The matrix metalloproteinases (MMPs) are a family of extracellular proteases that have been found to be involved in a number of normal physiological and abnormal pathological processes. Currently, 22 distinct genes have been identified in murine species, and 23 in humans. Although MMPs were initially only associated with increased metastatic phenotype, it is now known that MMPs are capable of contributing to multiple stages of tumor progression. The Min mouse model of intestinal neoplasia is the result of a single point mutation in the adenomatous polyposis coli (Apc) gene which causes the development of numerous spontaneous intestinal tumors. One MMP of interest, MMP-7, is expressed only by Paneth cells in murine small intestine; however, as in human tumor samples, MMP-7 expression was detected in 88% of Min adenomas by in situ hybridization analysis. To determine if MMP-7 contributed to early stage tumor formation, mice deficient for MMP-7 were crossed with Min mice. Compared to normal Min mice, animals deficient for MMP-7 exhibited nearly a 60% reduction in tumor multiplicity. Additionally, genetic ablation of MMP-7 resulted in increased expression of other MMPs, suggesting a possible compensatory mechanism of MMP gene regulation. With recent advances in genomic sequencing several novel MMPs have been discovered. In order to analyze the expression pattern of all currently known MMPs simultaneously, we have developed a proprietary microarray containing probes for more than 1200 human and murine proteases. This array contains probes for all known human and murine MMPs, which includes several MMPs that have not been previously analyzed in intestinal tumors. Initial microarray analysis of pooled adenoma samples found that MMPs-3, -8, -12, -15, -19 and -23 expression was restricted to adenoma tissue while MMPs-2, -7, -9, -10, -13, -14, and -17 were detected in both tumor and normal ileal tissue. MMPs-1, -11, -16, -20, -21, -24, -25, -27, and -28 were not detected in either adenoma or normal ileal tissue. Preliminary in situ hybridization analyses has confirmed microarray results, though further investigation of the expression patterns of these MMPs is still in progress. Additionally, we have collected several colonic tumors induced by azoxymethane (AOM) treatment, as well as spontaneous colonic tumors from Min mice. Initial microarray analysis of these samples indicate minimal expressional differences between colonic and ileal as well as between chemical and genetic models of intestinal tumorigenesis. Furthermore, these results suggest roles of MMP-19 and -23, which have not been previously been examined in the Min model system of intestinal neoplasia.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]