**Involvement of Squamous Cell Carcinoma Antigen in Invasion and Metastasis of Squamous Cell Carcinoma of Uterine Cervix**

Akihiro Murakami\*, Keiko Yoshidomi and Norihiro Sugino *Yamaguchi University Graduate School of Medicine, Department of Obstetrics and Gynecology, Ube Japan* 

## **1. Introduction**

152 Squamous Cell Carcinoma

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epidermal growth factor receptor gene in human squamous carcinoma cell lines.

expression and survival in head and neck squamous cell carcinoma. *Arch* 

A tumor-related protein, squamous cell carcinoma antigen (SCCA) was first discovered in uterine cervical squamous cell carcinoma [1], and subsequently has been used as a useful tumor marker for squamous cell carcinoma of various organs [2-4]. Cloning and characterization of *SCCA* cDNA has revealed that SCCA belongs to serine proteinase inhibitor (serpin) family [5]. Since SCCA is present not only in squamous cell carcinomas but also in normal squamous epithelium, the biological function of SCCA is of great interest. The present paper reviews the current understanding of SCCA, focusing on its biological function in uterine cervical squamous cell carcinoma.

## **2. Characteristics of SCCA**

SCCA consists of more than 10 protein fractions with different isoelectric points, ranging from 5.9 to 6.6, which are roughly divided into two groups: the acidic SCCAs with pIs of less than 6.25 and the neutral SCCAs with pIs of 6.25 or higher [6]. The neutral SCCAs are generally present inside the cell, whereas the acidic SCCAs are often increased in squamous cell carcinomas and is easily secreted by the cell [6]. In 1991, our laboratory reported the cloning of *SCCA* cDNA, which consist of 1,170 nucleotides coding for 390 amino acids [5]. Schneider et al. also found two *SCCA* genes (*SCCA1* and *SCCA2*) and these two genes were tandemly arrayed at the human chromosome 18q21.3 locus [7, 8]. The predicted amino acid sequences of SCCA1 and SCCA2 are 92% identical and have identical predicted secondary structures, which suggests that *SCCA1* gene encodes the neutral SCCA, while *SCCA2* gene encodes the acidic SCCA [7]. SCCA1 inhibits the activities of serine proteinases, e.g. chymotrypsin and cysteine proteinases, e.g. cathepsin K, L, S and papain, whereas SCCA2 inhibits serine proteinases such as cathepsin G and chymase *in vitro* [9-12] (Table 1). For these reasons, SCCA1 and SCCA2 are thought to have different biological functions. It is thus of interest to better understand the biological behaviors of SCCAs in normal squamous epithelium and squamous cell carcinomas.

<sup>\*</sup>Corresponding Author

Involvement of Squamous Cell Carcinoma Antigen in

of integuments during evolutional change.

magnification: X 100).

of acidic SCCA [21].

Invasion and Metastasis of Squamous Cell Carcinoma of Uterine Cervix 155

shows that SCCA is present in the spinous and granular compartments, but not in the basal and parabasal cells [17] (Fig. 1). SCCA is not present in the epithelial region adjacent to the squamo-columnar junction of the uterine cervix. Interestingly, SCCA levels begin to increase at 18-20 weeks of pregnancy for the first time when the fetal epidermis begins to cornify during the development of human fetal skins [18]. *SCCA* genes has been found in most of the eutheria (placental mammals), but not in other vertebrates [19]. Furthermore, several eutherian species show heterogeneous patterns of *SCCA* nucleotides in Southern blot analyses [19]. This suggests that SCCA has had a role in the stratification and differentiation

Fig. 1. Immunohistochemistry for SCCA expression in normal cervical squamous epithelium. SCCA is expressed in all epithelial layers except the basal layer (original

The stratification and cornification of normal squamous epithelial cells are influenced by extracellular calcium concentrations. Calcium concentrations are low in the parabasal layer but high in the granular layers. Keratinocytes begin to stratify and cornify in the presence of high concentrations of calcium [20]. High concentrations of calcium stimulate the production of neutral SCCA, whereas low concentration of calcium stimulate the production

The final stage of differentiation of squamous epithelial cells is modulated by several cysteine proteinases, such as cathepsin L, calpain, and epidermal transglutaminase [20].


