Significance of coexpression of urokinase-type plasminogen activator, and matrix metalloproteinase 3 (stromelysin) and 9 (gelatinase B) in colorectal carcinoma.

Our previous study showed that proMMP-9 was activated by MMP-3 directly, and that proMMP-3 was activated by plasmin. It was postulated that the proMMP-9 activation mechanism through the protease-protease cascade existed even in vivo. The purpose of the present study was to clarify the clinical significance of the combined expression of MMP-9, MMP-3, and urokinase-type plasminogen activator (uPA) in colorectal cancer, and the role of MMP-3 or uPA expression as an activator for MMP-9. The expression of both MMP-9 and uPA was found to be correlated with liver metastasis, and with survival rate. The coexpression of MMP-9 and uPA by tumor cells was also significantly correlated with postoperative hepatic recurrence and survival rate. MMP-9 tended to be coexpressed with uPA, and was consistently associated with MMP-3 localized at the tumor-invasive front with inflammatory cells such as monocyte-macrophages. In gelatin zymography, the MMP-9 active form tended to be identified in the tumors that coexpressed both MMP-9 and uPA. We concluded that coexpression of MMP-9 and uPA in tumor tissues might be a useful predictive factor for postoperative survival and hepatic metastasis. The following activation mechanism for proteinase might occur: uPA coexpressed with MMP-9 activated plasminogen, and plasmin activated proMMP-3, which was secreted depending upon inflammatory infiltration, and then MMP-3 activated proMMP-9, resulting in colorectal cancer progression and metastasis.