endothelin-1 and Uterine-Cervical-Neoplasms

The endothelin system comprises the three peptide hormones endothelin (ET)-1, -2, -3, their G protein-coupled receptors, endothelin-A-receptor (ET(A)R) and endothelin-B-receptor (ET(B)R), and the enzymes of endothelin biosynthesis and degradation. In the past two decades, an impressive amount of data has been accumulated investigating the role of the endothelin system in a variety of malignancies. In many cancers, ET-1/ET(A)R interaction induces proliferation, angiogenesis, antiapoptosis and resistance to chemotherapy. Data indicate a pivotal role of the endothelin system in tumorigenesis, local progression and metastasis. Subsequently, novel drugs have been designed inhibiting ET-1 biosynthesis or ET(A)R interaction. A wide range of preclinical data is available on the role of ET(A)R antagonists in gynecological, urological and breast cancers providing evidence for their antiangiogenic, proapoptotic and growth inhibitory effects. Of particular interest is the anti-invasive and antimetastatic efficacy of ET(A)R antagonists and synergism when co-administered with established cancer therapies. Data indicate a future role of ET(A)R antagonists in oncologic therapies.

Topics: Animals; Antineoplastic Agents; Aspartic Acid Endopeptidases; Breast Neoplasms; Endometrial Neoplasms; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Female; Humans; Kidney Neoplasms; Male; Metalloendopeptidases; Ovarian Neoplasms; Prostatic Neoplasms; Receptors, Endothelin; Urinary Bladder Neoplasms; Urogenital Neoplasms; Uterine Cervical Neoplasms

The endothelin axis (ET axis), comprising the three peptides endothelin (ET)-1, -2, -3 and their receptors ET(A)R and ET(B)R, is expressed in various cells and tissues. The biologically active ET-1 is formed by endothelin-converting enzyme (ECE) from inactive big-ET-1. ET-1 has emerged as an important peptide in a host of biological functions, including development, cellular proliferation, apoptosis and angiogenesis, thereby playing an important physiological and pathophysiological role. As these effects are mediated by ET(A)R, activation of ET(B)R prevents apoptosis, inhibits ECE expression and mediates the clearance of ET-1. Emerging data indicate that the ET axis is involved in tumourigenesis and tumour progression of various cancers. Expression of the ET axis has been demonstrated in a wide range of human tumours. Since most data have been reported for female malignancies, this review will focus on the role of the ET axis in cancers of the ovary, the cervix and the breast. In ovarian cancer, activation of ET(A)R by ET-1 is a key mechanism in the cellular signalling network promoting cancer growth and progression. Similar effects have been shown for cervical and endometrial cancer. In breast cancer, ET-1 via ET(A)R promotes proliferation and invasion, mediates bone metastases and predicts unfavourable response to chemotherapy. The outstanding role of ET-1 and ET(A)R in carcinogenesis and tumour progression has led to an extensive search for interfering agents, resulting in the development of selective ET(A)R antagonists on the one hand and inhibitors of the endothelin-converting enzyme (ECE) on the other. Targeting the ET axis via ET(A)R or ECE blockade seems to be a promising approach in the treatment of female malignancies.

Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Aspartic Acid Endopeptidases; Breast Neoplasms; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-2; Endothelin-3; Endothelin-Converting Enzymes; Enzyme Inhibitors; Female; Humans; Metalloendopeptidases; Molecular Sequence Data; Neoplasms; Ovarian Neoplasms; Receptor, Endothelin A; Receptor, Endothelin B; Uterine Cervical Neoplasms

