Plasminogen Activation and Cancer

Plasminogen is present in the plasma and interstitial fluids as a zymogen that is locally converted to an active serine protease by the action of either of two plasminogen activators, urokinase-type PA (uPA) and tissue-type PA. It seems that uPA-dependent activation mediates physiological and pathological tissue remodeling processes.191 Both uPA and plasmin are inhibited by the action of specific inhibitors, plasminogen activator inhibitor (PAI-1) and a2-antiplasmin, respectively; uPA is secreted as a proenzyme that is reciprocally activated by the action of plasmin. Activation of the cascade is locally confined by the high-affinity binding between uPA or pro-uPA and the cell surface receptor uPAR. Mice lacking uPA display defects in extravascular fibrin degradation while cooperation is observed in transgenic animals that coexpress uPA and uPAR.192 In a similar manner to MMPs, stromal cells appear to be the major sources of plasminogen activity in most tumors. The stromal cell type producing uPA depends on the origin of the tumor, myofibroblasts being responsible in breast and colon and macrophages in prostate cancer. Elevated levels of uPA and uPAR in the blood and tissue are associated with poor prognosis in many types of cancer, regardless of their respective sources.193,194 Manipulation of uPA levels by overexpression, treatment with anti-uPA antibodies, or using uPA-deficient mice has demonstrated a key role in cancer growth, invasion, and metastasis.191,195

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