Table 1. Inhibitory effects of SCCAs on proteinases.

## **3. Evaluation of SCCA in clinical practice**

Serum SCCA levels have been used as an indicator of a variety of squamous cell carcinomas, including skin cancers, head and neck cancers, esophageal cancers, lung cancers, bladder cancers, epidermoid cancers of the anal canal, and malignant transformation of mature cystic ovarian teratoma [13]. Serum SCCA levels are especially useful for monitoring treatment efficacy, disease progression and recurrence. In general, increased serum SCCA levels reflect disease progression and poor prognosis in squamous cell carcinomas [13]. In advanced cancers, pretreatment serum SCCA levels are associated with clinical stages, tumor sizes, and lymph node involvement. Furthermore, over 6 ng/ml of serum SCCA level shows a significant independent effect on survival and disease-free survival [14]. Even in the early stage of uterine squamous cell carcinomas, elevated serum SCCA levels predict pelvic lymph node involvement and are associated with a poor prognosis [15]. Recently, patients with elevated *SCCA2/SCCA1* mRNA ratios in uterine squamous cell carcinoma tissues were found to be at higher risk for recurrence in early stage uterine cervical cancers, suggesting SCCA2 is increased during cervical carcinogenesis [16]. In addition to malignant diseases, several benign and chronic inflammatory skin diseases, such as psoriasis, pemphigus, or eczema are often characterized by elevated SCCA levels [13]. SCCA will be a useful marker for monitoring the status of these diseases not only for malignant diseases but also for non-malignant diseases.

#### **4. Role of SCCA in normal squamous epithelial cells**

Human squamous epithelium is composed of four compartments; *stratum germinativus*, *stratum spinosum*, *stratum granulosum* and *stratum corneum*. Immunohistochemical staining

Serum SCCA levels have been used as an indicator of a variety of squamous cell carcinomas, including skin cancers, head and neck cancers, esophageal cancers, lung cancers, bladder cancers, epidermoid cancers of the anal canal, and malignant transformation of mature cystic ovarian teratoma [13]. Serum SCCA levels are especially useful for monitoring treatment efficacy, disease progression and recurrence. In general, increased serum SCCA levels reflect disease progression and poor prognosis in squamous cell carcinomas [13]. In advanced cancers, pretreatment serum SCCA levels are associated with clinical stages, tumor sizes, and lymph node involvement. Furthermore, over 6 ng/ml of serum SCCA level shows a significant independent effect on survival and disease-free survival [14]. Even in the early stage of uterine squamous cell carcinomas, elevated serum SCCA levels predict pelvic lymph node involvement and are associated with a poor prognosis [15]. Recently, patients with elevated *SCCA2/SCCA1* mRNA ratios in uterine squamous cell carcinoma tissues were found to be at higher risk for recurrence in early stage uterine cervical cancers, suggesting SCCA2 is increased during cervical carcinogenesis [16]. In addition to malignant diseases, several benign and chronic inflammatory skin diseases, such as psoriasis, pemphigus, or eczema are often characterized by elevated SCCA levels [13]. SCCA will be a useful marker for monitoring the status of these diseases not only for malignant diseases but also for non-malignant diseases.

Human squamous epithelium is composed of four compartments; *stratum germinativus*, *stratum spinosum*, *stratum granulosum* and *stratum corneum*. Immunohistochemical staining

Table 1. Inhibitory effects of SCCAs on proteinases.

