Overexpression of matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 in liver from patients with gastrointestinal adenocarcinoma and no detectable metastasis

Abstract

Degradation of basement membranes is a key step in tumoral invasion, mainly mediated by matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). Since the liver is a main target for metastases from gastrointestinal adenocarcinoma, we have investigated MMP2 and TIMP2 expression by RT-PCR, in situ hybridization and zymography in the liver of patients with gastrointestinal adenocarcinomas and no detectable hepatic metastasis (n = 12), in tumoral and nontumoral liver from patients with hepatic metastasis (n = 9) and in control liver (n = 4). MMP2 and TIMP2 mRNA levels were increased in liver from patients with gastrointestinal adenocarcinomas and no detectable metastasis, compared with those of either control liver (5-fold and 3.2-fold, respectively) or nontumoral areas of liver from patients with metastasis (7.8-fold and 3-fold, respectively). MMP2 and TIMP2 transcripts were located in mesenchymal cells of portal tracts and sinusoids. MMP2 was mainly in its latent form. In liver from patients with hepatic metastasis, the tumoral/nontumoral ratios for MMP2 and TIMP2 mRNA were 6.2 ± 4 and 1.5 ± 0.4, respectively. Both transcripts were localized in the stromal cells of liver metastases, and the active form of MMP2 was found only in the tumoral areas. In the matching nontumoral areas the signals for MMP2 and TIMP2 mRNA were restricted to mesenchymal cells in portal tracts and sinusoidal cells. Our data show that liver stromal cells express high levels of MMP2 and TIMP2 in patients with colonic carcinoma without liver metastasis, suggesting the distant induction of these transcripts by the primary tumor.