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

Abstract

The endothelin-1 (ET-1)/ET A receptor (ETAR) axis is involved in the pathobiology of different tumors, including ovarian carcinoma. Acting selectively on ETAR, ET-1 regulates, through multiple signaling pathways, mitogenesis, cell survival, angiogenesis, lymphangiogenesis, invasion, and metastatic dissemination. Moreover, ET-1/ETAR 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 ETAR pathways provides an opportunity for the development of new mechanism-based antitumor strategies by using ETAR antagonists alone and in combination with cytotoxic drugs or molecular inhibitors. A specific ETAR 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 ETAR in ovarian cancer will be of paramount importance in the study of ETAR-targeted therapy that, regulating EMT and other tumor-associated processes, represents an attractive but challenging approach to improve clinical management of ovarian cancer.