Skip global navigation and read the article

Skip global navigation and go to local navigation

Skip global navigation and go to footer navigation



Home  > Press Release  > “The first genetically engineered mouse model of diffuse-type gastric cancer”

“The first genetically engineered mouse model of diffuse-type gastric cancer”

Yasuhito Yuasa
Professor, Department of Molecular Oncology
Graduate School of Medical and Dental Sciences (right)

Shu Shimada
Assistant Professor,
Department of Molecular Oncology
Graduate School of Medical and Dental Sciences (left)


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 DGCs, and genetic and/or epigenetic alterations of CDH1 are frequently detected in sporadic DGCs. Genetic alterations of TP53 are also frequently found in DGCs. To examine the synergistic effect of loss of E-cadherin and p53 on gastric carcinogenesis, we established a mouse line in which E-cadherin and p53 are specifically inactivated in the stomach parietal cell lineage.

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 and 9 months, respectively. Fatal DGCs developed at 100% penetrance within a year, and frequently metastasised to lymph nodes. Gene expression profiles of DGCs in the double conditional knockout (DCKO) mice also resembled those of human DGCs.

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

Figure 1.
We crossed Atp4b-Cre mice with Cdh1-loxP and Trp53-loxP mice, and established Atp4b-Cre+;Cdh1loxP/loxP;Trp53loxP/loxP DCKO mice. E-cadherin and p53 are specifically inactivated in the gastric parietal cell lineage in DCKO mice, and these cells can undergo malignant transformation.

Figure 2.
Infiltrating gastric cancer cells are distributed from the mucosal layers to the muscularis propria (left), as well as lymph node metastases are frequently observed in DCKO mice (right).

Publication information

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
Gut, in press.
Gut doi:10.1136/gutjnl-2011-300050.

Contact

Yasuhito Yuasa, M.D., Ph.D.
Department of Molecular Oncology,
Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University,
1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan
E-mail; yuasa.monc@tmd.ac.jp
URL: http://www.tmd.ac.jp/grad/monc/english/index.html