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.
Bagnato
Anna
A
Molecular Pathology Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. bagnato@ifo.it
Spinella
Francesca
F
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008222:Lymphokines / Q000378:metabolism*; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009687:Nuclear Proteins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors