Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality in the US. Clearly, new strategies for therapeutic intervention are necessary. While carcinogenesis is related to genetic and epigenetic events, NSCLC 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 aberrant angiogenesis allows for the perpetuation allows for the perpetuation of tumor growth and eventual metastasis. However, the mediators that orchestrate this aberrant neovascular response in NSCLC have not been fully elucidated. Members of the CXC chemokine family exert disparate function in regulating angiogenesis related to three amino acid residues (the 'ELR' motif in the NH2-terminus of these cytokines. CXC chemokines have potent angiogenic (ELR+) and angiostatic (ELR-) activity. Our central hypothesis is that net angiogenesis during tumorigenesis of NSCLC is determined, in part, by an imbalance in the expression/function of CXC angiogenesis during tumorigenesis of NSCLC is determined, in part, by an imbalance in the expression/function of CXC chemokines. This paradigm predicts an environment that perpetuates an angiogenic phenotype of the endothelium promoting tumorigenesis, and metastases. The proposed studies will focus on the following specific aims: I) To demonstrate that vascular endothelial growth factor (VEGF)-mediated angiogenesis is related to enhanced endothelial cell survival by Bcl-2- and interleukin-8/ELR+ CXC chemokine mediated angiogenesis is related to enhanced endothelial cell survival by Bcl-2- and interleukin-8-dependent mechanism(s). II) To establish that the CXC chemokine receptor, CXCR2, is the putative receptor for IL-8/ELR+ CXC chemokine mediated angiogenesis. III) To determine the mechanism(s) for agnostic interferon (IFN)- IV) To demonstrate in vivo that the IFN-inducible angiostatic ELR+ CXC chemokines account for the angiostatic effects of IL-18, IL-12 and IFN- gamma in mediating inhibition of tumor-derived angiogenesis, tumorigenesis, and spontaneous metastases. V) To establish that human specimens of NSCLC demonstrate an imbalance in the expression of angiogenic ELR+, as compared to angiostatic IFN-inducible ELR-CXC chemokines, and this imbalance is directly correlated to tumor-derived angiogenesis and recurrence of surgical stage I and II NSCLC. These experiments will use molecular, cellular, whole animal models, whole animal models, and human specimens to assess angiogenesis related to NSCLC tumorigenesis. The experiments designed in this proposal will demonstrate that CXC chemokines mechanistically play critical roles in regulating angiogenesis during NSCLC tumorigenesis. These experiments will provide the foundation for the development of novel therapeutic strategies to modulate this biology and attenuate tumor- derived angiogenesis, that ultimately will reduce NSCLC tumorigenesis and metastases.
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