VEGF SIGNAL TRANSDUCTION AND TUMOR ANGIOGENESIS

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The proliferation and invasive nature of a growing tumor, and ultimately the pathologic consequence, is largely governed by its ability to undergo an "angiogenic switch". With this change in phenotype, the tumors growth properties are critically aided by its acquired ability to stimulate the invasion and new growth of a capillary blood supply. Vascular Endothelial Growth Factor is a cytokine essential for vascular development and angiogenesis (13, 27). It is specific for vascular endothelium, where it is a potent mitogen, increases endothelial cell permeability, stimulates endothelial cell migration, induces differentiation, and acts as an endothelial cell survival factor (25, 126). These actions all ultimately regulate the angiogenic response. VEGF is now believed to be a critical mediator of tumor angiogenesis and this factor is markedly upregulated by cellular transformation and by the hypoxic conditions found in growing neoplasms. Dysregulation of VEGF production is now implicated as a causative agent in the hemangiomas and renal cell carcinomas of patients who have von Hippel-Lindau disease. The signal transduction mechanisms responsible for the angiogenic response remain largely unknown. This study is being undertaken to investigate the role of Ras and Ras-related signal transduction in mediating several of the known actions of VEGF related to angiogenesis. These experiments will use inducible, ectopic expression of mutant signaling molecules to genetically manipulate signal transduction pathways in primary endothelial cells. Signal transduction pathways that appear to be critical for the angiogenic responses to VEGF in vitro, will also be tested in an in vivo model of tumor angiogenesis employing xenografts of a VEGF-dependent renal cell carcinoma. This will provide a oasis for understanding angiogenesis at the molecular level and ultimately will allow for designing new approaches to therapeutically target tumor growth.