3.膵発がん幹細胞候補の同定

抄録

Pancreatic ductal adenocarcinoma is one of the most debilitating malignancies in humans with median survival times after treatment being less than 12 months. For the improvement of survivals, development of appropriate animal models which biologically mimic the human lesion is urgently required. Recent studies indicated that biological characteristics of tumor is dependent on cells in which a tumor grows, termed cancer stem cells. Although the data have been provided to support this theory in human tumors of blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Although, pancreas ductal carcinomas were induced by induction of activated K-ras gene into the precursor gene in mouse, the responsible cells are not directly indicated. We conducted the study to determine if targeted activation of a human oncogenic-ras transgene in rat fully developed pancreas cell would induce carcinomas correspondent to human pancreatic ductal adenocarcinomas. Thus, transgenic (Hras250) rats in which expression of a human Ha-ras^G12V oncogene is regulated by the Cre/lox system is established. Targeted pancreatic activation of the transgene was accomplished by injection of Cre carrying adenovirus into the pancreatic ducts and acini through the common bile duct. Adenoviral infection of injected animals was exclusive to the pancreas; infected cells could be identified in duct, intercalated duct, centroacinar, and, less frequently, acinar cells, but not in endocrine islet cells. Four weeks after injection, proliferative lesions were exclusively observed in the duct epithelium, intercalated ducts, and centroacinar cells, but not acinar cells. Most lesions, including atypical duct proliferative lesions, PanIN-like lesions, and carcinomas, were positive for cyokeratins 19 and 7, cyclooxigenase 2, and MMP-7 but negative for amylase and chymotrypsin. Many adenocarcinoma lesions were positive for EGF and EGFR. Duct epithelial and atypical duct proliferative lesions and carcinoma lesions were all positive for transduced Ha-ras^G12V oncogene expression. This model exhibits close similarities to the human lesions and promises to advance our understanding of biological characteristics of pancreas adenocarcinomas. Results indicate that pancreatic duct epithelium, intercalated duct cells and centroacinar cells are possible candidate of cancer stem cells pancreas duct carcinomas.