Matrix metalloproteinases (MMPs) classically have been implicated in basement membrane destruction associated with late-stage tumor cell invasion and metastasis. However, recent studies have demonstrated that one MMP family member, matrilysin, is expressed in a high percentage of early-stage human colorectal tumors. We analyzed matrilysin expression in benign intestinal tumors from mice heterozygous for the Apc Min allele (Min͞؉) and found that the mRNA was induced in the majority (88%) of these adenomas. Protein was detected in the tumor cells, where, surprisingly, it was predominantly immunolocalized to the lumenal surface of dysplastic glands rather than the basement membrane or extracellular matrix. To address the role of matrilysin in Min intestinal tumorigenesis, we generated Min͞؉ mice deficient in this MMP by gene targeting and homologous recombination. The absence of matrilysin resulted in a reduction in mean tumor multiplicity in Min͞؉ animals of approximately 60% and a significant decrease in the average tumor diameter. Based on these findings, we conclude that matrilysin is a suppressor of the Min phenotype, possibly by functioning in a capacity independent of matrix degradation. These results argue for the use of MMP inhibitors in the treatment and prevention of early-stage colon cancer.Inhibitor studies have demonstrated that destruction of basement membrane components and connective tissue by matrix metalloproteinases (MMPs) is critical for tumor cell invasion and dissemination (reviewed in ref. 1). The MMPs compose a family of structurally similar metal-dependent enzymes that includes the collagenases, gelatinases A and B, the stromelysins, matrilysin, metalloelastase, and the membrane-type metalloproteinases. In many of the neoplastic lesions that have been examined in humans, the expression of most MMPs is restricted to the stromal component (reviewed in ref. 2). However, matrilysin (MMP-7, pump-1; EC 3.4.24.23) localizes primarily to the tumor cells in lesions of epithelial origin (reviewed in ref.3) and can be detected readily in normal epithelium of specific glandular organs in both humans (4) and mice (5). Matrilysin mRNA has been detected in human adenomas, as well as carcinomas and adenocarcinomas, of the breast and colon (6-11). Furthermore, ectopic expression of matrilysin cDNA in a colorectal carcinoma cell line was found to increase its tumorigenicity in nude mice but did not affect metastasis (12). Taken together, these results suggest that matrilysin may contribute to early tumor development, particularly in the gastrointestinal tract.The Min (multiple intestinal neoplasia) mouse has proven to be a powerful model system to study molecules involved in the progression of intestinal adenomas. It has been determined that a nonsense autosomal dominant germline mutation in the adenomatous polyposis coli (Apc) gene (the Apc Min allele) induces spontaneous intestinal tumors in these mice, providing a model that closely mimics the human hereditary colon cancer syndrome, familial aden...

To explore the role of the matrix metalloproteinase matrilysin (MAT) in normal tissue remodeling, we cloned the murine homologue of MAT from postpartum uterus using RACE polymerase chain reaction and examined its pattern of expression in embryonic, neonatal, and adult mice. The murine coding sequence and the corresponding predicted protein sequence were found to be 75% and 70% identical to the human sequences, respectively, and organization of the six exons comprising the gene is similar to the human gene. Northern analysis and in situ hybridization revealed that MAT is expressed in the normal cycling, pregnant, and postpartum uterus, with levels of expression highest in the involuting uterus at early time points (6 h to 1.5 days postpartum). The mRNA was confined to epithelial cells lining the lumen and some glandular structures. High constitutive levels of MAT transcripts were also detected in the small intestine, where expression was localized to the epithelial Paneth cells at the base of the crypts. Similarly, MAT expression was found in epithelial cells of the efferent ducts, in the initial segment and cauda of the epididymis, and in an extra-hepatic branch of the bile duct. MAT transcripts were detectable only by reverse transcription-polymerase chain reaction in the colon, kidney, lung, skeletal muscle, skin, stomach, juvenile uterus, and normal, lactating, and involuting mammary gland, as was expression primarily late in embryogenesis. Analysis of MAT expression during postnatal development indicated that although MAT is expressed in the juvenile small intestine and reproductive organs, the accumulation of significant levels of MAT mRNA appears to correlate with organ maturation. These results show that MAT expression is restricted to specific organs in the mouse, where the mRNA is produced exclusively by epithelial cells, and suggest that in addition to matrix degradation and remodeling, MAT may play an important role in the differentiated function of these organs.