The controlled induction of angiogenesis plays a critical role in a variety of both physiological and pathological states. In particular the formation of new blood vessels in response to the hypoxic environment that develops within a tumor mass is crucial for the survival of advanced malignancies. However, the role of angiogenesis in the pathogenesis of benign precursor lesions is unknown. In the well-described progression of colon cancer, angiogenesis begins early at the stage of the premalignant adenomatous polyp. In colonic epithelial cells, this is associated with upregulation of the key pro-angiogenic factor VEGF. The genetic mechanisms underlying this upregulation of VEGF in benign colonic polyps are poorly described. Activation of the Wnt (APC beta-catenin) and K-ras signaling pathways is characteristically observed in these colon polyps. Preliminary studies demonstrate the novel upregulation of VEGF by Wnt signaling. In addition, K-ras regulates VEGF expression in a phosphatidyl inositol 3-kinase dependent manner. Furthermore, K-ras functions synergistically with the Wnt pathway to upregulate VEGF. To address the hypothesis that these signaling pathways that are frequently altered in early colonic neoplasia may also play an important role in angiogenesis through the regulation of VEGF, the following specific aims are proposed: (1) to define the critical cis-regulatory elements in the VEGF promoter that mediate Wnt signaling. (2) to define the K-ras effector pathways that regulate VEGF expression, and (3) to define the interaction of hypoxia with Wnt signaling in the upregulation of VEGF. Collectively, these studies will highlight the important role of angiogenesis in premalignant colonic polyps and provide the foundation for novel strategies that specifically target angiogenesis in the prevention of these colon cancer precursors.
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