**3. Evaluation of SCCA in clinical practice** 

**4. Role of SCCA in normal squamous epithelial cells** 

shows that SCCA is present in the spinous and granular compartments, but not in the basal and parabasal cells [17] (Fig. 1). SCCA is not present in the epithelial region adjacent to the squamo-columnar junction of the uterine cervix. Interestingly, SCCA levels begin to increase at 18-20 weeks of pregnancy for the first time when the fetal epidermis begins to cornify during the development of human fetal skins [18]. *SCCA* genes has been found in most of the eutheria (placental mammals), but not in other vertebrates [19]. Furthermore, several eutherian species show heterogeneous patterns of *SCCA* nucleotides in Southern blot analyses [19]. This suggests that SCCA has had a role in the stratification and differentiation of integuments during evolutional change.

Fig. 1. Immunohistochemistry for SCCA expression in normal cervical squamous epithelium. SCCA is expressed in all epithelial layers except the basal layer (original magnification: X 100).

The stratification and cornification of normal squamous epithelial cells are influenced by extracellular calcium concentrations. Calcium concentrations are low in the parabasal layer but high in the granular layers. Keratinocytes begin to stratify and cornify in the presence of high concentrations of calcium [20]. High concentrations of calcium stimulate the production of neutral SCCA, whereas low concentration of calcium stimulate the production of acidic SCCA [21].

The final stage of differentiation of squamous epithelial cells is modulated by several cysteine proteinases, such as cathepsin L, calpain, and epidermal transglutaminase [20].

Involvement of Squamous Cell Carcinoma Antigen in

into metastatic tumors (Fig. 2).

**6. Conclusions** 

**7. Conflict of interest** 

The authors declare no conflict of interest.

Invasion and Metastasis of Squamous Cell Carcinoma of Uterine Cervix 157

activated E-cadherin – SCCA system, which leads to their aggregation, survival, and growth

Fig. 2. Possible roles of SCCA in tumor cell survival and metastasis in uterine cervical squamous cell carcinoma. Cancer cells with abnormally high expression of SCCA are resistant to apoptosis induced by the immune system and therapeutic modalities. In contrast, cancer cells with abnormally low expression of SCCA show loss of E-cadherin expression, resulting in detachment from the primary tumor lesion. These cells migrate, attach to the vessels, and metastasize in other organs through blood and lymph fluid flow.

SCCAs have been regarded as a useful tumor marker for squamous cell carcinoma in clinical practice. Furthermore, they have some interesting biological functions. SCCAs are regarded as a useful tumor marker for squamous cell carcinoma in clinical practice. In normal squamous epithelium, SCCA may have roles in the stratification, cornification, barrier functions and structure of the epithelium. In squamous cell carcinomas, both SCCA1 and SCCA2 suppress apoptosis by inhibiting serine and cysteine proteinases concerned that function in the apoptotic pathway, resulting in the proliferation of cancer cells. Furthermore, suppression of SCCA2 promoted cancer cell invasion and migration with the decreased expression of E-cadherin, resulting in cancer cell metastases. Thus, SCCA appears to have roles not only in the normal squamous epithelium but also in the squamous cell carcinomas.

SCCA1 inhibits cathepsin L and some of the proteinases in the spinous and granular layers, suggesting that SCCA1 inhibits UV-induced apoptosis of squamous epithelial cells to maintain barrier functions in the squamous epithelium. On the other hand, SCCA2 may act outside of the cells to enhance the cell adhesion system in the parabasal layer [22, 23], suggesting that SCCA2 may play important roles to maintain the structure of the normal squamous epithelium, particularly structure of the thick stratum corneum in mammalian species.

## **5. Role of SCCA in squamous cell carcinoma of uterine cervix**

Anti-tumor therapeutics inhibits the cancer cell proliferation and induce necrotic and apoptotic cell death. However, some cancer cells acquire the ability to resist anti-tumor therapeutics. Thus, proliferation, cell invasion and migration are the most crucial biological events in the progression of cancer.

