Abstract 4272: Hexastatin is a potent therapeutic agent for targeting tumor angiogenesis and tumor growth

Abstract

Abstract Peptides or short protein domains derived from the extracellular matrix are reported to possess anti-tumor properties. In the present study, one such molecule “Hexastatin or [α6(IV)NC1]” a non-collagenous domain of α6 chain of type (IV) collagen was derived from the carboxy terminal and was found to inhibit tumor growth, but the mechanism by which it inhibits the growth of solid tumors has not been reported yet. In the present study, we identified that the biological functions of hexastatin are attributed to its binding to different cell surface integrins. We identified that hexastatin binds to α3β1, αVβ3 and α5β1 integrins and inhibits p38-MAPK signaling. Hexastatin competes with human vascular endothelial cells in binding to α1β1 integrins on type IV collagen, and or with α5β1/αVβ3 integrins on fibronectin/vitronectin matrix, thus inhibiting endothelial migration and tube formation. Interestingly, p38-MAPK phosphorylation was not inhibited in α3 and β3 integrin null endothelial cells upon treatment with Hexastatin which confirms that the antiangiogenic functions of Hexastatin are possibly mediated through α3β1 and αVβ3 integrins. While both the integrins (α3β1 and α5β1) are required for the inhibition of tube formation by Hexastatin in endothelial cells, only α3β1 integrin was found to regulate endothelial cells migration. In addition we also demonstrate that Hexastatin inhibits tumor growth, tumor angiogenesis and circulating endothelial cells in-vivo. These in-vitro and in-vivo findings indicate that α3β1 and αVβ3 integrins are critical for Hexastatin mediated inhibition of angiogenic signaling and tumor progression. Collectively, our findings demonstrate that hexastatin is a potent therapeutic agent for targeting tumor angiogenesis and tumor growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4272. doi:10.1158/1538-7445.AM2011-4272