5. Clinical diagnosis and biomarkers for PCa

The diagnosis and follow-up of PCa patients are often difficult because of the absence of specific markers that could change accordingly to the status of disease, the best therapy, and the existence of future complications caused by the chosen treatment.

For several decades many researchers joined efforts to study biomarkers of prognosis and treatment for PCa. Almost 50-years, PSA measurement represented the best marker for PCa. The primary idea was to substitute the digital rectal examination by PSA screening; nevertheless this was not possible despite the low specificity and false positive rate, as it is also observed in BPH [54]. No significant progress in the use of PSA as a precise biomarker of PCa was achieved during the past years.

Beyond this scenario, advances in genetic testing for PCa risk and new molecular diagnostic assays have been designed to improve diagnostic accuracy and treatment decision beyond prostate-specific antigen (PSA) testing. PSA is a protein of the kallikrein family synthesized in the prostatic epithelium and secreted in the seminal fluid. From its discovery in 1970 to the present day, it is a diagnostic tool used as a tumor marker for early diagnosis, treatment and monitoring of patients with neoplasia in conjunction with the rectal examination. However, many studies have questioned the use of this biomarker for a diagnosis, due to the exponential increase in the diagnosis of PCa and, consequently, the increase of unnecessary hormonal, radiotherapeutic, chemotherapeutic and surgical treatments such as radical prostatectomy [55, 56]. PSA evaluation is performed by its measurement in serum using immunoassay (34 kDa). Normal values vary according to the method used. In most tests, values of up to 2.5 ng/ mL are allowed as normal. If this value is higher, it is indicated to request the dosage of fractionated PSA, which relates total PSA to free PSA (fPSA). The result is expected to be equal to or greater than 20%; if it is lower, there is a probability that it is a PCa [57]. However, this test does not have 100% of specificity or sensitivity, insofar as there is PCa whose PSA is not altered, and there are other transient factors that can raise serum PSA levels, such as prostatitis [58], benign prostatic hyperplasia [59], prostatic biopsies [60] and trauma, due to prostatic cell lysis releasing PSA into the bloodstream [61].

main factors for this association: the improvement of diagnostic methods and the extended life expectancy of men over the years; since PCa has slow growth and its incidence is ageassociated, it is very comprehensible the increased detection of this malignant neoplasia lately in the years. The origin of PCa and the several processes giving direction to PCa carcinogenesis are still unclear, but often are assumed that several components may influence it, among which stands out: diet, genetic, hormonal, and environmental factors; all currently being widely

The treatment of PCa can be very controversial because there are many variables, such as the patient's age, prostatic specific antigen (PSA) concentrations and the stage of the tumor. Patients in inoperable conditions, due to age, are treated with hormone therapy or radiation. The most common hormone therapy for PCa is the androgen deprivation, since the prostate gland is a highly androgen dependent gland, and because the majority of prostate tumors originate from androgen-dependent glandular epithelial cells of the prostate [53]. The thera-

The diagnosis and follow-up of PCa patients are often difficult because of the absence of specific markers that could change accordingly to the status of disease, the best therapy, and

For several decades many researchers joined efforts to study biomarkers of prognosis and treatment for PCa. Almost 50-years, PSA measurement represented the best marker for PCa. The primary idea was to substitute the digital rectal examination by PSA screening; nevertheless this was not possible despite the low specificity and false positive rate, as it is also observed in BPH [54]. No significant progress in the use of PSA as a precise biomarker of PCa

Beyond this scenario, advances in genetic testing for PCa risk and new molecular diagnostic assays have been designed to improve diagnostic accuracy and treatment decision beyond prostate-specific antigen (PSA) testing. PSA is a protein of the kallikrein family synthesized in the prostatic epithelium and secreted in the seminal fluid. From its discovery in 1970 to the present day, it is a diagnostic tool used as a tumor marker for early diagnosis, treatment and monitoring of patients with neoplasia in conjunction with the rectal examination. However, many studies have questioned the use of this biomarker for a diagnosis, due to the exponential increase in the diagnosis of PCa and, consequently, the increase of unnecessary hormonal, radiotherapeutic, chemotherapeutic and surgical treatments such as radical prostatectomy [55, 56]. PSA evaluation is performed by its measurement in serum using immunoassay (34 kDa). Normal values vary according to the method used. In most tests, values of up to 2.5 ng/ mL are allowed as normal. If this value is higher, it is indicated to request the dosage of fractionated PSA, which relates total PSA to free PSA (fPSA). The result is expected to be equal to or greater than 20%; if it is lower, there is a probability that it is a PCa [57]. However, this test does not have 100% of specificity or sensitivity, insofar as there is PCa whose PSA is not altered, and there are other transient factors that can raise serum PSA levels, such as prostatitis

pies in use for PCa will be best addressed later in this chapter.

the existence of future complications caused by the chosen treatment.

