Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation
| Autor: | Sorina Radulescu, Satish Patel, Richard Poulsom, Owen J. Sansom, D. M. Pritchard, P. Salgueiro, Dimitris Athineos, Andreas Jung, Jens Neumann, James R. Woodgett, Nick Barker, Karin A. Oien, Rachel A. Ridgway, Julia B. Cordero |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
medicine.medical_specialty Beta-catenin Adenomatous polyposis coli GSK3 Familial adenomatous polyposis Mice GSK-3 Stomach Neoplasms Internal medicine Genetics medicine Animals Transgenes Molecular Biology beta Catenin Parietal cell biology gastric cancer digestive oral and skin physiology Wnt signaling pathway LRP6 LRP5 Cell Differentiation β-catenin medicine.disease digestive system diseases APC Mice Inbred C57BL Wnt Proteins Disease Models Animal Endocrinology medicine.anatomical_structure Cell Transformation Neoplastic Adenomatous Polyposis Coli biology.protein Cancer research Original Article Signal Transduction |
| Zdroj: | Oncogene |
| ISSN: | 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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