Plasminogen Activators: Regulators of Tumor Cell Adherence to Sites of Lower Urinary Tract Surgical Trauma

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Abstract
Tumor cell adherence (TCA) to sites of surgical injury is a requisite step in implantation-mediated tumor recurrence. This study examined the relationship between tumor-associated plasminogen activator (PA) and the ability of tumor cells to remain adherent to surgical injury sites. High (1E8) and low (3A9) PA producing clones from the murine transitional carcinoma cell line 4909 were selected using an in vitro 125I fibrinolysis assay. Net cellular PA activity of each clone was determined from cell lysates using a chromogenic substrate assay. In vitro TCA and fibrin substrate lysis as a function of time were simultaneously measured using a tetrazolium dye assay in combination with an 125I fibrinolysis assay. In vivo TCA to in situ cautery-injured rat bladders was measured 30 minutes (n = 12 animals/cell line) and 24 hours (n = 18 animals/cell line) following tumor exposure with a radiolabeled TCA assay. In vitro and in vivo competitive binding assays evaluated the relative adherence of mixtures of the 1E8 and 3A9 clones. Cellular PA activity was 0.022, 0.014 and 0.007 units per mg. protein for the 1E8, 4909 and 3A9 cell lines. In vitro TCA to fibrin in the presence of plasminogen was significantly different for each cell line and demonstrated an inverse relationship with both plasminogen-dependent fibrin lysis and cellular PA activity (p < 0.0001). The in vivo assay showed that the percentage of 1E8 cells remaining adherent 24 hours after tumor exposure was significantly less than that of the 3A9 cells (p = 0.01). Both in vitro and in vivo competitive binding assays demonstrated preferential adherence of the 3A9 cell line. Cellular PA production appears to be a tumor-intrinsic variable that modulates TCA to surgical injury sites.