For tumors to grow and metastasize, they induce the generation of new blood vessels, a process referred to as angiogenesis. Inhibition of angiogenesis, thus provides an important new therapeutic target. The angiogenesis inhibitor angiostatin is a kringle containing internal fragment of plasminogen, which has been shown to inhibit cancer growth in numerous animal models, including prostate cancer. In prior research by Soff and colleagues, the mechanism by which plasminogen is converted to angiostatin was elucidated, which involves plasmin autoproteolysis within kringle 5 [Gately et al, 1997] [Gately et al, 2000]. The isoform resulting from this process, referred to as Angiostatin4.5 (AS4.5) since it includes kringles 1 through 4 and most of 5, has been shown to be a naturally occurring angiogenesis inhibitor [Gately et al, 2000]. Most recently, we have demonstrated that the human PC-3 prostate carcinoma cell line expresses a high affinity receptor for plasmin on the cell surface, which binds plasmin and facilitates proteolytic conversion of plasmin to AS4.5. Plasmin, when bound to the PC-3 receptor, thus undergoes autoproteolysis, to yield AS4.5. The plasmin receptor protects plasmin catalytic activity from the neutralizing activity of alpha 2-antiplasmin (alpha 2AP), found in plasma, which may explain how Angiostatin4.5 is generated in vivo, despite the presence of alpha 2AP in plasma. In this project, we shall: (1) Complete the purification, and identification of the plasmin receptor and determine which cells and under what circumstances the receptor is expressed, (2) Determine the mechanism by which the plasmin receptor promotes plasmin autoproteolysis, (3) Determine if the levels of the receptor correlate with the plasma levels of Angiostatin4.5 in patients with cancer, and (4) determine if the levels of the receptor correlate with the local and metastatic progression in patients with prostate cancer.
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