title: PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine.
abstract: Mutation or loss of the genes PTEN and KRAS have been implicated in human colorectal cancer (CRC), and have been shown to co-occur despite both playing a role in the PI3' kinase (PI3'K) pathway. We investigated the role of these genes in intestinal tumour progression in vivo, using genetically engineered mouse models, with the aim of generating more representative models of human CRC. Intestinal-specific deletion of Pten and activation of an oncogenic allele of Kras was induced in wild-type (WT) mice and mice with a predisposition to adenoma development (Apc(fl/+) ). The animals were euthanized when they became symptomatic of a high tumour burden. Histopathological examination of the tissues was carried out, and immunohistochemistry used to characterize signalling pathway activation. Mutation of Pten and Kras resulted in a significant life-span reduction of mice predisposed to adenomas. Invasive adenocarcinoma was observed in these animals, with evidence of activation of the PI3'K pathway but no metastasis. However, mutation of Pten and Kras in WT animals not predisposed to adenomas led to perturbed homeostasis of the intestinal epithelium and the development of hyperplastic polyps, dysplastic sessile serrated adenomas and metastasizing adenocarcinomas with serrated features. These studies demonstrate synergism between Pten and Kras mutations in intestinal tumour progression, in an autochthonous and immunocompetent murine model, with potential application to preclinical drug testing. In particular, they show that Pten and Kras mutations alone predispose mice to the spectrum of serrated lesions that reflect the serrated pathway of CRC progression in humans.
authors.affiliation: Cardiff School of Biosciences, Cardiff University, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Davies
authors.forename: Victoria
authors.initials: V
authors.lastname: Marsh Durban
authors.forename: Valerie
authors.initials: V
authors.lastname: Meniel
authors.forename: Geraint T
authors.initials: GT
authors.lastname: Williams
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D006965:Hyperplasia; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D047368:Tumor Burden
chemical_list: D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: APC; KRAS; PTEN; colorectal cancer metastasis model; genetically engineered mouse model; serrated adenocarcinoma; serrated adenoma