VEGFR-3 (alternatively denoted Fms-like tyrosine kinase 4, Flt4, in the mouse) is activated by the binding of VEGFC or VEGFD. VEGFR-3 and its ligands are key players in the regulation of normal and tumor lymphangiogenesis. Indeed, gene inactivation to VEGF in Cancer: Biology and Clinical Implications 241 eliminate expression of VEGFC alone, or combined deletion of VEGFC and VEGFD, unexpectedly resulted in defects mainly in lymphatic vessels, while blood vessels remained unaffected in mouse models. In adult tissues, VEGFR-3 has an essential role in lymphatic endothelial cells, but its expression is also induced in endothelial cells engaged in active angiogenesis, such as in tumor vessels. The expression of VEGFR-3 in tumor cells is controversial; however, it has been clearly demonstrated that inhibition of VEGFR-3 activity arrests tumor vascularization, leading to decreased vascular density in several tumor models. The axis VEGFC/VEGFR-3 plays a fundamental role in the tumor microenvironment by promoting the formation of new lymphatic vessels from preexisting ones. VEGFC, produced by tumor cells, induces lymphatic endothelial destabilization, resulting in endothelial sprouting as well as leakage and enlargement of the vessels. These changes facilitate entry of tumor cells into the lymphatics and further dissemination of metastasis to sentinel lymph nodes.
Rapisarda A, Melillo G. Role of the VEGF/VEGFR axis in cancer biology and therapy[J]. Advances in cancer research, 2011, 114: 237-267.