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Anti-Angiogenic Action of Neutral Endopeptidase

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Annual rept. 1 Nov 2004-31 Oc 2005

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Angiogenesis, or the formation of new blood vessels from existing vasculature is an important event in tumor progression. It results from a complex, multistep biochemical cascade that is initiated by the activation of endothelial cells in response to angiogenic factors. In prostate cancers, angiogenic factors are produced by epithelial and stromal cells, and are believed critical to prostate cancer growth and progression. One of the most important of these factors is basic fibroblast growth factor bFGF, which plays an important role in angiogenesis through the stimulation of endothelial cell proliferation, migration, and protease production this is more of an in vitro phenomenon. A number of studies both in vitro and in patient specimens suggest that enhanced expression of bFGF contributes to more aggressive prostate cancer. Clearly, a better understanding of the pathways regulating angiogenesis in the prostate and how these pathways change during malignant transformation and prostate cancer progression will assist in developing more effective therapies for patients with prostate cancer. Cell-surface peptidases are the guardians of the cell against small stimulatory peptides, functioning to control growth and differentiation in normal cells by regulating peptide access to their cell-surface receptors. They are integral membrane proteins with their enzymatic site exposed to the external cell surface, Neutral endopeptidase NEP is a cell-surface peptidase normally expressed by prostatic epithelial cells, whose expression is lost in over half of prostate cancers. NEP substrates include small peptides that have been implicated in prostate cancer progression, including endothelin-1, bombesin and neurotensin. We have recently discovered that bFGF is also a substrate for NEP. This is unexpected as previous NEP substrates have been considerably smaller in size 35 amino acids compared with 150 amino acids for bFGF.

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  • Medicine and Medical Research

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