{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:05:33Z","timestamp":1792008333392,"version":"4.4.0"},"reference-count":100,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Spasmolytic Polypeptide-Expressing Metaplasia (SPEM) is a gastric fundic gland metaplasia resembling deep antral glands, associated with drug injury, <jats:italic>Helicobacter pylori<\/jats:italic> (<jats:italic>H. pylori<\/jats:italic>), or bile reflux. Early-stage SPEM acts as a reparative response, but if the damaging stimuli persist, the metaplastic changes may become irreversible, raising the risk of gastric cancer development. Traditionally, SPEM arises via passive transdifferentiation of chief cells following parietal cell loss. However, recent lineage tracing and genetic models challenge this, suggesting active depletion of chief cells and involvement of isthmus stem cells also contribute to SPEM development, intensifying debate over its cellular origins. This review synthesizes SPEM\u2019s physicochemical drivers and critically evaluates evidence for the three proposed sources: (1) passive chief cell transdifferentiation (2), active chief cell loss, and (3) isthmus stem cells. Clarifying the heterogeneity in the origin of SPEM is challenging until more specific cell ablation techniques are developed, but timely classification of existing research may be instructive.<\/jats:p>","DOI":"10.3389\/fonc.2025.1642559","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T04:12:29Z","timestamp":1761019949000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Cellular lineage origins of spasmolytic polypeptide-expressing metaplasia (SPEM): persistent and intensifying debates"],"prefix":"10.3389","volume":"15","author":[{"given":"Xiaofeng","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingbin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoxin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Rong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"B1","article-title":"A human model of gastric carcinogenesis","volume":"48","author":"Correa","year":"1988","journal-title":"Cancer Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s10120-009-0527-6","article-title":"Current understanding of SPEM and its standing in the preneoplastic process","volume":"12","author":"Weis","year":"2009","journal-title":"Gastric Cancer"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0255601","article-title":"Predictors for regression and progression of intestinal metaplasia (IM): A large population-based study from low prevalence area of gastric cancer (IM-predictor trial)","volume":"16","author":"Aumpan","year":"2021","journal-title":"PloS One"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/apt.14424","article-title":"Reversibility of atrophic gastritis and intestinal metaplasia after Helicobacter pylori eradication - a prospective study for up to 10 years","volume":"47","author":"Hwang","year":"2018","journal-title":"Alimentary Pharmacol Ther"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2478\/raon-2024-0028","article-title":"Pathogenesis and potential reversibility of intestinal metaplasia - a milestone in gastric carcinogenesis","volume":"58","author":"Drnovsek","year":"2024","journal-title":"Radiol Oncol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2028","DOI":"10.1053\/j.gastro.2010.09.005","article-title":"Mature chief cells are cryptic progenitors for metaplasia in the stomach","volume":"139","author":"Nam","year":"2010","journal-title":"Gastroenterology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1053\/j.gastro.2019.09.037","article-title":"Proliferation and differentiation of gastric mucous neck and chief cells during homeostasis and injury-induced metaplasia","volume":"158","author":"Burclaff","year":"2020","journal-title":"Gastroenterology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1053\/j.gastro.2017.11.278","article-title":"Metaplastic cells in the stomach arise, independently of stem cells, via dedifferentiation or transdifferentiation of chief cells","volume":"154","author":"Radyk","year":"2018","journal-title":"Gastroenterology"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00351.2017","article-title":"Mature gastric chief cells are not required for the development of metaplasia","volume":"314","author":"Kinoshita","year":"2018","journal-title":"Am J Physiol Gastrointestinal Liver Physiol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e6","DOI":"10.1053\/j.gastro.2017.05.050","article-title":"A summary of the 2016 james W. Freston conference of the american gastroenterological association: intestinal metaplasia in the esophagus and stomach: origins, differences, similarities and