Abstract

Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and the ET receptors, ET_AR and ET_BR, represents a novel target in tumor treatment. ET-1 may directly contribute to tumor growth and indirectly modulate tumor–host interactions in various tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast carcinoma, Kaposi’s sarcoma, brain tumors and melanoma. Extensive experimental evidence links ET_AR overexpression with tumor progression in ovarian cancer. ET_AR engagement can in fact activate multiple signal transduction pathways including protein kinase C, phosphati-dylinositol 3-kinase, mitogen-activated protein kinase and transactivate epidermal growth factor receptor, which play a role in ovarian tumor growth and invasion. The effects of ET_AR signaling are wide ranging and involve both cancer cells and their surrounding stroma, including the vasculature. Upon being activated, the ET_AR mediates multiple tumor-promoting activities, including enhanced cell proliferation, escape from apoptosis, angiogenesis, epithelial–mesenchymal transition and increased motility and invasiveness. These findings indicate that activation of ET_AR by ET-1 is a key mechanism in the cellular signaling network promoting ovarian cancer growth and progression. The predominant role played by ET_AR in cancer has led to the development of small molecules that antagonize the binding of ET-1 to ET_AR. The emerging preclinical data presented here provide a rationale for the clinical evaluation of these molecules in which targeting the related signaling cascade via ET_AR blockade may be advantageous in the treatment of advanced stage ovarian carcinoma.