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Tumor-associated Trypsin Participates in Cancer Cell-mediated Degradation of Extracellular Matrix¹

Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Haartmaninkatu 2, SF-00290 Helsinki [E. K., A. R., O. I., S. O., U-H. S.], and Department of Biochemistry, University of Helsinki, Unioninkatu 35, SF-00170 Helsinki [M. V.], Finland

We have recently demonstrated that many cancer cell lines produce a novel trypsinogen isoenzyme called tumor-associated trypsinogen 2 (TAT-2). It was found during a search of the target protease for tumor-associated trypsin inhibitor (TATI). We now show that degradation of subendothelial cell extracellular matrix (ECM) by four different cell lines (COLO 205 colon carcinoma, K-562 erythroleukemia, CAPAN-1 pancreatic carcinoma, and HT 1080 fibrosarcoma) can be partially inhibited by TATI or neutralizing trypsin antibodies. When cells were cultured in serum-free medium on ECM, TATI and trypsin antibodies inhibited the release of immunoreactive fibronectin fragments from ECM by 47–54 and 40%, respectively. Degradation of isotopically labeled ([³H]serine, [³H]proline, and [³⁵S]sulfate) ECM was also significantly prevented by TATI. At its maximum, it exerted a 57% inhibition on the degradation of [³H]serine-labeled ECM. Plasminogen added exogenously to the culture medium further potentiated the proteolysis of ECM. Interestingly, addition of enteropeptidase, an activator of TAT-2, also enhanced cell-mediated proteolysis as assessed by degradation of purified fibronectin coated onto the surface of wells. Immunoblot analysis showed that enteropeptidase-mediated proteolysis generated a pattern of fibronectin fragments similar to that obtained by digestion of purified fibronectin by TAT-2. These results demonstrate the existence of a proteolytic system in tumor cells which is dependent on the activation of TAT-2. We suggest that TAT-2 is involved in a protease cascade-stimulating tumor cell invasion and degradation of extracellular matrix.

¹ This work was supported by grants from the Academy of Finland, the Finnish Cancer Society, the Finnish Social Security Institution, the Jenny and Antti Wihuri Foundation, and the Ida Montin Foundation.

² To whom requests for reprints should be addressed.

Received 7/31/90. Accepted 2/ 4/91.

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