significance","volume":"153","author":"Spechler","year":"2017","journal-title":"Gastroenterology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of cancer: new dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.24","article-title":"Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style","volume":"17","author":"Merrell","year":"2016","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e12320","DOI":"10.1111\/hel.12320","article-title":"Serum Level of Trefoil Factor 2 can Predict the Extent of Gastric Spasmolytic Polypeptide-Expressing Metaplasia in the H. pylori-Infected Gastric Cancer Relatives","volume":"22","author":"Kuo","year":"2017","journal-title":"Helicobacter"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.11.058","article-title":"A molecular signature of gastric metaplasia arising in response to acute parietal cell loss","volume":"134","author":"Nozaki","year":"2008","journal-title":"Gastroenterology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/cas.12236","article-title":"Functional role of CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia","volume":"104","author":"Wada","year":"2013","journal-title":"Cancer Sci"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2019-318930","article-title":"Single-cell transcriptional analyses of spasmolytic polypeptide-expressing metaplasia arising from acute drug injury and chronic inflammation in the stomach","volume":"69","author":"Bockerstett","year":"2020","journal-title":"Gut"},{"key":"B17","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.jcmgh.2021.08.017","article-title":"Up-regulation of aquaporin 5 defines spasmolytic polypeptide-expressing metaplasia and progression to incomplete intestinal metaplasia","volume":"13","author":"Lee","year":"2022","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2015.3090","article-title":"TFF2, a MUC6-binding lectin stabilizing the gastric mucus barrier and more (Review)","volume":"47","author":"Hoffmann","year":"2015","journal-title":"Int J Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-022-03387-4","article-title":"Human epididymis protein 4 (HE4) is a novel immunohistochemical marker of neuroendocrine differentiation","volume":"481","author":"Su","year":"2022","journal-title":"Virchows Archiv"},{"key":"B20","article-title":"Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma","volume":"79","author":"Schmidt","year":"1999","journal-title":"Lab Investigation; J Tech Methods Pathol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1023\/A:1017920220149","article-title":"Identification of spasmolytic polypeptide expressing metaplasia (SPEM) in remnant gastric cancer and surveillance postgastrectomy biopsies","volume":"47","author":"Yamaguchi","year":"2002","journal-title":"Digestive Dis Sci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.100328","article-title":"The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia, dysplasia, and carcinoma","volume":"177","author":"Lennerz","year":"2010","journal-title":"Am J Pathol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1023\/A:1022564027468","article-title":"Spasmolytic polypeptide-expressing metaplasia (SPEM) associated with gastric cancer in Iceland","volume":"48","author":"Halld\u00f3rsd\u00f3ttir","year":"2003","journal-title":"Digestive Dis Sci"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2013-305964","article-title":"Cell lineage distribution atlas of the human stomach reveals heterogeneous gland populations in the gastric antrum","volume":"63","author":"Choi","year":"2014","journal-title":"Gut"},{"key":"B25","doi-asserted-by":"publisher","first-page":"G999","DOI":"10.1152\/ajpgi.00187.2006","article-title":"Differentiation of the Gastric Mucosa III. Animal models of oxyntic atrophy and metaplasia","volume":"291","author":"Goldenring","year":"2006","journal-title":"Am J Physiology-Gastrointestinal Liver Physiol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700682","article-title":"Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori","volume":"87","author":"Yoshizawa","year":"2007","journal-title":"Lab Investigation; J Tech Methods Pathol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-006-0350-x","article-title":"Localization of TFF3 peptide in human esophageal submucosal glands and gastric cardia: differentiation of two types of gastric pit cells along the rostro-caudal axis","volume":"328","author":"Kouznetsova","year":"2007","journal-title":"Cell Tissue Res"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12935-024-03598-6","article-title":"Intestinal metaplasia key molecules and UPP1 activation via Helicobacter pylori \/NF-kB: drivers of Malignant progression in gastric cancer","volume":"24","author":"Chen","year":"2024","journal-title":"Cancer Cell Int"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.12.037","article-title":"Amphiregulin-deficient