PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine. Issue 1 (23rd January 2014)

• Record Type: Journal Article
• Authors: Davies, Emma J; Marsh Durban, Victoria; Meniel, Valerie; Williams, Geraint T; Clarke, Alan R
• Is Part Of: Journal of pathology. Volume 233:Issue 1(2014)
• Page Start: 27
• Page End: 38
• Publication Date: 2014-01-23
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4312
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main" id="path4312-abs-0001"> <title>Abstract</title> <p id="path4312-para-0001">Mutation or loss of the genes <italic>PTEN</italic> and <italic>KRAS</italic> 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 <italic>in vivo</italic>, using genetically engineered mouse models, with the aim of generating more representative models of human CRC. Intestinal‐specific deletion of <italic>Pten</italic> and activation of an oncogenic allele of <italic>Kras</italic> was induced in wild‐type (WT) mice and mice with a predisposition to adenoma development (<italic>Apc<sup>fl/+</sup></italic>). 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 <italic>Pten</italic> and <italic>Kras</italic> 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 <italic>Pten</italic> and <italic>Kras</italic> 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 <italic>Pten</italic> and <italic>Kras</italic> mutations in intestinal tumour progression, in an autochthonous and immunocompetent murine model, with potential application to preclinical drug testing. In particular, they show that <italic>Pten</italic> and <italic>Kras</italic> mutations alone predispose mice to the spectrum of serrated lesions that reflect the serrated pathway of CRC progression in humans. Published by John Wiley & Sons, Ltd. <ext-link ext-link-type="uri" xlink:href="http://www.pathsoc.org.uk" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">www.pathsoc.org.uk</ext-link></p> </abstract>