Prognostic significance of matrix metalloproteinase expression in colorectal carcinomas

The matrix metalloproteinases (MMPs) are a family of enzymes that degrade the extracellular matrix (ECM) and are considered to be important in neoplastic cell invasion and metastasis. Structural changes in the extracellular matrix are necessary for cell migration during tissue remodeling and neoplastic cell invasion. Histochemical expression of MMP-2, -3, -9, -10, and -13 was observed in 19 human colorectal carcinomas (CCs) employing an indirect alkaline phosphatase (AP) conjugated antigen detection technique. Evaluation of the results was based on (a) the percent of neoplastically transformed cells that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of stromelysin (SL), types 1 (MMP-3) and 2 (MMP-10), share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by cytokines and growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in all CC cases observed, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two MMPs in the ECM surrounding over 90% of the neoplastically transformed cells, and the staining intensity was also the strongest possible (A,B). Weak (surrounding anywhere between 10% and 90% of the neoplastically transformed cells, and of strong A,B intensity) expression of MMP-2 (gelatinase A) and MMP-9 (gelatinase B), two cytokine-induced MMPs, was also observed in CCs. Expression of collagenase-3 (MMP-13), an endopeptidase characterized by a potent degrading activity against a wide spectrum of substrates, was not defined in the CCs cases observed by us. It is clear that the activation of MMPs and their inhibitors occurs in a very well orchestrated manner. The necessity of these same enzymes for the extravasation and infiltration of lymphocytes into regions of chronic local inflammation, as associated with neoplastically transformed masses of cells, may aid the transformed cells which have already acquired a metastatic immunophenotype to enter the peripheral circulation. Further characterization of the expression and utilization of MMPs and their inhibitors in the progression of solid human neoplasms should lead to the development of novel anti-cancer therapies.