mice develop spasmolytic polypeptide expressing metaplasia and intestinal metaplasia","volume":"136","author":"Nam","year":"2009","journal-title":"Gastroenterology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1053\/j.gastro.2014.02.007","article-title":"Macrophages promote progression of spasmolytic polypeptide-expressing metaplasia after acute loss of parietal cells","volume":"146","author":"Petersen","year":"2014","journal-title":"Gastroenterology"},{"key":"B31","first-page":"92","article-title":"Overview of current concepts in gastric intestinal metaplasia and gastric cancer","volume":"14","author":"Jencks","year":"2018","journal-title":"Gastroenterol Hepatology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2207","DOI":"10.1053\/j.gastro.2010.04.023","article-title":"Spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia: time for reevaluation of metaplasias and the origins of gastric cancer","volume":"138","author":"Goldenring","year":"2010","journal-title":"Gastroenterology"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1097\/mog.0000000000000472","article-title":"Guilt by association","volume":"34","author":"Graham","year":"2018","journal-title":"Curr Opin Gastroenterology"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2021.10.036","article-title":"Cellular plasticity, reprogramming, and regeneration: metaplasia in the stomach and beyond","volume":"162","author":"Goldenring","year":"2022","journal-title":"Gastroenterology"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2018-105752","article-title":"Evidence for heightened genetic instability in precancerous spasmolytic polypeptide expressing gastric glands","volume":"57","author":"Chen","year":"2020","journal-title":"J Med Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1113\/JP275512","article-title":"Injury, repair, inflammation and metaplasia in the stomach","volume":"596","author":"Meyer","year":"2018","journal-title":"J Physiol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.06.005","article-title":"Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression","volume":"41","author":"Wang","year":"2023","journal-title":"Cancer Cell"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-0520-5","article-title":"An LCM-based genomic analysis of SPEM, Gastric Cancer and Pyloric Gland Adenoma in an Asian cohort","volume":"33","author":"Srivastava","year":"2020","journal-title":"Modern Pathol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.05.029","article-title":"Spasmolytic polypeptide expressing metaplasia to preneoplasia in H","volume":"127","author":"Nomura","year":"2004","journal-title":"felis -infected mice. Gastroenterol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.12998\/wjcc.v11.i16.3714","article-title":"Helicobacter pylori plays a key role in gastric adenocarcinoma induced by spasmolytic polypeptide-expressing metaplasia","volume":"11","author":"Li","year":"2023","journal-title":"World J Clin cases"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1186\/1478-811x-9-28","article-title":"Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori","volume":"9","author":"Backert","year":"2011","journal-title":"Cell Communication Signaling"},{"key":"B42","doi-asserted-by":"publisher","first-page":"69","DOI":"10.3390\/toxins2010069","article-title":"The versatility of the helicobacter pylori vacuolating cytotoxin vacA in signal transduction and molecular crosstalk","volume":"2","author":"Backert","year":"2010","journal-title":"Toxins"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2017.00020","article-title":"Inflammation, DNA Damage, Helicobacter pylori and gastric tumorigenesis","volume":"8","author":"Kalisperati","year":"2017","journal-title":"Front Genet"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1126\/science.1099513","article-title":"Gastric cancer originating from bone marrow-derived cells","volume":"306","author":"Houghton","year":"2004","journal-title":"Science"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.10.036","article-title":"Helicobacter pylori infection recruits bone marrow\u2013derived cells that participate in gastric preneoplasia in mice","volume":"142","author":"Varon","year":"2012","journal-title":"Gastroenterology"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1128\/msystems.01098-23","article-title":"Remodeling of the gastric environment in Helicobacter pylori-induced atrophic gastritis","volume":"9","author":"Shuman","year":"2024","journal-title":"MSystems"},{"key":"B47","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1053\/j.gastro.2018.09.050","article-title":"Tropism for spasmolytic polypeptide-expressing metaplasia allows helicobacter pylori to expand its