Activation of Pro-uPA Is Critical for Initial Escape from the Primary Tumor and Hematogenous Dissemination of Human Carcinoma Cells

摘要: Urokinase-type plasminogen activator (uPA) and plasmin have long been implicated in cancer progression. However, the precise contributions of uPA/plasmin system to specific steps involved cell dissemination not fully established. Herein, we used a highly disseminating variant human PC-3 prostate carcinoma line, PC-hi/diss, as prototype aggressive carcinomas investigate mechanisms whereby pro-uPA activation uPA-generated functionally contribute stages metastasis. The PC-hi/diss cells secrete activate significant amounts pro-uPA, leading efficient generation solution at surface. In mouse orthotopic xenograft model, treatment with activation-blocking antibody mAb-112 significantly inhibited local invasion distant metastasis cells. To mechanistically examine uPA/plasmin-mediated aspects tumor dissemination, anti-pro-uPA potent serine protease inhibitor, aprotinin, were parallel number vivo assays modeling various rate-limiting early metastatic spread. Our findings demonstrate that, by generating plasmin, activated tumor-derived uPA facilitates specifically escape from primary intravasation. Moreover, through series vitro analyses, suggest that PC-hi/diss-invasive may be enhanced cleavage stromal fibronectin plasmin. Together, our point inhibition apex cascade therapy-valid approach control onset ensuing