Abstract 514: Integrins dependent regulation of endothelial cell migration and tube formation by α6(IV)NC1

Abstract

Abstract Peptides or short protein domains derived from extracellular matrix were shown to possess anti-tumor properties. One such molecule, α6(IV)NC1 was derived from the carboxy terminal non-collagenous domain fragment of α6 chain, type (IV) collagen and was found to inhibit angiogenesis and tumor growth but the mechanism by which it inhibits the growth of solid tumors has not been reported yet. In the present study we demonstrate that the biological functions of α6(IV)NC1 are attributed to its binding to different integrins. In addition, we also demonstrate that α6(IV)NC1 binds to α3β1and α5β1 integrins and competes with the cells binding to α1β1 integrins on type IV collagen, and / with α5β1 integrins on fibronectin and inhibits migration and tube formation of human vascular and lymphatic endothelial cells. We further evaluated the role of α3β1 and α5β1 integrins in tube formation and regulation of cell migration by α6(IV)NC1. While both the integrins (α3β1 and α5β1) are required for the inhibition of tube formation by α6(IV)NC1 in human vascular and lymphatic endothelial cells, only α3β1 integrin was found to regulate lymphatic endothelial cells migration. In addition we also demonstrate that α6(IV)NC1 inhibits tumor growth, tumor lymphatic angiogenesis and circulating endothelial cells in-vivo. These in-vitro and in-vivo findings identify that α3β1 and α5β1 integrins are critical for α6(IV)NC1 mediated inhibition of angiogenic and lymph angiogenic signaling and inhibition of tumor progression. Collectively, our findings first time demonstrate that α6(IV)NC1 is a potent therapeutic candidate for targeting tumor angiogenesis and tumor lymphatic angiogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 514.