Abstract
Abstract Angiogenesis contributes to the development and progression of malignant tumors. An expanding body of evidence also suggests that the response of both vascular and tumor cells to growth factor stimulation depends in part on cellular communication with the extracellular matrix (ECM), and studies have documented important roles for the integrin family of ECM receptors in modulating growth factor signaling. Therefore, uncovering molecular mechanisms by which integrin-mediated cellular communication with the ECM modulate the specificity of growth factor signaling during pathological angiogenesis may provide unique insight into malignant tumor progression. Here we provide evidence that disruption of αvβ3-dependent interaction with the ECM enhance expression of Insulin-like growth factor binding protein-4 (IGFBP-4), a well-known regulator of IGF-1 signaling. Interestingly, IGFBP-4 significantly (P<0.05) inhibited IGF-1 and bFGF-induced angiogenesis by greater than 50%. In contrast, IGFBP-4 alone failed to inhibit VEGF-induced angiogenesis in chick CAM. Levels of phosphorylated p38 MAP kinase were elevated in chick CAM tissues treated with VEGF as compared to those in tissues stimulated with either IGF-1 or bFGF. Surprisingly, while the p38 MAP kinase inhibitor SB 202190 alone had little effect on VEGF-induced angiogenesis, a combination of IGFBP-4 and the p38 MAP kinase inhibitor significantly (P<0.05) inhibited VEGF-induced angiogenesis. These novel findings are consistent with a role for elevated levels of activated p38 MAP kinase in modulating the anti-angiogenic activity of IGFBP-4 in vivo. Taken together, our experimental findings provide additional molecular insight into how integrin-mediated interactions with the local ECM microenvironment may modulate the responses of cells to distinct growth factor signaling pathways during angiogenesis. 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 3485. doi:10.1158/1538-7445.AM2011-3485
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