{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T02:37:57Z","timestamp":1783996677176,"version":"3.55.0"},"reference-count":45,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,11,27]],"date-time":"2018-11-27T00:00:00Z","timestamp":1543276800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007664","name":"Manpei Suzuki Diabetes Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic inflammation and intestinal metaplasia are strongly associated with gastric carcinogenesis. <jats:italic>Kras<\/jats:italic> activation and <jats:italic>Pten<\/jats:italic> deletion are observed in intestinal\u2010type gastric cancer, and <jats:italic>Cdh1<\/jats:italic> mutation is associated with diffuse\u2010type gastric cancer. Although various mouse models of gastric carcinogenesis have been reported, few mouse lines enable gene manipulation selectively in the stomach. Here we established a <jats:italic>Tff1<\/jats:italic>\u2010Cre bacterial artificial chromosome transgenic mouse line in an attempt to induce gene modification specifically in the gastric pit lineage. In the stomach, <jats:italic>Tff1\u2010<\/jats:italic>Cre\u2010mediated recombination was most evident in the pit lineage in the corpus and in entire antral glands; recombination was also observed in a few gastric chief and parietal cells. Outside the stomach, recombination was patchy throughout the intestines, and particularly frequently in the duodenum (Brunner glands), cecum, and proximal colon. In the stomachs of <jats:italic>Tff1<\/jats:italic>\u2010Cre;<jats:italic>LSL<\/jats:italic>\u2010<jats:italic>Kras<\/jats:italic><jats:sup><jats:italic>G12D<\/jats:italic><\/jats:sup> mice, proliferating cell clusters expanded throughout the corpus glands, with foveolar cell expansion with ectopic Alcian blue\u2010positive mucins, oxyntic atrophy, and pseudopyloric changes with spasmolytic polypeptide\u2010expressing metaplasia; however, gastric cancer was not observed even at 12 months of age. Corpus\u2010derived organoids from <jats:italic>Tff1<\/jats:italic>\u2010Cre;<jats:italic>LSL<\/jats:italic>\u2010<jats:italic>Kras<\/jats:italic><jats:sup><jats:italic>G12D<\/jats:italic><\/jats:sup> mice exhibited accelerated growth and abnormal differentiation with a loss of chief and parietal cell markers. <jats:italic>Tff1<\/jats:italic>\u2010Cre;<jats:italic>Pten<\/jats:italic><jats:sup><jats:italic>flox\/flox<\/jats:italic><\/jats:sup> mice displayed similar changes to those seen in <jats:italic>Tff1<\/jats:italic>\u2010Cre;<jats:italic>LSL<\/jats:italic>\u2010<jats:italic>Kras<\/jats:italic><jats:sup><jats:italic>G12D<\/jats:italic><\/jats:sup> mice, both with aberrant ERK activation within 3 months. In contrast, <jats:italic>Tff1\u2010<\/jats:italic>Cre;<jats:italic>Cdh1<\/jats:italic><jats:sup><jats:italic>flox\/flox<\/jats:italic><\/jats:sup> mice initially showed signet ring\u2010like cells that were rapidly lost with disruption of the mucosal surface, and later developed gastric epithelial shedding with hyperproliferation and loss of normal gastric lineages. Eventually, the glandular epithelium in <jats:italic>Tff1\u2010<\/jats:italic>Cre;<jats:italic>Cdh1<\/jats:italic><jats:sup><jats:italic>flox\/flox<\/jats:italic><\/jats:sup> mice was completely replaced by squamous epithelium which expanded from the forestomach. <jats:italic>Tff1\u2010<\/jats:italic>Cre mice offer an additional useful tool for studying gastric carcinogenesis both <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. Copyright \u00a9 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5163","type":"journal-article","created":{"date-parts":[[2018,8,31]],"date-time":"2018-08-31T03:41:21Z","timestamp":1535686881000},"page":"35-47","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Three types of metaplasia model through <i>Kras<\/i> activation, <i>Pten<\/i> deletion, or <i>Cdh1<\/i> deletion in the gastric epithelium"],"prefix":"10.1002","volume":"247","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8179-6017","authenticated-orcid":false,"given":"Hiroto","family":"Kinoshita","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Graduate School of Medicine The University of Tokyo  Tokyo 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