5. Clinical diagnosis and biomarkers for PCa

investigated in the literature.

188 Pathophysiology - Altered Physiological States

was achieved during the past years.

Despite results enhancing detection at earlier stage and decreasing the number of metastatic patients, the use of prostate-specific antigen (PSA) to detect PCa has low specificity, unnecessary biopsies and frequently mistaken diagnoses. Also, PCa has various features so prognosis following diagnosis is greatly variable. Hence, there is a requirement for new prognostic biomarkers, particularly to differentiate between inactive and aggressive forms of the disease, to improve clinical management of PCa patients. Research continues into finding additional markers that may allow this goal to be attained.

In order to improve the specificity of PSA as a tumor biomarker, tests called PHI (Prostatic Health Index), that predicts the risk of having PCa and 4 K score™ (predicts the risk of having high-risk of PCa) were launched on the American and European markets [62]. 4 K score™ blood test combines 4 prostatic biomarkers (total PSA, fPSA, intact PSA, and human kallekrein 2(hK2)) with the age of the patient, the digital rectal exam (DRE) findings (presence of a nodule or not), and the result of previous biopsies [63]. The higher the score, the greater the probability of finding tumor cells in a biopsy (Gleason ≥ 7). This test combination is interesting because it does not allow unnecessary biopsies to be performed, whereas post-operative, as well as any surgery, has risks and can lead to future complications for the patient, affecting his quality of life.

Another non-invasive test available is the ExoDxTM Prostate (IntelliScore) Test18, which, through urinalysis, assesses the risk of developing invasive PCa, and thereby target the best treatment by molecular analysis of three specific genes in exosome and microvesic RNAs released by tumor cells, called extracellular vesicles (further discussed in this chapter) [64]. These related genes (ERG, PCA3 and SPDEF) are most commonly related to tumor progression and, consequently, its aggressiveness and invasion [65].

It is important to note that these tests are not accessible to the entire population, either because of the high cost of the technology, or because some countries have still not approved it. Thus, the main diagnostic method used nowadays for the screening and detection of the PCa remains PSA testing and rectal examination (DRE). If the results of these exams are altered, a biopsy is necessary to confirm the diagnosis, and determine the aggressiveness and prognosis of the cancer. This is done by histological analysis of the biopsied tissue, following classification according to the Gleason Scale. This system consists of the sum of 2 values that represent the degree of the tumor, and that determine the dominant cellular pattern and the most frequent cellular pattern, respectively. Tumor grades range from 1 to 5, the former representing more differentiated and prostate restricted tumors, while the latter represents totally undifferentiated tumors that have normally infiltrated the glandular stoma. The score, therefore, ranges from 2 (1 + 1) to 10 (5 + 5), and values below 4 on the Gleason Scale represent a well differentiated PCa; between 5 and 7, an intermediate PCa; and between 8 and 10, advanced PCa [66]. The determination of the degree and stage of cancer allows classification into high, intermediate and low risk categories.

The clinical picture of castrated-resistant prostate cancer (CRPC) is quite heterogeneous, ranging from the asymptomatic increase in the PSA indices to the distant metastasis (commonly bone metastasis), with an important impairment of the patient's quality of life [66]. This is a reflection of the complexity and diversity of biomolecular alterations already found in biopsies. Tumor progression is related to a number of genetic changes that can affect AR, signaling cascades, apoptosis mechanisms and cell regulation, or, as in many cases, a combination of all of them [67].

Biomolecular techniques, such as fluorescent in situ hybridization (FISH) and Microarray, for example, have identified a variety of key factors genes, oncogenes and tumor suppressor genes, related to the development and progression of PCa [68, 69]. The use of molecular techniques also allowed the identification of some genes related to the suppressive function of metastasis, opening a new perspective for researching the phenomenon of tumor invasion to other tissues and, with that, to identify and elucidate new indicators of prognosis, or even PCa target therapies. As example, some studies have focused attention on the CDH1 gene and its protein expression, located on chromosome 16q22, which encodes the E-cadherin, a glycoprotein responsible for cell-cell adhesion, an important cellular function that prevents EMT in tumor progression [70].