Cervical cancer has an increasing incidence in developing countries with a predominance of squamous cell carcinoma. In this work, we aimed to analyze the role of EZH2, Endothelin-1, and CD34 as indicators of the aggressiveness in cervical squamous cell carcinoma.. Immunohistochemical expression of EZH2, Endothelin-1, and CD34 was studied in 54 paraffin-embedded tissue specimens of cervical squamous cell carcinoma. Their correlation to the clinicopathologic features and the potential angiogenic role were analyzed.. High EZH2 expression was noted in 78% of cervical squamous cell carcinoma with a significant relation with tumor grade, FIGO stage and lymph node metastasis (p= < 0.001, p=0.007, p=0.03 respectively). Endothelin-1 overexpression was detected in 63% of the studied cases with a significant association with tumor size, FIGO stage and lymph node metastasis (p=0.009, p=0.002, p=0.02 respectively). High CD34 expression (MVD) was noted in 56% of the cases and associated with the tumor size, FIGO stage and lymph node metastasis (p < 0.001, p < 0.001, p=0.04 respectively). The three markers were significantly associated (p < 0.05).. EZH2, ET-1, and CD34 may act as biomarkers of aggressive cervical squamous cell carcinoma. They may contribute to the signaling pathway of angiogenesis. Therefore, they could potentially be used in targeted therapy.

Topics: Adult; Aged; Antigens, CD34; Biomarkers, Tumor; Carcinoma, Squamous Cell; Endothelin-1; Enhancer of Zeste Homolog 2 Protein; Female; Humans; Immunohistochemistry; Middle Aged; Neovascularization, Pathologic; Retrospective Studies; Uterine Cervical Neoplasms

We used cDNA microarray analysis of RNA extracted from normal, dysplastic, and cancerous cervical tissues to identify the changes in gene expression during the procession from normal to cancerous cervical epithelial cells. We found the expression of 5 genes in cancerous cervical epithelial cells that were not found in normal cervical epithelial cells, among which were lymphoid-restricted membrane protein, protease serine 2, WD repeat domain 59, thyrotropin-releasing hormone degrading enzyme, and the endothelin-3 growth factor. We then analyzed the expression levels of endothelin growth factors 1, 2, and 3 (ET-1, ET-2, and ET-3) and their receptors A and B (ETR-A and ETR-B) by reverse transcriptase-polymerase chain reaction in 3 cervical cancer cell lines and by immunohistochemical staining in cervical normal, dysplastic, and cancer tissues. ET-1, ET-2, and ET-3 growth factor levels were detectable in the maturing layer of cervical epithelium but not in the germinal layer. All 3 growth factors (ET-1, ET-2, and ET-3) were detected in the cytoplasm of the maturing normal cervical epithelial cells. In addition, there were decreased levels of ET-3 and increased levels of ET-1, ET-2, ETR-A, and ETR-B in cancerous cervical epithelial cells compared with normal cervical epithelial cells. These results suggest that the reduction of ET-3 growth factor levels may be important in the transition from normal to cancerous cervical epithelium.

Topics: Cell Line, Tumor; Cervix Uteri; Endothelin-1; Endothelin-2; Endothelin-3; Endothelins; Female; Humans; Immunohistochemistry; Oligonucleotide Array Sequence Analysis; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; Tissue Array Analysis; Uterine Cervical Neoplasms

Human papilloma viruses are associated with cervical cancer and enhance signal transduction of growth factors. In human papilloma virus-positive cervical cancer cells, the endothelin-A receptor mediates the endothelin-1-induced mitogenic effect, and sustains the basal growth rate of unstimulated cervical tumor cells. In this study, the action of a specific endothelin-A receptor antagonist (atrasentan) and a truly 'balanced' endothelin-A/endothelin-B antagonist (A-182086), was analysed in the human cervical carcinoma cells, CaSki and C33A. CaSki cells are human papilloma virus-16-positive, produce endothelin-1 and possess endothelin-A and endothelin-B receptors, whereas the C33A line is human papilloma virus-negative, does not secrete endothelin-1 and has only endothelin-B receptors. In human papilloma virus-positive cancer cells both antagonists caused a similar drastic reduction in BrdU incorporation and in the growth rate. These data clearly demonstrate that A-182086 and atrasentan show similar potency and also indicate that blocking of the endothelin-B receptor by A- 182086 does not increase the anti-proliferative effect. This finding suggests that the endothelin-B receptor does not participate in the growth control of CaSki cells. Results from C33A cells reinforce this previous conclusion as both compounds are ineffective in altering the BrdU uptake of these cells in basal and endothelin-1 stimulated conditions. In conclusion, targeting the endothelin-A receptor, but not the endothelin-B receptor, may be a valid tool in the therapy of cervical carcinoma.

