Tissue inhibitor of metalloproteinase-3 is a basement membrane-associated protein that is significantly decreased in human colorectal cancer

PURPOSE: The balance between local levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases is believed to play a key role in tumor invasion and metastases. Because tissue inhibitor of metalloproteinase-3 suppresses tumorigenicity and tumor invasionin vitro, the aim of this study was to determine its expression in human colorectal cancer. METHODS: Thirty-nine human colorectal cancer specimens, three adenomas, and matched normal adjacent mucosa from 39 colorectal cancer patients were analyzed. Tissue inhibitor of metalloproteinase-3 ribonucleic acid and protein expression were analyzed by Northern blot hybridization and Western blot analysis, respectively. The cellular localizations of tissue inhibitor of metalloproteinase-3 ribonucleic acid and protein were determined byin situ hybridization and immunolocalization. RESULTS: Tissue inhibitor of metalloproteinase-3 ribonucleic acid expression was increased in colorectal cancer compared with paired normal mucosa. In contrast, tissue inhibitor of metalloproteinase-3 protein level was higher in normal mucosa than in the corresponding colorectal cancer. In addition, tissue inhibitor of metalloproteinase-3 protein levels progressively decreased with advancing colorectal cancer stages. Tissue inhibitor of metalloproteinase-3 protein tumor to normal mucosa ratio was 0.74 ± 0.12, 0.51 ± 0.18, 0.48 ± 0.12, and 0.45 ± 0.2 for Dukes A (n=8), B (n=9), C (n=9), and D (n=13) stages, respectively. Both tissue inhibitor of metalloproteinase-3 messenger ribonucleic acid and protein were located predominantly within spindle-shaped and round stromal cells. Furthermore, in colonic epithelium, tissue inhibitor of metalloproteinase-3 and type IV collagen protein were similarly concentrated in the basal region. CONCLUSIONS: These data provide the first detailed description of the cellular expression of tissue inhibitor of metalloproteinase-3 in colorectal cancer and identify it as a basement membrane-associated protein. This is an important observation, because the presence of tissue inhibitor of metalloproteinase-3 protein near the basement membrane supports its role in preventing proteolytic degradation, angiogenesis, and apoptosis.