A RAT MODEL OF PANCREATIC DUCTAL ADENOCARCINOMA - TARGETING CHEMICAL CARCINOGENS

Background. Current experimental models of pancreatic cancer either fa il to reproduce the ductal phenotype or cause simultaneous cancers in other organs also. To develop an animal model of pancreatic cancer tha t accurately mimics the human condition, we restricted carcinogenic ex posure to the pancreas and specifically targeted ductal epithelial cel ls. Three different carcinogens were either implanted directly into th e pancreas or infused into the pancreatic duct, with or without near-t otal pancreatectomy (as a means of inducing pancreatic ductal cell pro liferation). Methods. Groups of male Sprague-Dawley rats were exposed to varying doses of dimethylbenzanthracine (DMBA), methynitronitrosogu anidine, or ethylnitronitrosoguanidine either through direct implantat ion into the pancreas or infusion into the pancreatic duct. Near-total pancreatectomy was added in all groups except two DMBA implantation g roups. Surviving rats were killed at 3, 6, 9, or 12 months, and the pa ncreata were evaluated histologically. Results. All three carcinogens caused pancreatic inflammation, ductal hyperplasia, atypia, and dyspla sia beginning by 3 months and becoming more prominent at later time po ints. Only DMBA caused frequent invasive pancreatic ductal adenocarcin oma, which was first evident by 6 months. The prevalence of pancreatic cancer among DMBA-treated rats evaluated after 10 months was 39% (19 of 49). The addition of pancreatic resection did not enhance pancreati c cancer development. Conclusions. Of the strategies tested, only dire ct implantation of DMBA into the rat pancreas frequently produces panc reatic cancer histologically similar to human ductal adenocarcinoma. T he development of hyperplastic, atypical, and dysplastic changes prece ding and accompanying carcinomas suggests that these lesions are prene oplastic. This model recapitulates the progression from normal to neop lastic epithelium and is likely to be useful for the study of morpholo gic and molecular mechanisms underlying the early stages of pancreatic carcinogenesis and for the investigation of novel diagnostic and ther apeutic techniques.