Figure 1. Representative TEM images of exosomes derived from (a) C42 PCa cell line, (b) LNCaP xenograft serum and (c) patient plasma by ultracentrifugation method. Exosomes were negatively stained with 2% uracyl acetate after removal of moisture. Arrows indicate cup-shaped structures which are identified as exosomes (30–100 nm in diameter). From: Kharmate et al. [86]. Online available at: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154967.

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Figure 2. Schematic representation of possible role of EGFR-exosomes in cancer progression. Ligand binding induces rapid activation and internalization of EGFR and endocytosis. Whether EGFR escapes lysosomal degradation and is released extracellularly via exosomes is unknown. The transfer of EGFR via exosomes may significantly alter the tumor microenvironment and could be relevant to progression of an aggressive PCa. From: Kharmate et al. [86]. Online available at:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154967.

The Metastatic prostate adenocarcinoma (metPA) is diagnosed by immunohistochemistry. Nowadays very promising biomarkers have been used to determine prostatic origin of metPA, such as prostate specific membrane antigen (PSMA) and NKX3.1 [71]. PSMA is a type II membrane protein not secreted and is expressed in all forms of prostate tissue, but it is expressed at high levels on malignant prostate cells with limited extraprostatic expression [72]. Many approaches to target PSMA include DNA-based vaccines, as well as passive administration of monoclonal antibodies (PSMA-mAb), including 7E11.C5.3, that has already been approved by USA FDA (Food and Drug Administration); the medication is commercially available as ProstaScint® [72, 73].

Compared to PSA, PSMA is upregulated with androgen deprivation, and its expression was correlated with cancer aggressiveness and poor prognosis, while PSA decreases with androgen deprivation [72]. PSMA was also evaluated in PCa using PET molecular imaging system. After all, PSMA is not specific only to prostate gland; it is expressed in other normal tissues (such as salivary glands, duodenal mucosa, renal tubular cells, and neuroendocrine cells in the colon), and in malignant cells (renal cell carcinomas, colon carcinomas, and endothelial cells that surround or are into the tumors) [74].

Although multiple independent studies sought to demonstrate evidence that genetic variations may be independent predictors of PCa risk in addition to family history and serum PSA levels, the challenge in the years to come will be to introduce these new gene-based diagnostic and prognostic tests in algorithms integrating the other known risk factors including age, ethnicity, family history and PSA level to better tailor diagnostic and therapeutic strategies for PCa.

#### 5.1. The extracellular vesicles (exosomes) and PCa: beyond classical biomarkers

Several studies have related to novel PCa biomarkers that can precisely detect, and treat, types of aggressive cancer by headlining circulating tumor cells (CTCs) and circulating extracellular vesicles (EVs) (Figure 1). Notably, EVs are released by almost all the cells, and brings lots of molecular information. The study based on EVs provides lots of information about its content, An Overview on Prostate Pathophysiology: New Insights into Prostate Cancer Clinical Diagnosis http://dx.doi.org/10.5772/intechopen.74269 191

reflection of the complexity and diversity of biomolecular alterations already found in biopsies. Tumor progression is related to a number of genetic changes that can affect AR, signaling cascades, apoptosis mechanisms and cell regulation, or, as in many cases, a combination of all

Biomolecular techniques, such as fluorescent in situ hybridization (FISH) and Microarray, for example, have identified a variety of key factors genes, oncogenes and tumor suppressor genes, related to the development and progression of PCa [68, 69]. The use of molecular techniques also allowed the identification of some genes related to the suppressive function of metastasis, opening a new perspective for researching the phenomenon of tumor invasion to other tissues and, with that, to identify and elucidate new indicators of prognosis, or even PCa target therapies. As example, some studies have focused attention on the CDH1 gene and its protein expression, located on chromosome 16q22, which encodes the E-cadherin, a glycoprotein responsible for cell-cell adhesion, an important cellular function that prevents EMT in

