Localization of tissue inhibitor of metalloproteinases 1 (TIMP‐1) in human colorectal adenoma and adenocarcinoma

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Abstract
Tissue inhibitor of matrix metalloproteases 1 (TIMP‐1) inhibits the proteolytic activity of matrix metalloproteases and hereby prevents cancer invasion. However, TIMP‐1 also possesses other functions such as inhibition of apoptosis, induction of malignant transformation and stimulation of cell‐growth. We have previously demonstrated that TIMP‐1 is elevated in blood from colorectal cancer patients and that high TIMP‐1 levels predict poor prognosis. To clarify the role of TIMP‐1 in colorectal tumorigenesis, the expression pattern of TIMP‐1 in benign and malignant colorectal tumors was studied. In all of 24 cases of colorectal adenocarcinoma TIMP‐1 mRNA was detected by in situ hybridization. In all cases TIMP‐1 expression was found in fibroblast‐like cells located at the invasive front but was seen only sporadically in normal mucosa. No TIMP‐1 mRNA was seen in any of the cases in benign or malignant epithelial cells, in vascular cells or smooth muscle cells. Comparison of sections processed for TIMP‐1 in situ hybridization with sections immunohistochemically stained with antibodies against TIMP‐1 showed good correlation between TIMP‐1 mRNA and immunoreactivity. Combining TIMP‐1 in situ hybridization with immunohistochemical staining for α‐smooth muscle actin or CD68 showed TIMP‐1 mRNA in myofibroblasts but not in macrophages. TIMP‐1 mRNA was detected in 2 of 7 adenomatous polyps in the adenoma area: in both cases associated with focal stromal inflammation at the epithelial‐stromal interface. In conclusion, TIMP‐1 expression is a rare event in benign human colon tissue but is highly expressed by myofibroblasts in association with invading colon cancer cells.
Funding Information
  • The Danish Cancer Society
  • European Commission (QLG1-CT-2000-0111131)
  • Weimann Foundation