title: Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer.
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/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Shimada
authors.forename: Ayako
authors.initials: A
authors.lastname: Mimata
authors.forename: Masaki
authors.initials: M
authors.lastname: Sekine
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukamachi
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Eishi
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Yuasa
mesh_terms: D000818:Animals; D015820:Cadherins / Q000172:deficiency / Q000502:physiology*; D016764:Cell Polarity / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D007108:Immune Tolerance; D008207:Lymphatic Metastasis; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010295:Parietal Cells, Gastric / Q000378:metabolism / Q000473:pathology; D017494:Proton Pumps / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology*
chemical_list: D015820:Cadherins; D004273:DNA, Neoplasm; D017494:Proton Pumps; D016159:Tumor Suppressor Protein p53