The Metastatic prostate adenocarcinoma (metPA) is diagnosed by immunohistochemistry. Nowadays very promising biomarkers have been used to determine prostatic origin of metPA, such as prostate specific membrane antigen (PSMA) and NKX3.1 [71]. PSMA is a type II membrane protein not secreted and is expressed in all forms of prostate tissue, but it is expressed at high levels on malignant prostate cells with limited extraprostatic expression [72]. Many approaches to target PSMA include DNA-based vaccines, as well as passive administration of monoclonal antibodies (PSMA-mAb), including 7E11.C5.3, that has already been approved by USA FDA (Food and Drug Administration); the medication is commercially

Compared to PSA, PSMA is upregulated with androgen deprivation, and its expression was correlated with cancer aggressiveness and poor prognosis, while PSA decreases with androgen deprivation [72]. PSMA was also evaluated in PCa using PET molecular imaging system. After all, PSMA is not specific only to prostate gland; it is expressed in other normal tissues (such as salivary glands, duodenal mucosa, renal tubular cells, and neuroendocrine cells in the colon), and in malignant cells (renal cell carcinomas, colon carcinomas, and endothelial cells that

Although multiple independent studies sought to demonstrate evidence that genetic variations may be independent predictors of PCa risk in addition to family history and serum PSA levels, the challenge in the years to come will be to introduce these new gene-based diagnostic and prognostic tests in algorithms integrating the other known risk factors including age, ethnicity, family history and PSA level to better tailor diagnostic and therapeutic strategies for PCa.

Several studies have related to novel PCa biomarkers that can precisely detect, and treat, types of aggressive cancer by headlining circulating tumor cells (CTCs) and circulating extracellular vesicles (EVs) (Figure 1). Notably, EVs are released by almost all the cells, and brings lots of molecular information. The study based on EVs provides lots of information about its content,

5.1. The extracellular vesicles (exosomes) and PCa: beyond classical biomarkers

of them [67].

190 Pathophysiology - Altered Physiological States

tumor progression [70].

available as ProstaScint® [72, 73].

surround or are into the tumors) [74].

Figure 1. Representative TEM images of exosomes derived from (a) C42 PCa cell line, (b) LNCaP xenograft serum and (c) patient plasma by ultracentrifugation method. Exosomes were negatively stained with 2% uracyl acetate after removal of moisture. Arrows indicate cup-shaped structures which are identified as exosomes (30–100 nm in diameter). From: Kharmate et al. [86]. Online available at: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154967.

Figure 2. Schematic representation of possible role of EGFR-exosomes in cancer progression. Ligand binding induces rapid activation and internalization of EGFR and endocytosis. Whether EGFR escapes lysosomal degradation and is released extracellularly via exosomes is unknown. The transfer of EGFR via exosomes may significantly alter the tumor microenvironment and could be relevant to progression of an aggressive PCa. From: Kharmate et al. [86]. Online available at: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154967.

such as: lipids, proteins, nucleic acids and metabolites [75, 76]. All of each can be isolated in small volumes from body fluids, just by using some steps of ultracentrifugation, as a noninvasive method to monitor disease progression, and are proposed to function as tumorspecific molecular signatures. They are small structures (50–150 nm) that carry genetic and/or nongenetic materials from tumor cells. Recent study analyzed the presence of CD9 and CD63 (a housekeeping exosome marker) positive EVs, demonstrating that patients with metastatic cancer and detectable CTCs have higher CD9 detectable in plasma [77]. The CD9 positive EVs were found higher in plasma of PCa patients compared to HPB patients, and were related to paracrine signaling that contributes to PCa progression [77]. In silico reanalysis of genes involved in vesicular trafficking demonstrated that the expression of required well-known endosomal sorting complexes, such as RAB27A, RAB27B and VPS36, are downregulated in patients with advanced PCa [78].

Additionally to androgens (as described in Section 3), prostate physiology is, in part, regulated by the epidermal growth factor (EGF), whose action is mediated by its receptor (EGFR). EGFR is one of the mediators of cell proliferation, and its overexpression has been associated with aggressiveness and invasion of PCa. It has been described and identified as an important anti-PCa target, and some inhibitors of EGFR were tested with limited effectiveness in prostate cancer patients; they are Gefitinib, Lapatinib, and Erlotinib [83–85].

