K-Ras and cyclooxygenase-2 coactivation augments intraductal papillary mucinous neoplasm and Notch1 mimicking human pancreas lesions.

Mutational activation of K-Ras is an initiating event of pancreatic ductal adenocarcinomas (PDAC) that may develop either from pancreatic intraepithelial neoplasia (PanIN) or intraductal papillary mucinous neoplasms (IPMN). Cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) is causally related to pancreatic carcinogenesis. Here, we deciphered the impact of COX-2, a key modulator of inflammation, in concert with active mutant K-Ras(G12D) on tumor burden and gene expression signature using compound mutant mouse lines.

Preinvasive duct-derived neoplasms in pancreas of keratin 5-promoter cyclooxygenase-2 transgenic mice.

Background & Aims: Basic research aimed at a better understanding of pancreatic carcinogenesis and improving the treatment of this disease is crucial because the majority of pancreatic cancers are highly aggressive and therapeutically nonaccessible. Cyclooxygenase (COX)-2, which is a key enzyme of prostaglandin (PG) biosynthesis, is overexpressed in around 75% of human carcinomas including those of the pancreas.

Methods: The pathologic changes of transgenic mouse pancreas with keratin 5-promoter-driven expression and activity of COX-2 were characterized.