Differing effects of endogenous and synthetic inhibitors of metalloproteinases on intestinal tumorigenesis.

Matrix metalloproteinase (MMP) activity has been associated with tumor invasion and metastasis in many different tumor types, but recent studies also support a role for these enzymes in earlier stages of the tumor progression continuum. Specifically, the expression pattern of MMPs in benign human and mouse gastrointestinal tumors suggests that they may function in the development or growth of non-invasive tumors. To address the contribution of MMP activity to the development of intestinal adenomas, we administered the synthetic MMP inhibitor batimastat and expressed the tissue inhibitor of metalloproteinases-1 (TIMP-1) in the gastrointestinal tract of Min mice, which spontaneously develop pre-malignant small and large intestinal tumors. Batimastat administration resulted in a 48% decrease in the number of Min tumors. This reduction in tumor number is similar to that observed in mice lacking the metalloproteinase matrilysin, and demonstrates the therapeutic and chemopreventive potential of MMP inhibitors for pre-malignant intestinal tumors. In contrast, forced TIMP-1 expression in transgenic mice had no effect or, in one line, unexpectedly augmented Min tumor multiplicity by 32%. This observation supports an in vivo tumor-promoting activity of TIMP-1 that could be related to the growth stimulatory effects of TIMP that have been documented in vitro. Taken together, these 2 approaches of modulating MMP activity in Min mice support a critical function of MMPs in Min tumorigenesis, underscore the importance of an MMP/inhibitor balance in maintaining tissue homeostasis and demonstrate that endogenous MMP inhibitors can have complex effects in particular cellular contexts.