Emerging role of the endothelin axis in ovarian tumor progression

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(A)R and ET(B)R, 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(A)R overexpression with tumor progression in ovarian cancer. ET(A)R 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(A)R signaling are wide ranging and involve both cancer cells and their surrounding stroma, including the vasculature. Upon being activated, the ET(A)R 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(A)R by ET-1 is a key mechanism in the cellular signaling network promoting ovarian cancer growth and progression. The predominant role played by ET(A)R in cancer has led to the development of small molecules that antagonize the binding of ET-1 to ET(A)R. 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(A)R blockade may be advantageous in the treatment of advanced stage ovarian carcinoma.