RT Journal Article
SR Electronic
T1 Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 344
OP 353
DO 10.1136/gutjnl-2011-300050
VO 61
IS 3
A1 Shimada, Shu
A1 Mimata, Ayako
A1 Sekine, Masaki
A1 Mogushi, Kaoru
A1 Akiyama, Yoshimitsu
A1 Fukamachi, Hiroshi
A1 Jonkers, Jos
A1 Tanaka, Hiroshi
A1 Eishi, Yoshinobu
A1 Yuasa, Yasuhito
YR 2012
UL http://gut.bmj.com/content/61/3/344.abstract
AB 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.