Inhibition of the soluble and the tumor cell receptor-bound plasmin by urinary trypsin inhibitor and subsequent effects on tumor cell invasion and metastasis.

The present study was undertaken to determine whether highly purified human urinary trypsin inhibitor (UTI) efficiently inhibits the soluble and the tumor cell receptor-bound plasmin. The ability of plasmin inhibitors to regulate invasion by tumor cells which express membrane-associated plasmin was also examined. UTI and two other plasmin inhibitors [alpha 2-anti-plasmin (alpha 2AP) and alpha 2-macroglobulin (alpha 2M)] were used. alpha 2AP and alpha 2M, as well as UTI, rapidly inactivate the soluble plasmin that is not bound to cells. Experiments were performed in vitro using cultures of ovarian cancer HOC-I cells and gestational choriocarcinoma SMT-ccl cells. HOC-I and SMT-ccl cells had plasmin(ogen) on their cell surface, and the plasmin activity was detected on their cell surface enzymologically and immunologically. Receptor-bound plasmin reacted effectively with UTI and was directly inactivated by UTI. In contrast, receptor-bound plasmin was not inhibited by alpha 2AP and alpha 2M. Using a modified Boyden chamber and an artificial basement membrane, Matrigel, it was found that UTI, but not alpha 2AP or alpha 2M, can inhibit HOC-I and SMT-ccl cells invasion in vitro. Furthermore, in the experimental lung metastasis model, UTI inhibited the formation of lung metastasis by Lewis lung carcinoma cells. The inhibition of tumor cell invasion was not due to direct antitumor effects of UTI. These results suggest that inhibition of receptor-bound plasmin by UTI is associated with significantly reduced tumor cell invasiveness in vitro and with a decreased number of metastasis in vivo.