Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer

Shu Shimada, Ayako Mimata, Masaki Sekine, Kaoru Mogushi, Yoshimitsu Akiyama, Hiroshi Fukamachi, Jos Jonkers, Hiroshi Tanaka, Yoshinobu Eishi, Yasuhito Yuasa

Research output: Contribution to journalArticlepeer-review

75 Citations (Scopus)

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 Cdh1 loxP/loxP and Trp53 loxP/loxP mice, and the gastric phenotype of Atp4b-Cre +;Cdh1 loxP/loxP;Trp53 loxP/loxPdouble 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.

Original languageEnglish
Pages (from-to)344-353
Number of pages10
JournalGut
Volume61
Issue number3
DOIs
Publication statusPublished - 2012 Mar

ASJC Scopus subject areas

  • Gastroenterology

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