Recently, much attention has been focused on the role of proteinases and their inhibitors in the malignant behavior of cancer cells. Proteinase inhibitors are thought to suppress the apoptotic process of cancer cells. Apoptosis involves complicated mechanisms with multistep pathways. Some serpins are involved in the apoptotic process. In squamous cell carcinoma tissues, the expression levels of SCCA2 are higher than those in normal squamous epithelial tissues, suggesting that SCCA2 plays a role in suppressing apoptotic cell death [24, 25]. Both SCCA1 and SCCA2 belong to the ov-serpin family, and some of the ov-serpins have been reported to inhibit apoptosis [5]. In fact, SCCA1 inhibits both serine proteinases and cysteine proteinases, and SCCA2 inhibits serine proteinases [9-12]. Although the target proteinases are different, both SCCA1 and SCCA2 inhibit apoptosis. SCCA1 suppresses apoptosis induced by activated natural killer cells, TNF-, irradiation and anti-tumor agents, while SCCA2 suppresses apoptosis induced by irradiation and TNF- [26-28]. Both SCCAs suppress the activity of caspase-3 and caspase-9 via down-regulation of p38 MAPK and/or MKK3/MKK6 [27]. These results suggest that SCCAs in tumor cells help to protect cancer cells from apoptotic cell death, both from therapeutic modalities and the immune systems. Proteinase inhibitors are also thought to suppress the invasion and metastasis of cancer cells by inhibiting proteinase activities that disrupt the cell-to-cell adhesion system. In the first step of cancer metastasis, loss of E-cadherin expression causes detachment of cancer cells from the primary tumor lesion. After the detachment from the primary tumor, cancer cells migrate, attach to vessels, and move to other organs through blood and lymph fluid flow. In fact, suppression of SCCA2 expression promoted cell invasion and cell migration with the decreased expression of E-cadherin [29, 30]. Blockage of E-cadherin action suppressed SCCA production in squamous cell carcinoma cell lines [31]. Our immunohistochemical study on cervical squamous cell carcinoma revealed that SCCA2 expression was significantly related with E-cadherin expression and that mixed pattern with loss and positive stained of SCCA2 and E-cadherin in primary lesions was strongly associated with high incidence of lymph node metastasis [32]. These facts strongly suggest that cancer cells with loss of SCCA2 expression, as well as loss of E-cadherin expression, metastasize to other organs including the lymph nodes. In contrast, increased expression of E-cadherin induces the increase of SCCA2 expression through a PI3K - Akt pathway in uterine squamous cell carcinoma cells [33]. These results suggest that the decrease in Ecadherin expression causes cancer cells to detach from the primary tumor, and acquire the activated E-cadherin – SCCA system, which leads to their aggregation, survival, and growth into metastatic tumors (Fig. 2).

Fig. 2. Possible roles of SCCA in tumor cell survival and metastasis in uterine cervical squamous cell carcinoma. Cancer cells with abnormally high expression of SCCA are resistant to apoptosis induced by the immune system and therapeutic modalities. In contrast, cancer cells with abnormally low expression of SCCA show loss of E-cadherin expression, resulting in detachment from the primary tumor lesion. These cells migrate, attach to the vessels, and metastasize in other organs through blood and lymph fluid flow.

## **6. Conclusions**

156 Squamous Cell Carcinoma

SCCA1 inhibits cathepsin L and some of the proteinases in the spinous and granular layers, suggesting that SCCA1 inhibits UV-induced apoptosis of squamous epithelial cells to maintain barrier functions in the squamous epithelium. On the other hand, SCCA2 may act outside of the cells to enhance the cell adhesion system in the parabasal layer [22, 23], suggesting that SCCA2 may play important roles to maintain the structure of the normal squamous epithelium, particularly structure of the thick stratum corneum in mammalian

Anti-tumor therapeutics inhibits the cancer cell proliferation and induce necrotic and apoptotic cell death. However, some cancer cells acquire the ability to resist anti-tumor therapeutics. Thus, proliferation, cell invasion and migration are the most crucial biological