intragastric niche","volume":"156","author":"S\u00e1enz","year":"2019","journal-title":"Gastroenterology"},{"key":"B48","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1053\/j.gastro.2015.09.004","article-title":"Pathobiology of helicobacter pylori\u2013induced gastric cancer","volume":"150","author":"Amieva","year":"2016","journal-title":"Gastroenterology"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/nature01322","article-title":"Inflammation and cancer","volume":"420","author":"Coussens","year":"2002","journal-title":"Nature"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/nature08467","article-title":"The DNA-damage response in human biology and disease","volume":"461","author":"Jackson","year":"2009","journal-title":"Nature"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms25073888","article-title":"Helicobacter pylori Eradication Reverses DNA Damage Response Pathway but Not Senescence in Human Gastric Epithelium","volume":"25","author":"Kalisperati","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.10.005","article-title":"Cellular senescence: defining a path forward","volume":"179","author":"Gorgoulis","year":"2019","journal-title":"Cell"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1007\/s10120-015-0462-7","article-title":"Helicobacter pylori eradication cannot reduce the risk of gastric cancer in patients with intestinal metaplasia and dysplasia: evidence from a meta-analysis","volume":"19","author":"Chen","year":"2016","journal-title":"Gastric Cancer: Off J Int Gastric Cancer Assoc Japanese Gastric Cancer Assoc"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2000.01932.x","article-title":"Sustained increase in gastric antral epithelial cell proliferation despite cure of Helicobacter pylori infection","volume":"95","author":"El-Zimaity","year":"2000","journal-title":"Am J Gastroenterology"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/s0016-5085(00)70361-1","article-title":"Reversible drug\u2013induced oxyntic atrophy in rats","volume":"118","author":"Goldenring","year":"2000","journal-title":"Gastroenterology"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00160.2004","article-title":"Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild-type and gastrin-deficient mice","volume":"288","author":"Nomura","year":"2005","journal-title":"Am J Physiology-Gastrointestinal Liver Physiol"},{"key":"B57","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1053\/j.gastro.2011.09.050","article-title":"Tamoxifen induces rapid, reversible atrophy, and metaplasia in mouse stomach","volume":"142","author":"Huh","year":"2012","journal-title":"Gastroenterology"},{"key":"B58","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.jcmgh.2020.04.012","article-title":"Tamoxifen acts as a parietal cell protonophore","volume":"10","author":"Manning","year":"2020","journal-title":"Cell Mol Gastroenterol Hepatology"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-006-3151-x","article-title":"Omeprazole treatment ameliorates oxyntic atrophy induced by DMP-777","volume":"51","author":"Ogawa","year":"2006","journal-title":"Digestive Dis Sci"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.01.159","article-title":"Deoxycholic acid-stimulated macrophage-derived exosomes promote spasmolytic polypeptide-expressing metaplasia in the stomach","volume":"524","author":"Xu","year":"2020","journal-title":"Biochem Biophys Res Commun"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2022\/2642551","article-title":"Bile reflux gastritis: insights into pathogenesis, relevant factors, carcinomatous risk, diagnosis, and management","volume":"2022","author":"Shi","year":"2022","journal-title":"Gastroenterol Res Practice"},{"key":"B62","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41420-022-00962-1","article-title":"Roles and action mechanisms of bile acid-induced gastric intestinal metaplasia: a review","volume":"8","author":"He","year":"2022","journal-title":"Cell Death Discov"},{"key":"B63","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.gande.2024.12.003","article-title":"The complexity of mucosal damage in gastroesophageal airway reflux disease: A molecular perspective","volume":"3","author":"Chen","year":"2025","journal-title":"Gastroenterol Endoscopy"},{"key":"B64","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1186\/s13148-022-01406-4","article-title":"DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity","volume":"14","author":"Fritsche","year":"2022","journal-title":"Clin Epigenet"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v30.i32.3783","article-title":"Autoimmune gastritis studies and gastric cancer: True renaissance or bibliometric illusion","volume":"30","author":"Isakov","year":"2024","journal-title":"World