Figure 1.

A, Schematic diagram showing intra-cellular functions of the Bcl family of proteins. VEGF induces Bcl-2 expression via the VEGFR-2, PI3K/Akt signalling pathway. Pro-apoptotic proteins such as Bad and Bid heterodimerize with Bcl-2/Bcl-X_L thus regulating their ability to inhibit activation of other pro-apoptotic proteins like Bax. Activation of Bax results in the release of cytochrome c from the mitochondrial outer membrane, which together with Apaf1, causes caspase activation. This induces cell apoptosis. Bcl-2 also acts as a pro-angiogenic signalling molecule, by activating the NF-κB signaling pathway, inducing expression of the pro-angiogenic chemokine, CXCL8. B, A partial model schematic diagram. Tumor cells produce VEGF under conditions of hypoxia, which binds to endothelial cells via cell surface receptors resulting in receptor dimerization and activation. This elicits a proliferative and chemotactic response from the endothelial cells. Further, this causes over-expression of the pro-survival protein Bcl-2, which in turn results in up-regulation of CXCL8 production by them. CXCL8 in turn induces cell proliferation and chemotaxis. The endothelial cells begin to aggregate and differentiate into microvessels, that eventually fuse with mouse vessels and become blood borne, resulting in oxygenation of the tumor.