Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41598-018-20572-1
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Funding
- National Cancer Center Research and Development Fund [29-E-2]
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Ministry of Health, Labour and Welfare (R.O.), Development of Innovative Research on Cancer Therapeutics (P-DIRECT)/Ministry of Education, Culture, Sports, Science and Technology of Japan
- Takeda Science Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Daiichi-Sankyo Foundation of Life Science
- Foundation for Promotion of Cancer Research in Japan
- Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University, Japan
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p53 mutations are frequently detected in malignant gastric cancers. However, the molecular mechanisms by which loss of p53 function promotes gastric cancer are not clear. We utilized Gan mice (K19-Wnt1/C2mE), which have functional p53 and develop intestinal-type gastric tumors, to investigate the role of p53 in gastric cancer progression by knocking out p53. We found that gastric epithelial cells acquire tumorigenicity in the subcutis of C57BL/6 mice as a result of Wnt activation, COX-2 activation and p53 deficiency. With repeated allograft transfers, these gastric epithelial cells gradually acquired the properties of malignant gastric cancer. Loss of p53 conferred cell stemness and induced epithelial to mesenchymal transition (EMT) in gastric epithelial cells, and these properties were further enhanced by the in vivo microenvironment, ultimately leading to gastric cancer formation and metastasis. We also found that the in vivo microenvironment enhanced activation of the COX-2 pathway, which further contributed to cancer progression. With this system, we have succeeded in recapitulating the development of malignant gastric cancer from gastric epithelial cells in a normal immune environment.
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