pietras RJ, Blackmore PF.

[148] Scarpin KM, Graham JD, Mote PA,

[149] Clarke RB, Spence K, Anderson E, Howell A, Okano H, Potten CS. A putative human breast stem cell population is enriched for steroid receptor-positive cells. Developmental

Biology. 2005;**277**(2):443-456

[150] Fox EM, Davis RJ, Shupnik MA. ERbeta in breast cancer—Onlooker, passive player, or active protector? Steroids. 2008;**73**(11):1039-1051

[151] Shibuya R, Suzuki T, Miki Y, Yoshida K, Moriya T, Ono K, et al. Intratumoral concentration of sex steroids and expression of sex steroidproducing enzymes in ductal carcinoma in situ of human breast. Endocrine-Related Cancer. 2008;**15**(1):113-124

[152] Sasano H, Harada N. Intratumoral

endometrial, and ovarian malignancies. Endocrine Reviews. 1998;**19**(5):593-607

aromatase in human breast,

2001;**7**(12 Suppl):4338s-4342s;

Membrane receptors for steroid hormones: Signal transduction and physiological significance. Journal of Cellular Biochemistry.

Clarke CL. Progesterone action in human tissues: Regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression. Nuclear Receptor Signaling. 2009;**7**:e009-e

discussion 411s-412s

2003;**88**(3):438-445

**142**

[161] Nakai A, Hayano Y, Furuta F, Noda M, Suzuki K. Control of lymphocyte egress from lymph nodes through beta2-adrenergic receptors. The Journal of Experimental Medicine. 2014;**211**(13):2583-2598

[162] Luker KE, Luker GD. Functions of CXCL12 and CXCR4 in breast cancer. Cancer Letters. 2006;**238**(1):30-41

[163] Dayer R, Babashah S, Jamshidi S, Sadeghizadeh M. Upregulation of CXC chemokine receptor 4-CXC chemokine ligand 12 axis ininvasive breast carcinoma: A potent biomarker predicting lymph node metastasis. Journal of Cancer Research and Therapeutics. 2018;**14**(2):345-350

[164] Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M, et al. Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis. Cancer Cell. 2004;6(5):459-469

[165] Mukherjee D, Zhao J. The role of chemokine receptor CXCR4 in breast cancer metastasis. American Journal of Cancer Research. 2013;**3**(1):46-57

[166] Palacios-Arreola MI, Nava-Castro KE, Castro JI, Garcia-Zepeda E, Carrero JC, Morales-Montor J. The role of chemokines in breast cancer pathology and its possible use as therapeutic targets. Journal of Immunology Research. 2014;**2014**:849720

[167] Herve J, Dubreil L, Tardif V, Terme M, Pogu S, Anegon I, et al. beta2-Adrenoreceptor agonist inhibits antigen cross-presentation by dendritic cells. Journal of Immunology. 2013;**190**(7):3163-3171

[168] Panina-Bordignon P, Mazzeo D, Lucia PD, D'Ambrosio D, Lang R,

Fabbri L, et al. Beta2-agonists prevent Th1 development by selective inhibition of interleukin 12. The Journal of Clinical Investigation. 1997;**100**(6):1513-1519

[169] Abdi K, Singh NJ, Matzinger P. Lipopolysaccharide-activated dendritic cells: "exhausted" or alert and waiting? Journal of immunology (Baltimore, MD: 1950). 2012;**188**(12):5981-5989

[170] Ben-Eliyahu S, Shakhar G, Shakhar K, Melamed R. Timing within the oestrous cycle modulates adrenergic suppression of NK activity and resistance to metastasis: Possible clinical implications. British Journal of Cancer. 2000;**83**(12):1747-1754

[171] Scanzano A, Cosentino M. Adrenergic regulation of innate immunity: A review. Frontiers in Pharmacology. 2015;**6**:171

[172] Hollmen M, Karaman S, Schwager S, Lisibach A, Christiansen A, Maksimow M, et al. G-CSF regulates macrophage phenotype and associates with poor overall survival in human triple-negative breast cancer. Scandinavian Journal of Immunology. 2016;**83**(5):373-374

[173] Shi M, Liu D, Duan H, Qian L, Wang L, Niu L, et al. The beta2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Research and Treatment. 2011;**125**(2):351-362

[174] Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva EV, et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity. 2016;**45**(5):1122-1134

**145**

Section 3

Prediction of Response

to Therapy and Drug

Resistance

### Section 3
