Bcl-2 Acts in a Proangiogenic Signaling Pathway through Nuclear Factor-κB and CXC Chemokines

Abstract

Vascular endothelial growth factor (VEGF) induces expression of Bcl-2 in tumor-associated microvascular endothelial cells. We have previously reported that up-regulated Bcl-2 expression in microvascular endothelial cells is sufficient to enhance intratumoral angiogenesis and to accelerate tumor growth. We initially attributed these results to Bcl-2-mediated endothelial cell survival. However, in recent experiments, we observed that conditioned medium from Bcl-2-transduced human dermal microvascular endothelial cells (HDMEC-Bcl-2) is sufficient to induce potent neovascularization in the rat corneal assay, whereas conditioned medium from empty vector controls (HDMEC-LXSN) does not induce angiogenesis. These results cannot be attributed to the role of Bcl-2 in cell survival. To understand this unexpected observation, we did gene expression arrays that revealed that the expression of the proangiogenic chemokines interleukin-8 (CXCL8) and growthrelated oncogene-A (CXCL1) is significantly higher in HDMEC exposed to VEGF and in HDMEC-Bcl-2 than in controls. Inhibition of Bcl-2 expression with small interfering RNA-Bcl-2, or the inhibition of Bcl-2 function with small molecule inhibitor BL-193, down-regulated CXCL8 and CXCL1 expression and caused marked decrease in the angiogenic potential of endothelial cells without affecting cell viability. Nuclear factor-KB (NF-KB) is highly activated in HDMEC exposed to VEGF and HDMEC-Bcl-2 cells, and genetic and chemical approaches to block the activity of NF-KB down-regulated CXCL8 and CXCL1 expression levels. These results reveal a novel function for Bcl-2 as a proangiogenic signaling molecule and suggest a role for this pathway in tumor angiogenesis. (Cancer Res 2005; 65(12): 5063-9)

Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones

“…The VEGF-dependent proliferative response overrides the anti-proliferative effects of anti-hormones in breast cancer cells. This might result from the direct effects of VEGF via its receptors and also from VEGF-dependent induction of anti-apoptotic Bcl-2 protein, which has recently been shown to induce angiogenesis (Karl et al 2005). These observations support the view that combined treatment modalities, including anti-hormones and anti-angiogenic compounds, should be considered for treating ER-and PR-positive breast cancers, especially those that express high levels of VEGF.…”

“…5-7A). Bcl-2 has previously been shown to be increased in response to VEGF in MDA-MB-231 cells (Pidgeon et al 2001) and has recently been implicated in angiogenesis and expansion of tumors (Karl et al 2005), although its role in breast cancer cells is not clear. Our data show that VEGF-induced Bcl-2 expression is a general phenomenon in breast cancer cells that may have a broader role than simply serving as an anti-apoptotic protein.…”

Systems approaches to preventing transplanted cell death in cardiac repair

“…Approaches to boosting cell survival for grafting applications in different tissues and organ systems have also been evaluated. Overexpression of Bcl-2 has been shown to improve survival of endothelial [81,82] and cardiac [83] cells implanted subcutaneously. Caspase inhibition provided to cultured cells, and delivered systemically after injection enhances survival of islet cells [84] and dopaminergic neurons [85,86].…”

Modulation of bcl-xL in Tumor Cells Regulates Angiogenesis through CXCL8 Expression

“…Moreover, treatment of melanoma cells with bcl-2/bcl-xL antisense oligonucleotides reduces angiogenic activity (8). The ability of bcl-2 to induce angiogenesis has also been shown in prostate carcinoma and microvascular endothelial cells (9,10).…”