J Gastroenterol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v21.i42.12179","article-title":"Autoimmune gastritis: Pathologist\u2019s viewpoint","volume":"21","author":"Coati","year":"2015","journal-title":"World J Gastroenterol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1080\/08830180590884567","article-title":"Mechanisms of gastric mucosal cell loss in autoimmune gastritis","volume":"24","author":"Marshall","year":"2005","journal-title":"Int Rev Immunol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.008","article-title":"Differentiated troy+ Chief cells act as reserve stem cells to generate all lineages of the stomach epithelium","volume":"155","author":"Daniel","year":"2013","journal-title":"Cell"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3541","article-title":"Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach","volume":"19","author":"Leushacke","year":"2017","journal-title":"Nat Cell Biol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1242\/dev.201494","article-title":"Gastric epithelial stem cells in development, homeostasis and regeneration","volume":"150","author":"Alvina","year":"2023","journal-title":"Development"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2019.07.002","article-title":"Defining Adult Stem Cell Function at Its Simplest: The Ability to Replace Lost Cells through Mitosis","volume":"25","author":"Post","year":"2019","journal-title":"Cell Stem Cell"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-325310","article-title":"Chief cell plasticity is the origin of metaplasia following acute injury in the stomach mucosa","volume":"71","author":"Caldwell","year":"2022","journal-title":"Gut"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2019-320368","article-title":"Dissecting transcriptional heterogeneity in primary gastric adenocarcinoma by single cell RNA sequencing","volume":"70","author":"Zhang","year":"2021","journal-title":"Gut"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/s0016-5085(00)70361-1","article-title":"Reversible drug-induced oxyntic atrophy in rats","volume":"118","author":"Goldenring","year":"2000","journal-title":"Gastroenterology"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(24)03561-3","article-title":"Slc26a9 governs gastric parietal cell identity and functions as an important protective role in the injuryinduced metaplasia","author":"Liu","year":"2024","journal-title":"Gastroenterology"},{"key":"B76","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/jcm11123523","article-title":"Endoscopic features of autoimmune gastritis: focus on typical images and early images","volume":"11","author":"Kishino","year":"2022","journal-title":"J Clin Med"},{"key":"B77","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.jcmgh.2016.11.001","article-title":"Murine models of gastric corpus preneoplasia","volume":"3","author":"Petersen","year":"2017","journal-title":"Cell Mol Gastroenterol Hepatology"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.03.027","article-title":"The epithelial-mesenchymal transition generates cells with properties of stem cells","volume":"133","author":"Mani","year":"2008","journal-title":"Cell"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgaa079","article-title":"Cooperative participation of epigenomic and genomic alterations in the clinicopathological diversity of gastric adenocarcinomas: significance of cell adhesion and epithelial\u2013mesenchymal transition-related signaling pathways","volume":"41","author":"Yang","year":"2020","journal-title":"Carcinogenesis"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-19-0015","article-title":"Cellular plasticity in cancer","volume":"9","author":"Yuan","year":"2019","journal-title":"Cancer Discovery"},{"key":"B81","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1053\/j.gastro.2016.12.001","article-title":"Targeted apoptosis of parietal cells is insufficient to induce metaplasia in stomach","volume":"152","author":"Burclaff","year":"2017","journal-title":"Gastroenterology"},{"key":"B82","doi-asserted-by":"publisher","first-page":"S","DOI":"10.1016\/s0016-5085(24)01164-8","article-title":"Chia deficiency in the chief cells promotes spasmolytic polypeptide-expressing metaplasia through pyroptosis mediated m2 macrophage polarization","volume":"166","author":"Liu","year":"2024","journal-title":"Gastroenterology"},{"key":"B83","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1053\/j.gastro.2011.01.043","article-title":"Loss of Runx3 is a key event in inducing precancerous state of the stomach","volume":"140","author":"Ito","year":"2011","journal-title":"Gastroenterology"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.3390\/cells12030408","article-title":"RUNX3 in stem cell and