{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:45:55Z","timestamp":1761007555211,"version":"build-2065373602"},"reference-count":32,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,10,1]],"date-time":"2015-10-01T00:00:00Z","timestamp":1443657600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001655","name":"German Academic Exchange Service","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001655","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":[[2016,1]]},"abstract":"Abstract<\/jats:title>In intestinal and pyloric epithelia, leucine\u2010rich repeat\u2010containing G protein\u2010coupled receptor 5 (Lgr5<\/jats:italic>)\u2010expressing cells represent long\u2010lived adult stem cells that give rise to all epithelial cell types, including endocrine cells. Ablation of the Apc<\/jats:italic> gene in Lgr5<\/jats:italic>\u2010expressing cells leads to intestinal and pyloric adenomas. To assess whether all epithelial tumours of the gastrointestinal tract are derived from LGR5<\/jats:styled-content>\u2010positive stem cells, we crossed Lgr5\u2013EGFP\u2013IRES\u2013creERT2<\/jats:sup><\/jats:styled-content> mice, which express EGFP<\/jats:styled-content> and Cre recombinase driven by the Lgr5<\/jats:italic> promoter, with CEA424\u2013SV40\u2013TAg<\/jats:styled-content> mice, which develop pyloric neuroendocrine carcinomas of epithelial origin. In 19 day\u2010old mice, single SV40<\/jats:styled-content> T antigen (TAg<\/jats:styled-content>)\u2010positive cells were identified preferentially at the the bases of pyloric glands, close to the stem cell compartment. However, contrary to previous publications describing subpopulations of LGR5<\/jats:styled-content>\u2010positive cells in gastrointestinal neoplasia, we could not detect Lgr5\u2013<\/jats:italic>EGFP<\/jats:styled-content>\u2010positive tumour cells in malignant lesions. The lack of expression of the Wnt target gene Lgr5<\/jats:italic> is probably not caused by suppression of Wnt signalling by TAg<\/jats:styled-content>, since \u03b2\u2010catenin\u2010mediated Wnt signalling, as measured by the TOPflash<\/jats:styled-content> assay, was not inhibited. To determine the cellular origin of CEA424\u2013SV40\u2013TAg<\/jats:styled-content> tumours, we performed tracing experiments using Lgr5\u2013EGFP\u2013IRES\u2013creERT2<\/jats:styled-content>:CEA424\u2013SV40\u2013TAg<\/jats:styled-content>:ROSA26\u2013tdRFP<\/jats:styled-content> mice. Following tamoxifen induction, it was possible to efficiently trace the progeny of Lgr5<\/jats:italic>\u2010expressing cells in gastrointestinal tissue via red fluorescent protein (RFP<\/jats:styled-content>) expression. No RFP<\/jats:styled-content>\u2010positive tumour cells were detected, even when RFP<\/jats:styled-content><\/jats:italic> gene activation occurred in 7 day\u2010old mice well before the appearance of TAg<\/jats:styled-content>\u2010positive tumour cells. Hence, we conclude that Lgr5<\/jats:italic>\u2010expressing stem cells probably do not constitute the cells of origin in CEA424\u2013SV40\u2013TAg<\/jats:styled-content> mice. Consequently, not all epithelial tumours in the pyloric region are initiated by transformation of LGR5<\/jats:styled-content>\u2010positive stem cells. Thus, additional long\u2010lived LGR5<\/jats:styled-content>\u2010negative stem cells or progenitor cells with a low turnover rate might exist in the pyloric region, which could give rise to tumours. Copyright \u00a9 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4629","type":"journal-article","created":{"date-parts":[[2015,9,3]],"date-time":"2015-09-03T06:49:29Z","timestamp":1441262969000},"page":"42-51","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Lgr5\u2010expressing stem cells are not the cells of origin of pyloric neuroendocrine carcinomas in mice"],"prefix":"10.1002","volume":"238","author":[{"given":"Elena","family":"Vetter","sequence":"first","affiliation":[{"name":"Tumour Immunology Laboratory, LIFE Centre University Hospital, Ludwig\u2010Maximilians University Munich Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mira","family":"Kronast","sequence":"additional","affiliation":[{"name":"Tumour Immunology Laboratory, LIFE Centre University Hospital, Ludwig\u2010Maximilians University Munich Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"T\u00f6lge","sequence":"additional","affiliation":[{"name":"Tumour Immunology Laboratory, LIFE Centre University Hospital, Ludwig\u2010Maximilians University Munich Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Tumour Immunology Laboratory, LIFE Centre University Hospital, Ludwig\u2010Maximilians University Munich Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,10]]},"reference":[{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1204040"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09781"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2657"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3038"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2014.02.005"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13023"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06196"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2009.11.013"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07602"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1224676"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0215(20000615)86:6<863::AID-IJC16>3.0.CO;2-4"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-14-0166"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307983101"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029846"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636745"},{"key":"e_1_2_7_18_1","first-page":"4169","article-title":"Mice transgenic for the human carcinoembryonic antigen gene maintain its spatiotemporal expression pattern","volume":"54","author":"Eades\u2010Perner AM","year":"1994","journal-title":"Cancer Res"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.03.002"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-010-1006-3"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-6-57"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3143"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10337"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.275.5307.1787"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/embr.201337799"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.008"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.08.003"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.08.002"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2011.09.001"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2014.09.003"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00415.2001"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1092360206"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(03)00240-9"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.6.4.1204"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.4629","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.4629","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.4629","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T14:20:46Z","timestamp":1760970046000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.4629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10]]},"references-count":32,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2016,1]]}},"alternative-id":["10.1002\/path.4629"],"URL":"https:\/\/doi.org\/10.1002\/path.4629","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"type":"print","value":"0022-3417"},{"type":"electronic","value":"1096-9896"}],"subject":[],"published":{"date-parts":[[2015,10]]},"assertion":[{"value":"2015-06-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-08-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-10-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}