TY - JOUR
T1 - Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer
AU - Shimada, Shu
AU - Mimata, Ayako
AU - Sekine, Masaki
AU - Mogushi, Kaoru
AU - Akiyama, Yoshimitsu
AU - Fukamachi, Hiroshi
AU - Jonkers, Jos
AU - Tanaka, Hiroshi
AU - Eishi, Yoshinobu
AU - Yuasa, Yasuhito
PY - 2012/3
Y1 - 2012/3
N2 - 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=84857036920&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84857036920&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2011-300050
DO - 10.1136/gutjnl-2011-300050
M3 - Article
C2 - 21865403
AN - SCOPUS:84857036920
VL - 61
SP - 344
EP - 353
JO - Gut
JF - Gut
SN - 0017-5749
IS - 3
ER -