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.