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Previous studies have demonstrated that PSA can be detectable in plasma and urine derived EV's [87]. Logozzi et al. [88] demonstrated that an acid microenvironment (such as the tumor microenvironment), functions as a key factor for the exosomal releasing, and determines the quality and quantity of released vesicles, including the ones containing PSA, an enzyme that

Figure 3. The prostate specific antigen (PSA) remains the most used biomarker in the management of early prostate cancer (PCa), in spite of the problems related to false positive results and overdiagnosis. New biomarkers have been proposed in recent years with the aim of increasing specificity and distinguishing aggressive from non-aggressive PCa. The emerging role of the prostate health index and the 4Kscore: both are blood-based tests related to the aggressiveness of the tumor, which provide the risk of suffering PCa and avoiding negative biopsies. Furthermore, the use of urine has emerged as a non-invasive way to identify new biomarkers in recent years, including the PCA3 and TMPRSS2: ERG fusion gene. Available results showed PCA3 score usefulness to decide the repetition of biopsy in patients with a previous negative result, although its relationship with the aggressiveness of the tumor is controversial. More recently, aberrant the microRNA expression in PCa has been reported by different authors. The utility of circulating and urinary microRNAs in the detection and prognosis of PCa has also been explored. Although several of these new biomarkers have been recommended by different guidelines, large prospective and comparative studies are necessary to establish their value in PCa detection and prognosis. From: Filella and Foj [69]. Online available at: http://www.mdpi.com/1422-0067/17/11/1784.

Recently, EGFR was also observed in EVs (Figure 2) of PCa patients [86].

needs an acidic microenvironment for full activation, in PCa.

Other studies suggest possible micro-RNAs roles in PCa [79] due to their recruitment to EVs present in various human body fluids; they are miR-2909 and miR-615-3p, which was detected in urinary-exosomal of PCa patients [80, 81]. Also EVs was useful to monitor the response to radiation therapy, in the search for a personalized treatment according to different profiling levels [82].


Table 1. Biomarkers in PCa detection and prognosis.

Additionally to androgens (as described in Section 3), prostate physiology is, in part, regulated by the epidermal growth factor (EGF), whose action is mediated by its receptor (EGFR). EGFR is one of the mediators of cell proliferation, and its overexpression has been associated with aggressiveness and invasion of PCa. It has been described and identified as an important anti-PCa target, and some inhibitors of EGFR were tested with limited effectiveness in prostate cancer patients; they are Gefitinib, Lapatinib, and Erlotinib [83–85]. Recently, EGFR was also observed in EVs (Figure 2) of PCa patients [86].

such as: lipids, proteins, nucleic acids and metabolites [75, 76]. All of each can be isolated in small volumes from body fluids, just by using some steps of ultracentrifugation, as a noninvasive method to monitor disease progression, and are proposed to function as tumorspecific molecular signatures. They are small structures (50–150 nm) that carry genetic and/or nongenetic materials from tumor cells. Recent study analyzed the presence of CD9 and CD63 (a housekeeping exosome marker) positive EVs, demonstrating that patients with metastatic cancer and detectable CTCs have higher CD9 detectable in plasma [77]. The CD9 positive EVs were found higher in plasma of PCa patients compared to HPB patients, and were related to paracrine signaling that contributes to PCa progression [77]. In silico reanalysis of genes involved in vesicular trafficking demonstrated that the expression of required well-known endosomal sorting complexes, such as RAB27A, RAB27B and VPS36, are downregulated in

Other studies suggest possible micro-RNAs roles in PCa [79] due to their recruitment to EVs present in various human body fluids; they are miR-2909 and miR-615-3p, which was detected in urinary-exosomal of PCa patients [80, 81]. Also EVs was useful to monitor the response to radiation therapy, in the search for a personalized treatment according to different profiling

patients with advanced PCa [78].

192 Pathophysiology - Altered Physiological States

Table 1. Biomarkers in PCa detection and prognosis.

levels [82].

Previous studies have demonstrated that PSA can be detectable in plasma and urine derived EV's [87]. Logozzi et al. [88] demonstrated that an acid microenvironment (such as the tumor microenvironment), functions as a key factor for the exosomal releasing, and determines the quality and quantity of released vesicles, including the ones containing PSA, an enzyme that needs an acidic microenvironment for full activation, in PCa.