Recently, much attention has been focused on the role of proteinases and their inhibitors in the malignant behavior of cancer cells. Proteinase inhibitors are thought to suppress the apoptotic process of cancer cells. Apoptosis involves complicated mechanisms with multistep pathways. Some serpins are involved in the apoptotic process. In squamous cell carcinoma tissues, the expression levels of SCCA2 are higher than those in normal squamous epithelial tissues, suggesting that SCCA2 plays a role in suppressing apoptotic cell death [24, 25]. Both SCCA1 and SCCA2 belong to the ov-serpin family, and some of the ov-serpins have been reported to inhibit apoptosis [5]. In fact, SCCA1 inhibits both serine proteinases and cysteine proteinases, and SCCA2 inhibits serine proteinases [9-12]. Although the target proteinases are different, both SCCA1 and SCCA2 inhibit apoptosis. SCCA1 suppresses apoptosis induced by activated natural killer cells, TNF-, irradiation and anti-tumor agents, while SCCA2 suppresses apoptosis induced by irradiation and TNF- [26-28]. Both SCCAs suppress the activity of caspase-3 and caspase-9 via down-regulation of p38 MAPK and/or MKK3/MKK6 [27]. These results suggest that SCCAs in tumor cells help to protect cancer cells from apoptotic cell death, both from therapeutic modalities and the immune systems. Proteinase inhibitors are also thought to suppress the invasion and metastasis of cancer cells by inhibiting proteinase activities that disrupt the cell-to-cell adhesion system. In the first step of cancer metastasis, loss of E-cadherin expression causes detachment of cancer cells from the primary tumor lesion. After the detachment from the primary tumor, cancer cells migrate, attach to vessels, and move to other organs through blood and lymph fluid flow. In fact, suppression of SCCA2 expression promoted cell invasion and cell migration with the decreased expression of E-cadherin [29, 30]. Blockage of E-cadherin action suppressed SCCA production in squamous cell carcinoma cell lines [31]. Our immunohistochemical study on cervical squamous cell carcinoma revealed that SCCA2 expression was significantly related with E-cadherin expression and that mixed pattern with loss and positive stained of SCCA2 and E-cadherin in primary lesions was strongly associated with high incidence of lymph node metastasis [32]. These facts strongly suggest that cancer cells with loss of SCCA2 expression, as well as loss of E-cadherin expression, metastasize to other organs including the lymph nodes. In contrast, increased expression of E-cadherin induces the increase of SCCA2 expression through a PI3K - Akt pathway in uterine squamous cell carcinoma cells [33]. These results suggest that the decrease in Ecadherin expression causes cancer cells to detach from the primary tumor, and acquire the

**5. Role of SCCA in squamous cell carcinoma of uterine cervix** 

species.

events in the progression of cancer.

SCCAs have been regarded as a useful tumor marker for squamous cell carcinoma in clinical practice. Furthermore, they have some interesting biological functions. SCCAs are regarded as a useful tumor marker for squamous cell carcinoma in clinical practice. In normal squamous epithelium, SCCA may have roles in the stratification, cornification, barrier functions and structure of the epithelium. In squamous cell carcinomas, both SCCA1 and SCCA2 suppress apoptosis by inhibiting serine and cysteine proteinases concerned that function in the apoptotic pathway, resulting in the proliferation of cancer cells. Furthermore, suppression of SCCA2 promoted cancer cell invasion and migration with the decreased expression of E-cadherin, resulting in cancer cell metastases. Thus, SCCA appears to have roles not only in the normal squamous epithelium but also in the squamous cell carcinomas.

## **7. Conflict of interest**

The authors declare no conflict of interest.

Involvement of Squamous Cell Carcinoma Antigen in

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**Part 4** 

**Role of Tumor Microenvironment in Head** 

**and Neck Squamous Cell Carcinoma** 

cancer cells by activating serine proteinase inhibitor squamous cell carcinoma antigen. Exp Cell Res 299: 525-532, 2004

