Emerging role of endothelin-1 in tumor angiogenesis.

Tumor vessels express distinct molecular markers that are functionally relevant in the angiogenic process. Although tyrosine kinase receptor agonists are the major mediators of angiogenesis, several G-protein-coupled receptor agonists have also been shown to have a role. Among these, endothelin-1 (ET-1), by acting directly on endothelial cells via the ET(B) receptor, modulates different stages of neovascularization, including proliferation, migration, invasion, protease production and morphogenesis, and also stimulates neovascularization in vivo. ET-1 can also modulate tumor angiogenesis indirectly through the induction of vascular endothelial growth factor (VEGF). Engagement of the ET(A) receptor by ET-1 induces VEGF production by increasing levels of hypoxia-inducible factor 1 alpha. Moreover, tumor cells themselves, predominantly expressing the ET(A) receptor, might form vessel-like channels within the tumors. The role of ET-1 and its signaling network in tumor angiogenesis suggests that new therapeutic strategies using specific ET(A)-receptor antagonists could improve antitumor treatment by inhibiting both neovascularization and tumor cell growth.