Inhibition of the soluble and the tumor cell receptor-bound plasmin by urinary trypsin inhibitor and subsequent effects on tumor cell invasion and metastasis
Kobayashi, H.; Shinohara, H.; Takeuchi, K.; Itoh, M.; Fujie, M.; Saitoh, M.; Terao, T.
Cancer Research 54(3): 844-849
1994
ISSN/ISBN: 0008-5472 PMID: 8306348 Document Number: 436841
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.