Modulation of VEGF signaling by extracellular matrix and neuropilins: impact on tumor progression, angiogenesis and anti-angiogenic therapy in prostate and pancreatic cancer

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It is generally accepted that the tumor microenvironment plays an active role in regulating expansion and metastatic progression. Matrix molecules serve as substrate for migration of tumor cells, as well as, provide differentiation cues for the maturation and stabilization of new vascular beds. In addition, through binding and interactions with specific growth factors, the extracellular matrix (ECM) offers a reservoir of growth regulatory signals. Previous work by Prof. Iruela-Arispe indicates that matrix-bound vascular endothelial growth factor (VEGF) is susceptible to proteolysis releasing a soluble receptor tyrosine kinase-activating fragment (N-terminal) and a smaller C-terminal matrix-bound peptide. Interestingly, this C-terminal VEGF peptide binds and activates neuropilin-1 (NRP1) in tumor and in endothelial cells, thereby possibly facilitating tumor growth and metastasis. The proposed project will test the hypothesis that: ¿Extracellular processing of VEGF results in the generation of bioactive peptides that continue to support angiogenic growth and more importantly mediate tumor progression. Furthermore, this C-terminal VEGF constitutes an untapped reservoir of growth factor that is not affected by the available VEGF-antagonist bevacizumab¿. For evaluation of the preceding hypothesis, models and human samples of prostate and pancreatic cancer will be applied, both representing tumor entities with a strong stroma/ECM reaction. In vitro experiments will address the angiogenic and tumor biological role of the C-terminal VEGF peptide and reveal the molecular signaling pathways that are activated downstream of NRP1 upon binding to C-terminal VEGF. Furthermore the impact of NRP1 blockade on tumor growth, angiogenic progression and metastatic expansion will be determined in xenograft models of prostate and pancreatic cancer overexpressing C-terminal VEGF. In addition, the presence of C-terminal and full-length VEGF will be determined in samples of human prostate and pancreatic tumors and its levels correlated with tumor progression and clinical follow-up. It is anticipated the execution of this project will expand and clarify the signaling pathways driven by VEGF in the context of ECM interactions that regulate angiogenic expansion in prostate and pancreatic cancer. This may reveal causes of present low response rates to bevacizumab in the clinic, offer a path for better stratification of patients for existing VEGF-directed therapeutic options, and potentially identifies new targets of VEGF signaling for future therapies.