cancer biology","volume":"12","author":"Chuang","year":"2023","journal-title":"Cells"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1186\/1471-230x-11-92","article-title":"Association between RUNX3 promoter methylation and gastric cancer: a meta-analysis","volume":"11","author":"Fan","year":"2011","journal-title":"BMC Gastroenterol"},{"key":"B86","first-page":"299","volume-title":"Roles of RUNX in solid tumors","author":"Chuang","year":"2017"},{"key":"B87","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1016\/j.stem.2022.04.001","article-title":"p57Kip2 imposes the reserve stem cell state of gastric chief cells","volume":"29","author":"Lee","year":"2022","journal-title":"Cell Stem Cell"},{"key":"B88","first-page":"24","volume-title":"Recent advancement in stem cell therapies for cancer treatment","author":"Saleem","year":"2024"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-023-00802-z","article-title":"The composition and roles of gastric stem cells in epithelial homeostasis, regeneration, and tumorigenesis","volume":"46","author":"Liu","year":"2023","journal-title":"Cell Oncol (Dordrecht Netherlands)"},{"key":"B90","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1002\/ar.1092360204","article-title":"Dynamics of epithelial cells in the corpus of the mouse stomach. III. Inward migration of neck cells followed by progressive transformation into zymogenic cells","volume":"236","author":"Karam","year":"1993","journal-title":"Anatomical Rec"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.21-3-322","article-title":"Defining epithelial cell progenitors in the human oxyntic mucosa","volume":"21","author":"Karam","year":"2003","journal-title":"Stem Cells"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.10.025","article-title":"The gastric epithelial progenitor cell niche and differentiation of the zymogenic (chief) cell lineage","volume":"325","author":"Bredemeyer","year":"2009","journal-title":"Dev Biol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1096-9896(199902)187:3<331::aid-path241>3.0.co;2-s","article-title":"The mucous neck cell in the human gastric corpus: a distinctive, functional cell lineage","volume":"187","author":"Hanby","year":"1999","journal-title":"J Pathology"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02700","article-title":"The maturation of mucus-secreting gastric epithelial progenitors into digestive-enzyme secreting zymogenic cells requires","volume":"134","author":"Ramsey","year":"2007","journal-title":"Development"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.10.003","article-title":"Mist1 expressing gastric stem cells maintain the normal and neoplastic gastric epithelium and are supported by a perivascular stem cell niche","volume":"28","author":"Hayakawa","year":"2015","journal-title":"Cancer Cell"},{"key":"B96","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1053\/j.gastro.2015.11.049","article-title":"Expression of activated ras in gastric chief cells of mice leads to the full spectrum of metaplastic lineage transitions","volume":"150","author":"Choi","year":"2016","journal-title":"Gastroenterology"},{"key":"B97","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.stem.2013.01.003","article-title":"Apoptosis differently affects lineage tracing of Lgr5 and Bmi1 intestinal stem cell populations","volume":"12","author":"Zhu","year":"2013","journal-title":"Cell Stem Cell"},{"key":"B98","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.jcmgh.2017.02.009","article-title":"Isthmus stem cells are the origins of metaplasia in the gastric corpus","volume":"4","author":"Hayakawa","year":"2017","journal-title":"Cell Mol Gastroenterol Hepatology"},{"key":"B99","doi-asserted-by":"publisher","first-page":"1650","DOI":"10.1053\/j.gastro.2020.01.046","article-title":"GPR30-expressing gastric chief cells do not dedifferentiate but are eliminated via PDK-dependent cell competition during development of metaplasia","volume":"158","author":"Hata","year":"2020","journal-title":"Gastroenterology"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-024-00963-y","article-title":"Structural and functional evidence that GPR30 is not a direct estrogen receptor","volume":"34","author":"Liu","year":"2024","journal-title":"Cell Res"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1642559\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T04:12:30Z","timestamp":1761019950000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1642559\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,21]]},"references-count":100,"alternative-id":["10.3389\/fonc.2025.1642559"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2025.1642559","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,21]]},"article-number":"1642559"}}