Expression of matrix metalloproteinase 2 (MMP-2), membrane-type 1 MMP and tissue inhibitor of metalloproteinase 2 and activation of proMMP-2 in pancreatic duct adenocarcinomas in hamsters treated with N-nitrosobis(2-oxopropyl)amine

In order to assess the significance of changes in metalloproteinase activit y in pancreatic carcinogenesis, the expression of matrix metalloproteinases 2 and 9 (MMP-2 and and MMP-9, respectively), tissue inhibitor of metallopr oteinase-1 (TIMP-1) and TIMP-2, and membrane-type 1 MMP (MT1-MMP) and MT2-M MP in ductal lesions in a rapid-production model for pancreatic duct carcin omas (PCs) in hamsters initiated with N-nitrosobis(2-osopropyl)amine (BOP) and in subcutaneous transplantable tumors of hamster pancreatic duct carcin oma (HPDs) was investigated. Northern analysis revealed MMP-2, MMP-9, TIMP- 2 and MT1-MMP mRNAs to be overexpressed in PCs, Immunohistochemically, elev ated levels of MMP-2 were apparent in early duct epithelial hyperplasias an d staining increased from atypical hyperplasias to carcinomas, Gelatin zymo graphy demonstrated clear activation of proMMP-2 but not proMMP-9 in both o f primary and HPD tumors, the MT1-MMP;IP mRNA level and proMMP-2 activation being significantly correlated (r = 0.893, P < 0.001), In our rapid produc tion 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 incide nce and number of carcinomas, Gelatin zymography demonstrated that OPB-3206 inhibited activation of proMMP-2 in pancreatic cancer tissues. These resul ts indicate that overexpression of MMP-2, TIMP-2 and MT1-MMP, and cell surf ace activation of proMMP-2 by MT1-MMP, are involved in the development of P Cs, and that MMP-2 expression at the protein level appears in the early pha se of pancreatic duct carcinogenesis. OPB-3206 may be a candidate chemoprev entive agent for pancreatic ductal adenocarcinomas.