Figure 3. The prostate specific antigen (PSA) remains the most used biomarker in the management of early prostate cancer (PCa), in spite of the problems related to false positive results and overdiagnosis. New biomarkers have been proposed in recent years with the aim of increasing specificity and distinguishing aggressive from non-aggressive PCa. The emerging role of the prostate health index and the 4Kscore: both are blood-based tests related to the aggressiveness of the tumor, which provide the risk of suffering PCa and avoiding negative biopsies. Furthermore, the use of urine has emerged as a non-invasive way to identify new biomarkers in recent years, including the PCA3 and TMPRSS2: ERG fusion gene. Available results showed PCA3 score usefulness to decide the repetition of biopsy in patients with a previous negative result, although its relationship with the aggressiveness of the tumor is controversial. More recently, aberrant the microRNA expression in PCa has been reported by different authors. The utility of circulating and urinary microRNAs in the detection and prognosis of PCa has also been explored. Although several of these new biomarkers have been recommended by different guidelines, large prospective and comparative studies are necessary to establish their value in PCa detection and prognosis. From: Filella and Foj [69]. Online available at: http://www.mdpi.com/1422-0067/17/11/1784.

To summarize, in recent years, many new promising PCa biomarkers have been identified (Table 1) (Figure 3), and found to be associated with tumor aggressiveness. Multiplied studies showed the utility of the PHI, the 4Kscore™ and the PCA3 score to reduce the number of unnecessary prostate biopsies in PSA tested men. Actually, these biomarkers have been recommended for different guidelines. Still, large prospective studies, avoiding bias due to selection of patients according to PSA serum levels, are necessary to compare the value of these biomarkers. Also, new efforts are necessary to standardize the methodology for the measurement of exosomal and non-exosomal miRNAs, in order to analyze accurately their usefulness in the management of patients with early PCa. Finally, the combined role of these biomarkers together with magnetic resonance imaging data should be elucidated [89].

AR gene that allow its activation by other endogenous steroids, increased production of growth factors activating AR even in the absence of androgen, changes in co-regulatory proteins and

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There are two drug lines for hormone therapy; the first line accounts for the central blockers that constitute the agonists of gonadotrophin-releasing hormone (GnRH agonists), and the peripheral androgen receptor blockers. Usually they are used in a comminuted way, since the central blockers, for example, Leuprolide (Lupron) and Gosserelin Acetate (Zoladex), acts through the interruption of the pituitary feedback mechanism, inhibiting LH realizing by the pituitary gland, and leading to a decreased testoterone production [63]. However, because these drugs initially boosted testosterone production, the combination with peripheral androgen receptor blockers, such as Bicalutamide (Casodex), Flutamide (Flutamide) and Androcur (Androcur), shall be indicated due to their binding capacity to the ARs in a way that inhibits

The second line of therapy is most commonly used when PCa is resistant to the first-line hormonal therapies stage. Abiraterone Acetate (Zytiga) is a drug that primarily acts on the adrenal gland through the inhibition of the 17α-hydroxylase/C17, 20-lyase (CYP17) enzyme, essential for androgen biosynthesis in tissues [94, 95]. Enzalutamide (Xtandi) is another drug of this therapeutic line that works by inhibiting androgen receptors, their signaling pathways,

It is important to emphasize that hormonal therapy is a palliative treatment, in that it acts to contain the progression of advanced PCa, and not its elimination. In this context, given the scarcity of effective treatments for these types of tumors, it is promising to still search for new biomarkers capable of not only diagnosing PCa early, but also being able to evaluate its

1 Research Associate at Department of Structural and Functional Biology, Biology Institute,

2 Faculty of Medicine of Santa Casa de Sao Paulo, Department of Morphology, FCMSCSP,

3 Undergraduated Medical Student at Faculty of Medicine of Jundiai, Jundiai-SP, Brazil

4 Department of Morphology and Basic Pathology, Faculty of Medicine of Jundiai, Jundiai-SP,

, Caroline Brito dos Santos<sup>3</sup>

\*

,

upregulation of enzymes related to androgen synthesis [92].

androgenic stimulation, deactivating their genetic expression [93].

and is able to act on anti-androgen-resistant tumor cells.

Gustavo Ferreira Simoes1,2, Paula Sakuramoto3

\*Address all correspondence to: taizea@gmail.com

Nilva Karla Cervigne Furlan<sup>4</sup> and Taize Machado Augusto<sup>4</sup>

aggressiveness and prognosis.

UNICAMP, Campinas-SP, Brazil

Author details

Sao Paulo-SP, Brazil

Brazil

Adapted from: Filella and Foj [69]. (\*Recommended by the National Comprehensive Cancer Network).
