Study on the mechanism of extracellular matrix degradation induced by tumor cell associated fibrinolytic enzyme

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Dissolution of and migration through basement membranes and extracellular matrices are critical steps for tumor cells. The fibrinolytic enzyme system such as urokinase type plasminogen activator (uPA) and its inhibitor (plasminogen activator inhibitor, PAI) seems to play an important role in tumor invasion and metastasis formation. The uPA,which can bind uPA receptor on the surface of tumor cell membrane, can make a complex with PAI (uPA/PAI complex). The uPA/PAI complex has no fibrinolytic activity, but has only PA inhibiting activity in vitro study. But high amounts of uPA in tumor cells show poor prognosis in patients with carcinoma. This fact seems contradictory.We proved that uPA activity of cell membrane reappear after incubation with uPA/PAI-1 complex a large amount of activated Protein C (APC) by flow cytometry and in fibrin plate assay. The uPA/PAI-1 complex was formed after 30 min incubation of 50 nM uPA and 50 nM PAI-1 at room temperature (RT), and then 30-fold molar of APC was added to the complex at RT for 30 min. The uPA/PAI-1 complex had no fibrinolytic activity, but after the incubation with APC the complex showed the fibrinolytic activity like uPA.In this study, we also proved APC could make APC/PAI-1 complex after incubation of uPA/PAI-1 complex with APC,and the activity of PAI-1 was inhibited. These facts show tumor cell associated uPA activity can be reversible even after the complex formation with PAI-1, and can degrade extracellular matrix.