Enhanced tumor growth and invasiveness in vivo by a carboxyl-terminal fragment of α1-proteinase inhibitor generated by matrix metalloproteinases -: A possible modulatory role in natural killer cytotoxicity

Matrix metalloproteinases (MMPs) are believed to contribute to the complex process of cancer progression. They also exhibit an alpha 1-proteinase inhibitor (alpha PI)-degrading activity generating a carboxyl-terminal fragment of similar to 5 kd (alpha PI-C). This study reports that overexpression of alpha PI-C in S2-020, a cloned subline derived from the human pancreas adenocarcinoma cell line SUIT-2, potentiates the growth capability of the cells in nude mice. After stable transfection of a vector containing a chimeric cDNA encoding a signal peptide sequence of tissue inhibitor of metalloproteinase-1 followed by cDNA for alpha PI-C into S2-020 cells, three clones that stably secrete alpha PI-C were obtained. The ectopic expression of alpha PI-C did not alter in vitro cellular growth. However, subcutaneous injection of the alpha PI-C-secreting clones resulted in tumors that mere 1.5 to 3-fold larger than those of control clones with an increased tendency to invasiveness and lymph node metastasis. These effects could be a result of modulation of natural killer (NK) cell-mediated control of tumor growth in nude mice, as the growth advantage of alpha PI-C-secreting clones was not observed in NK-depleted mice, and alpha PI-C-secreting clones showed decreased NK sensitivity ta vitro. In addition, production of alpha PI and generation of the cleaved form of alpha PI by MMP mere observed in various human tumor cell lines and in a highly metastatic subline of SUIT-2 in vitro. These results provide experimental evidence that the alpha PI-degrading activity of MMPs may play a role in tumor progression not only via the inactivation of alpha PI but also via the generation of alpha PI-C.