Role of TIMP-2 as an MMP-2 activation regulator in colon cancer invasion

K Ko, MD, PhD,a S Yazumi, MD, PhD,b T Chiba MD, PhD,b R Takahashi,MD, PhD,c

aDept. of Internal internal medicine, Mitsubishi Kyoto Hospital, bDept. of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto Univ., cDept. of Pathol. and Tumor Biology, Graduate School of Medicine, Kyoto Univ., Japan

Previously we reported that colon cancer cells could activate fibroblast derived matrix metalloproteinase-2 (MMP-2) in the in vitro co-culture systems. In these co-culture systems, certain inhibition of MMP-2 activation was observed in the contact co-cultures. Tissue inhibitor of metalloproteinase-2 (TIMP-2) has been known as an MMP-2 activation inhibitor. It is also known as an adapter molecule between MMP-2 and MT1-MMP in MMP-2 activation. To clarify this MMP-2 activation inhibitory mechanism in co-cultures, we re-analyzed expression of TIMP-2 and MT1-MMP expression in cancer cells and fibroblast cells. Expression of TIMP-2 and MTI-MMP in colon cancer cell lines Caco-2 and LoVo, and colon fibroblast CCD18-Co were analyzed by Western blot, ELISA and Reverse zymography. In ELISA study, although secretion of TIMP-2 was observed in colon cancer cell line Caco-2, LoVo did not secret any TIMP-2 into the culture media. MT1-MMP was expressed both in cancer cell lines and fibroblasts by Western blot analysis. In cancer cell lines, expression level of MT1-MMP was higher in Caco-2 than in LoVo. Cancer cells could regulate their invasion potential by expressing MMP-2 activation MT1-MMP and activation inhibitor TIMP-2.

KEY WORDS: Colon cancer, fibroblast, .

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Metastasis.