Expression of matrix metalloproteinases (MMPs) during hamster pancreatic duct carcinogenesis, detection of serum MMPs in tumor-bearing hamster and chemopreventive effect of hamster pancreatic cancer

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In order to assess the significance of changes in metalloproteinase activity in pancreatic carcinogenesis, the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in a rapid production model for pancreatic duct carcinomas in hamsters initiated with N-nitrosobis (2-oxopropyl) amine (BOP) was investigated. Northern analysis revealed MMP-2 and MMP-9 mRNAs to be overexpressed in pancreatic duct carcinomas. Immunohistochemically, elevated levels of MMP-2 were apparent in early duct epithelial hyperplasias and staining increased from atypical hyperplasias to carcinomas. Gelatin zymography demonstrated clear activation of proMMP-2 but not proMMP-9 in primary tumors. Moreover we also invetigated that sera from hamsters with transplantable hamster pancreatic duct carcinoma (HPDt) possessed serum MMP-2 levels five times higher than the control sera as determined by gelatin zymographic analysis.In our rapid production model, 0.1% and 0.2% OPB-3206, an inhibitor of MMPs, given in the diet after two cycles of augmentation pressures for 48 days decreased the incidence and number of carcinomas. Gelatin zymography demonstrated that OPB-3206 inhibited activation of proMMP-2 in pancreatic cancer tissues. These results indicate that over expression of MMP-2 and MMP-9 are involved in the development of pancreatic duct adenocarcinomas and that MMP-2 expression at the protein level appears in the early phase of pancreatic duct carcinogenesis. Serum MMPs may be useful markers for monitoring patients with pancreatic adenocarcinoma. OPB-3206 may be candidate chemopreventive agent for pancreatic ductal adenocarcinomas.