The importance of endothelin axis in initiation, progression, and therapy of ovarian cancer.

The endothelin-1 (ET-1)/ET A receptor (ET(A)R) axis is involved in the pathobiology of different tumors, including ovarian carcinoma. Acting selectively on ET(A)R, ET-1 regulates, through multiple signaling pathways, mitogenesis, cell survival, angiogenesis, lymphangiogenesis, invasion, and metastatic dissemination. Moreover, ET-1/ET(A)R axis appears to be critical in epithelial-to-mesenchymal transition (EMT), providing a mechanism of escape to a new, less adverse niche, in which resistance to apoptosis ensures cell survival in conditions of stress in the primary tumor, and acquisition of "stemness" ensures generation of the critical mass required for tumor progression. Emerging experimental and preclinical data demonstrate that interfering with ET(A)R pathways provides an opportunity for the development of new mechanism-based antitumor strategies by using ET(A)R antagonists alone and in combination with cytotoxic drugs or molecular inhibitors. A specific ET(A)R antagonist in combination with standard chemotherapy is currently evaluated in clinical and translational studies to provide us with new options to treat ovarian cancer and to predict response to therapy. Deeper understanding of molecular mechanism activated by ET(A)R in ovarian cancer will be of paramount importance in the study of ET(A)R-targeted therapy that, regulating EMT and other tumor-associated processes, represents an attractive but challenging approach to improve clinical management of ovarian cancer.