Abstract B44: A role for endothelial αvβ3 integrin in breast tumor cell migration

Abstract

Vascular endothelial growth factor (VEGF) and αvβ3 integrin are key molecules that actively participate in tumor angiogenesis and metastasis. Some integrin-blocking molecules are currently under clinical trials for cancer and metastasis treatment. However, the mechanism of action of such inhibitors is not completely understood and evasive resistance of antiangiogenic therapy has been reported. We have previously demonstrated the anti-angiogenic and anti-metastatic properties of DisBa-01, a recombinant His-tag RGD-disintegrin from Bothrops alternatus snake venom in experimental models. DisBa-01 blocks αvβ3 integrin binding to vitronectin and inhibits integrin mediated downstream signaling cascades and cell migration. Recently, we reported that DisBa-01 strongly decreases the expression of VEGF mRNA and of its receptors, vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2) in endothelial cells. Here, DisBa-01 was submitted to adhesion under flow and transmigration assays, both using different DisBa-01 concentrations and β3-siMDA-MB-231 cells. In the first assay, labeled tumor cells incubated with Disba-01 perfused for 5 minutes through a chamber containing endothelial cells as coat. In the second, labeled tumor cells incubated with DisBa-01 were attracted by complete medium and transmigrated through an endothelial cell coat. Individually, assays were photographed and the cells quantified. Results show that DisBa-01 dose-dependently inhibited adhesion of MDA-MB-231 cells to human endothelial cells under flow conditions, similarly to the effect observed by β3-siMDA-MB-231 cells. In addition, the disintegrin or β3-silencing inhibited the transmigration of tumor cells through endothelial cells in vitro. These results demonstrate that endothelial αvβ3 integrin has a key role in tumor cell adhesion and transmigration through the endothelium under flow conditions. Support: Fapesp (grant no. 1998/14138-2), CNPq, and CAPES (Brazil) Citation Format: Cyntia Freitas Montenegro, Araceli Cristina Durante, Kelli Cristina Micocci, Antonio Carlos Manucci Pereira, Jr., Heloisa Sobreiro Selistre-de-Araujo. A role for endothelial αvβ3 integrin in breast tumor cell migration. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B44.