Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation

Radulescu, S. et al. (2013) Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation. Oncogene, 32(16), pp. 2048-2057. (doi: 10.1038/onc.2012.224)

Abstract

A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ridgway, Dr Rachel and Salgueiro, Manuel and Cordero, Professor Julia and Oien, Professor Karin and Radulescu, Dr Sorina and Sansom, Professor Owen
• Authors: Radulescu, S., Ridgway, R.A., Cordero, J., Athineos, D., Salgueiro, P., Poulsom, R., Neumann, J., Jung, A., Patel, S., Woodgett, J., Barker, N., Pritchard, D.M., Oien, K., and Sansom, O.J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Oncogene
• Publisher: Nature Publishing Group
• ISSN: 0950-9232
• ISSN (Online): 1476-5594
• Copyright Holders: Copyright © 2013 Macmillan Publishers Limited
• First Published: First published in Oncogene 32(16):2048-2057
• Publisher Policy: Reproduced under a Creative Commons License