Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis

Vascular endothelial growth factor (VEGF) plays a major role in tumor angio genesis. VEGF-C, however, is thought to stimulate the growth of lymphatic v essels because an expression of its specific receptor, VEGF receptor-3 (VEG FR-3), was demonstrated to be restricted to lymphatic vessels. Here we demo nstrate that the inactivation of VEGFR-3 by a novel blocking monoclonal ant ibody (mAb) suppresses tumor growth by inhibiting the neo-angiogenesis of t umor-bearing tis-sues. Although VEGFR-3 is not expressed in adult blood ves sels, it is induced in vascular endothelial cells of the tumor-bearing tiss ues. Hence, VEGFR-3 is another receptor tyrosine kinase involved in tumor-i nduced angiogenesis. Micro-hemorrhage in the tumor-bearing tissue was the m ost conspicuous histologic finding specific to AFL4 mAb-treated mice, Scann ing microscopy demonstrated disruptions of the endothelial lining of the po stcapillary venule, probably the cause of micro-hemorrhage and the subseque nt collapse of the proximal vassals, These findings suggest the involvement of VEGFR-3 in maintaining the integrity of the endothelial lining during a ngiogenesis, Moreover, our results suggest that the VEGF-C/VEGFR-3 pathway may serve another candidate target for cancer therapy. (C) 2000 by The Amer ican Society of Hematology.