title: Epithelial tissues have varying degrees of susceptibility to Kras(G12D)-initiated tumorigenesis in a mouse model.
abstract: Activating mutations in the Kras gene are commonly found in some but not all epithelial cancers. In order to understand the susceptibility of different epithelial tissues to Kras-induced tumorigenesis, we introduced one of the most common Kras mutations, Kras(G12D), broadly in epithelial tissues. We used a mouse model in which the G12D mutation is placed in the endogenous Kras locus controlled by inducible, Cre-mediated recombination in tissues expressing cytokeratin 19 including the oral cavity, GI tract, lungs, and ducts of the liver, kidney, and the pancreas. Introduction of the Kras(G12D) mutation in adult mouse tissues led to neoplastic changes in some but not all of these tissues. Notably, many hyperplasias, metaplasias and adenomas were observed in the oral cavity, stomach, colon and lungs, suggesting that exposure to products of the outside environment promotes Kras(G12D)-initiated tumorigenesis. However, environmental exposure did not consistently correlate with tumor formation, such as in the small intestine, suggesting that there are also intrinsic differences in susceptibility to Kras activation. The pancreas developed small numbers of mucinous metaplasias with characteristics of early stage pancreatic intraepithelial neoplasms (PanINs), supporting the hypothesis that pancreatic ducts have the potential to give rise pancreatic cancer.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Ray
authors.forename: Kayla M
authors.initials: KM
authors.lastname: Bell
authors.forename: Jingbo
authors.initials: J
authors.lastname: Yan
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Gu
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Anna L
authors.initials: AL
authors.lastname: Means
mesh_terms: D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D005998:Glycine / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009062:Mouth Neoplasms / Q000235:genetics / Q000473:pathology; D020125:Mutation, Missense / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology; D010212:Papilloma / Q000235:genetics / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000502:physiology
chemical_list: D001224:Aspartic Acid; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D005998:Glycine