Cancer is one of the leading causes of mortality in the United States. Clearly, new strategies for therapeutic intervention are necessary. While carcinogenesis is related to multiple genetic and epigenetic events, tumor growth is dependent upon angiogenesis. Net tumor-derived angiogenesis is due to an imbalance in the over-expression of angiogenic, as compared to angiostatic factors. This dysregulation allows for the perpetuation of tumor growth and eventual metastasis. However, the mediators that orchestrate this aberrant neovascular response in cancer have not been fully elucidated. Members of the CXC chemokine family exert disparate function in regulating angiogenesis related to the presence or absence of three amino acid residues (the 'ELR' motif) in the NH2-terminus of these cytokines. CXC chemokines have potent angiogenic (ELR+) and angiostatic (ELR-) activity, and are important factors that regulate angiogenesis. The central hypothesis of this application is that net angiogenesis during tumorigenesis of solid tumors is determined, in part, by an imbalance in the expression/function of CXC chemokines that favor the over-expression of angiogenic as compared to angiostatic chemokines. This leads to an environment that perpetuates the angiogenic phenotype of the endothelium promoting tumorigenesis and metastases. The proposed studies will focus on the following specific aims: (1) To demonstrate that vascular endothelial growth factor (VEGF)-mediated angiogenesis is related to enhanced endothelial cell survival by Bcl-2- and interleukin-8-dependent mechanism(s). (2) To establish that the CXC chemokine receptor, CXCR2, is the receptor for IL-8/ELR+ CXC chemokine mediated angiogenesis. (3) To determine the mechanisms for angiostatic interferon-inducible chemokine inhibition of VEGF, bFGF, EGF, and other ELR+ CXC chemokine-induced angiogenesis. (4) To demonstrate in vivo that IFN-inducible angiostatic chemokines inhibit tumor-derived angiogenesis, tumorigenesis, and spontaneous metastases in murine models of tumorigenesis. These experiments will use molecular, cellular, and whole animal models of angiogenesis related to tumorigenesis. The experiments in this application are designed to demonstrate that CXC chemokines mechanistically play a critical role in regulating angiogenesis during tumorigenesis. It is speculated that these investigations will provide a foundation for the development of novel therapeutic strategies to modulate this biology and attenuate tumor-derived angiogenesis.
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