Topics: Antineoplastic Agents; Atrasentan; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Human papillomavirus 16; Humans; Pyrrolidines; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Uterine Cervical Neoplasms

Human papillomaviruses (HPVs) are associated with cervical cancer and interact with growth factors that may enhance malignant transformation of cervical carcinoma cells. Endothelin-1 (ET-1) is released from HPV-transfected keratinocytes and induces increased growth response in these cell lines in comparison with normal cells. HPV-positive cancer cells secrete ET-1 and express mRNA for ET-1 and its receptors, whereas HPV-negative carcinoma cell lines express only the ET(B) receptor (ET(B)R) mRNA and do not secrete ET-1. In HPV-positive cancer cells, ET(A)R mediates the ET-1-induced mitogenic effect and sustains the basal growth rate of unstimulated cervical tumour cells. Therefore, ET-1 may be involved in the neoplastic growth of HPV-associated cervical carcinoma, where the increased ET-1 autocrine loop can be targeted for antitumour therapy. In the present work, the action of specific antagonists of ET(A)R (BQ-123 and ABT-627), was analysed in CaSki and C33A cells that are derived from human cervical carcinoma. CaSki cells are HPV-16-positive, produce ET-1 and possess ET(A)R and ET(B)R, whereas the C33A line is HPV-negative, does not secrete ET-1 and has no ET(A)R. In HPV-positive cancer cells ABT-627 strongly inhibited the proliferation induced by ET-1 and substantially reduced the basal growth rate of unstimulated cervical tumour cells, whereas the ET(B)R antagonist had no effect. These results demonstrate that ET-1 participates in the progression of neoplastic growth in HPV-associated carcinoma, in which ET(A)R expression is increased and could be targeted for antitumour therapy. In conclusion, an ET-1 autocrine loop is involved in tumour cell proliferation via ET(A)R, and ABT-627 is effective in controlling proliferation of cervical carcinoma cells.

Topics: Atrasentan; Cell Division; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Papillomaviridae; Peptides, Cyclic; Pyrrolidines; Receptor, Endothelin A; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Human papillomaviruses (HPV) are associated with cervical cancer and interact with growth factors that may enhance malignant transformation of cervical carcinoma cells. Endothelin-1 (ET-1) is released from HPV transfected keratinocytes and induces increased growth response in these cell lines in comparison with normal cells. In the present study several cervical carcinoma cell lines have been analyzed to investigate the expression of ET-1 and its receptors as well as their involvement in tumor growth. All HPV-positive cancer cells secreted ET-1 and expressed mRNA for ET-1 and its receptors, whereas a HPV-negative carcinoma cell line expressed only the ETBR mRNA and didn't secrete ET-1. Binding studies showed that HPV-associated cells expressed an increased number of functional ETAR. ET-1 stimulated a marked dose-dependent increase in [3H]-thymidine incorporation with respect to the normal cells whereas ET-3 and ETBR agonists had no effect. In HPV-positive cancer cells, a specific antagonist of ETAR inhibited the proliferation induced by ET-1 and substantially reduced the basal growth rate of unstimulated cervical tumor cells, whereas the ETBR antagonist had no effect. These results demonstrate that ET-1 participates in the progression of neoplastic growth in HPV-associated carcinoma, in which ETAR are increased and could be targeted for antitumor therapy.

Topics: Antineoplastic Agents; Binding, Competitive; Cell Division; Cell Line; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Female; Gene Expression Regulation, Neoplastic; Humans; Oligopeptides; Papillomaviridae; Papillomavirus Infections; Peptides, Cyclic; Piperidines; Radioimmunoassay; Receptor, Endothelin A; Receptors, Endothelin; RNA, Messenger; Tumor Cells, Cultured; Tumor Virus Infections; Uterine Cervical Neoplasms; Viper Venoms