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Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer
  1. Shu Shimada1,
  2. Ayako Mimata1,
  3. Masaki Sekine2,
  4. Kaoru Mogushi3,
  5. Yoshimitsu Akiyama1,
  6. Hiroshi Fukamachi1,
  7. Jos Jonkers4,
  8. Hiroshi Tanaka3,
  9. Yoshinobu Eishi2,
  10. Yasuhito Yuasa1
  1. 1Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
  2. 2Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  3. 3Department of Systems Biology, Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan
  4. 4Division of Molecular Biology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
  1. Correspondence to Professor Yasuhito Yuasa, Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; yuasa.monc{at}tmd.ac.jp

Abstract

Background Gastric cancer is the second most frequent cause of death from cancer in the world, diffuse-type gastric cancer (DGC) exhibiting a poor prognosis. Germline mutations of CDH1, encoding E-cadherin, have been reported in hereditary DGC, and genetic and/or epigenetic alterations of CDH1 are frequently detected in sporadic DGC. Genetic alterations of TP53 are also frequently found in DGC. To examine the synergistic effect of the loss of E-cadherin and p53 on gastric carcinogenesis, a mouse line was established in which E-cadherin and p53 are specifically inactivated in the stomach parietal cell lineage.

Methods Atp4b-Cre mice were crossed with Cdh1loxP/loxP and Trp53loxP/loxP mice, and the gastric phenotype of Atp4b-Cre+;Cdh1loxP/loxP;Trp53loxP/loxP double conditional knockout (DCKO) mice was examined.

Results Non-polarised E-cadherin-negative parietal cells and proton pump-negative atypical foci were observed in DCKO mice. Intramucosal cancers and invasive cancers composed of poorly differentiated carcinoma cells and signet ring cells, histologically very similar to those in humans, were found from 6 to 9 months, respectively. Fatal DGC developed at 100% penetrance within a year, frequently metastasised to lymph nodes, and had tumourigenic activity in immunodeficient mice. Gene expression profiles of DGC in DCKO mice also resembled those of human DGC, and mesenchymal markers and epithelial-mesenchymal transition-related genes were highly expressed in mouse DGC as in human DGC.

Conclusion This mouse line is the first genetically engineered mouse model of DGC and is very useful for clarifying the mechanism underlying gastric carcinogenesis, and provides a new approach to the treatment and prevention of DGC.

  • Cancer
  • carcinogenesis
  • differentiation
  • E-cadherin
  • epithelial cell growth
  • epithelial proliferation
  • gastric cancer
  • gastrointestinal cancer
  • gene expression
  • genetically engineered mouse
  • intestinal development
  • intestinal metaplasia
  • p53
  • stem cells

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Footnotes

  • Funding This work was supported by a grant-in-aid for scientific research on priority areas cancer 17015013 from the Ministry of Education, Culture, Sports, Science and Technology, Japan, by the JSPS A3 Foresight Program and by a research grant from the Princess Takamatsu Cancer Research Fund.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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