Cooperation between integrin α5 and tetraspan TM4SF5 regulates VEGF-mediated angiogenic activity

Abstract

AbstractTetraspan TM4SF5 is highly expressed in a diverse number of tumor types. Here we explore the mechanistic roles of TM4SF5 in angiogenesis. We found that TM4SF5 overexpression correlates with vascular endothelial growth factor (VEGF) expression in SNU449 hepatocytes and with vessel formation in clinical hepatocarcinoma samples. Conditioned media from TM4SF5-expressing cells enhanced viability and tube formation of primary human umbilical vein endothelial cells, and outgrowth of endothelial cells from aorta ring segments, which was abolished by treatment with an anti-VEGF antibody. TM4SF5 retained integrin α5 on the cell surface for VEGF induction, and preincubation with anti–integrin α5 antibody abolished TM4SF5-mediated VEGF expression and secretion. TM4SF5-mediated effects required integrin α5, c-Src, and signal transducer and activator of transcription 3 (STAT3). In addition, tumors from nude mice injected with TM4SF5-expressing cells and from clinical human hepatocarcinoma tissues showed enhanced integrin α5 expression, vessel formation, and signaling activity, which were inhibited by administration of anti–integrin α5 or -VEGF antibody. This study suggests that TM4SF5 facilitates angiogenesis of neighboring endothelial cells through VEGF induction, mediated by cooperation between TM4SF5 and integrin α5 of epithelial cells.