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Molecular Biology, Pathobiology, and Genetics |
B and CXC Chemokines
1 Angiogenesis Research Laboratory, Department of Restorative Sciences; 2 Department of Biologic and Material Sciences; 3 Oral Medicine, Oral Pathology, and Oncology, School of Dentistry; 4 Internal Medicine; and 5 Pathology and Comprehensive Cancer Center, School of Medicine, University of Michigan, Ann Arbor, Michigan; 6 Department of Restorative Sciences, Tokyo Medical and Dental University, Tokyo, Japan; and 7 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California at Los Angeles, Los Angeles, California
Requests for reprints: Jacques E. Nör, Angiogenesis Research Laboratory, University of Michigan, 1011 North University Room 2309, Ann Arbor, MI 48109-1078. Phone: 734-936-9300; Fax: 734-936-1597; E-mail: jenor{at}umich.edu.
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 growth-related oncogene-
(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-
B (NF-B) is highly activated in HDMEC exposed to VEGF and HDMEC-Bcl-2 cells, and genetic and chemical approaches to block the activity of NF-B 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.
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