title: A genetically engineered mouse model developing rapid progressive pancreatic ductal adenocarcinoma.
abstract: The premalignant lesions of pancreatic cancer, pancreatic intraepithelial neoplasia (PanIN), have a high frequency of mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS), and genetic alterations in the retinoblastoma (Rb)-E2 factor (E2F) and transformed 3T3 cell double minute 2 (MDM2)-p53 pathways accelerate development of pancreatic ductal adenocarcinoma. The viral oncoprotein SV40 large T antigen (TAg) can inhibit the effects of the Rb family of molecules and of p53 on these pathways, and targeted expression of TAg in mouse pancreas is associated with the development of endocrine or acinar cell tumours. In this study, to determine whether the viral oncoprotein promotes pancreatic duct carcinogenesis initiated by oncogenic KRAS, we generated mice expressing temperature-sensitive SV40 large T antigen (tsTAg) on pancreatic epithelial cells in the presence or absence of Kras(G12D) . Mice with pancreas-specific tsTAg expression developed acinar cell dysplasia by 22 weeks without PanIN formation, while mice expressing both tsTAg and Kras(G12D) developed highly aggressive adenocarcinoma with a ductal cell phenotype within a short period, and died within 3 weeks. The tumours resembled human pancreatic ductal adenocarcinoma (PDAC) at the histological level, and oncogenic Kras and tsTAg synergistically activated E2f and Sre transcription in established PDAC cell lines. These results suggest that tsTAg synergistically promotes Kras(G12D) -associated PDAC formation, and our study identifies a new mouse model of PDAC that may allow a better understanding of the mechanism of carcinogenesis in pancreatic carcinoma, which shows a catastrophic clinical course.
authors.affiliation: Molecular Medicine Team, Research Centre for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Ibaraki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Sanae
authors.initials: S
authors.lastname: Ikehara
authors.forename: Hayao
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Ikehara
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000957:Antigens, Viral, Tumor; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KrasG12D; genetically engineered mouse model; temperature-sensitive T antigen