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 tu mor invasion and metastases. Because tissue inhibitor of metalloproteinase- 3 suppresses tumorigenicity and tumor invasion in vitro, the aim of this st udy was to determine its expression in human colorectal cancer. METHODS: Th irty-nine human colorectal cancer specimens, three adenomas, and matched no rmal adjacent mucosa from 39 colorectal cancer patients were analyzed. Tiss ue inhibitor of metalloproteinase-3 ribonucleic acid and protein expression were analyzed by Northern blot hybridization and Western blot analysis, re spectively. The cellular localizations of tissue inhibitor of metalloprotei nase-3 ribonucleic acid and protein were determined by in situ hybridizatio n and immunolocalization. RESULTS: Tissue inhibitor of metalloproteinase-3 ribonucleic acid expression was increased in colorectal cancer compared wit h paired normal mucosa. In contrast, tissue inhibitor of metalloproteinase- 3 protein level was higher in normal mucosa than in the corresponding color ectal cancer. In addition, tissue inhibitor of metalloproteinase-3 protein levels progressively decreased with advancing colorectal cancer stages. Tis sue inhibitor of metalloproteinase-3 protein tumor to normal mucosa ratio w as 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 (a = 9), and D (n = 13) stages, respectively. Both tissue inhibitor of metalloproteinase-3 messenger ribonucleic acid and prot ein were located predominantly within spindle-shaped and round stromal cell s. Furthermore, in colonic epithelium, tissue inhibitor of metalloproteinas e-3 and type IV collagen protein were similarly concentrated in the basal r egion. CONCLUSIONS: These data provide the first detailed description of th e cellular expression of tissue inhibitor of metalloproteinase-3 in colorec tal cancer and identify it as a basement membrane-associated protein. This is an important observation, because the presence of tissue inhibitor of me talloproteinase-3 protein near the basement membrane supports its role in p reventing proteolytic degradation, angiogenesis, and apoptosis.