{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T03:00:38Z","timestamp":1760151638599,"version":"build-2065373602"},"reference-count":119,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,26]],"date-time":"2022-03-26T00:00:00Z","timestamp":1648252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009729","name":"Ludwig Cancer Research","doi-asserted-by":"publisher","award":["not applicable"],"award-info":[{"award-number":["not applicable"]}],"id":[{"id":"10.13039\/100009729","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The adult gastric mucosa is characterised by deep invaginations of the epithelium called glands. These tissue architectural elements are maintained with the contribution of morphogen signals. Morphogens are expressed in specific areas of the tissue, and their diffusion generates gradients in the microenvironment. Cells at different positions in the gland sense a specific combination of signals that instruct them to differentiate, proliferate, regenerate, or migrate. Differentiated cells perform specific functions involved in digestion, such as the production of protective mucus and the secretion of digestive enzymes or gastric acid. Biopsies from gastric precancerous conditions usually display tissue aberrations and change the shape of the glands. Alteration of the morphogen signalling microenvironment is likely to underlie those conditions. Furthermore, genes involved in morphogen signalling pathways are found to be frequently mutated in gastric cancer. We summarise the most recent findings regarding alterations of morphogen signalling during gastric carcinogenesis, and we highlight the new stem cell technologies that are improving our understanding of the regulation of human tissue shape.<\/jats:p>","DOI":"10.3390\/ijms23073632","type":"journal-article","created":{"date-parts":[[2022,3,27]],"date-time":"2022-03-27T21:27:51Z","timestamp":1648416471000},"page":"3632","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Morphogen Signals Shaping the Gastric Glands in Health and Disease"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5280-8261","authenticated-orcid":false,"given":"Claudia","family":"Zagami","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2732-7543","authenticated-orcid":false,"given":"Diana","family":"Papp","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice Anna","family":"Daddi","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Boccellato","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s00441-018-2957-0","article-title":"Relationships of endocrine cells to each other and to other cell types in the human gastric fundus and corpus","volume":"376","author":"Fakhry","year":"2019","journal-title":"Cell Tissue Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"D286","DOI":"10.2741\/Karam","article-title":"Lineage commitment and maturation of epithelial cells in the gut","volume":"4","author":"Karam","year":"1999","journal-title":"Front. Biosci. A J. Virtual Libr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1002\/ar.1092360205","article-title":"Dynamics of epithelial cells in the corpus of the mouse stomach. IV. Bidirectional migration of parietal cells ending in their gradual degeneration and loss","volume":"236","author":"Karam","year":"1993","journal-title":"Anat. Rec."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1711","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":"ref_5","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.semcdb.2017.02.004","article-title":"Mechanisms of embryonic stomach development","volume":"66","author":"McCracken","year":"2017","journal-title":"Semin Cell Dev. Biol"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1242\/dev.124891","article-title":"Stomach development, stem cells and disease","volume":"143","author":"Kim","year":"2016","journal-title":"Development"},{"key":"ref_7","first-page":"1","article-title":"Regulation of Gastrointestinal Mucosal Growth","volume":"3","author":"Rao","year":"2010","journal-title":"Morgan Claypool Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"571536","DOI":"10.3389\/fcell.2020.571536","article-title":"Gastric Stem Cells: Physiological and Pathological Perspectives","volume":"8","author":"Xiao","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.stem.2009.11.013","article-title":"Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro","volume":"6","author":"Barker","year":"2010","journal-title":"Cell Stem Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"357","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":"Stange","year":"2013","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/nature23642","article-title":"Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis","volume":"548","author":"Sigal","year":"2017","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/s41586-020-1973-x","article-title":"AQP5 enriches for stem cells and cancer origins in the distal stomach","volume":"578","author":"Tan","year":"2020","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"800","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":"ref_14","doi-asserted-by":"crossref","first-page":"211","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":"ref_15","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1136\/gutjnl-2017-313874","article-title":"Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach","volume":"67","author":"Choi","year":"2018","journal-title":"Gut"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1053\/j.gastro.2008.06.049","article-title":"Murine embryonic stem cell-derived pancreatic acinar cells recapitulate features of early pancreatic differentiation","volume":"135","author":"Rovira","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/ncb2464","article-title":"Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling","volume":"14","author":"Wong","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.stem.2011.09.001","article-title":"Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice","volume":"9","author":"Arnold","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/path.5244","article-title":"Bmi1 marks gastric stem cells located in the isthmus in mice","volume":"248","author":"Yoshioka","year":"2019","journal-title":"J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15255","DOI":"10.1038\/s41598-018-33578-6","article-title":"Lrig1 marks a population of gastric epithelial cells capable of long-term tissue maintenance and growth in vitro","volume":"8","author":"Schweiger","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.stem.2019.07.008","article-title":"Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells","volume":"25","author":"Han","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1053\/j.gastro.2014.09.042","article-title":"In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection","volume":"148","author":"Bartfeld","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1136\/gutjnl-2017-314540","article-title":"Polarised epithelial monolayers of the gastric mucosa reveal insights into mucosal homeostasis and defence against infection","volume":"68","author":"Boccellato","year":"2019","journal-title":"Gut"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1136\/gutjnl-2014-307949","article-title":"A novel human gastric primary cell culture system for modelling Helicobacter pylori infection in vitro","volume":"65","author":"Schlaermann","year":"2014","journal-title":"Gut"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1136\/gutjnl-2020-320742","article-title":"Mist1+ gastric isthmus stem cells are regulated by Wnt5a and expand in response to injury and inflammation in mice","volume":"70","author":"Kim","year":"2021","journal-title":"Gut"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1053\/j.gastro.2015.02.049","article-title":"Helicobacter pylori Activates and Expands Lgr5(+) Stem Cells Through Direct Colonization of the Gastric Glands","volume":"148","author":"Sigal","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.cell.2018.07.027","article-title":"Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis","volume":"174","author":"Nanki","year":"2018","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1136\/gutjnl-2017-314549","article-title":"Human gastric cancer modelling using organoids","volume":"68","author":"Seidlitz","year":"2019","journal-title":"Gut"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.1053\/j.gastro.2010.08.052","article-title":"Bone Morphogenetic Protein Signaling Regulates Gastric Epithelial Cell Development and Proliferation in Mice","volume":"139","author":"Shinohara","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1053\/j.gastro.2021.04.062","article-title":"EGF and BMPs Govern Differentiation and Patterning in Human Gastric Glands","volume":"161","author":"Daddi","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"32759","DOI":"10.1038\/srep32759","article-title":"Loss of mesenchymal bone morphogenetic protein signaling leads to development of reactive stroma and initiation of the gastric neoplastic cascade","volume":"6","author":"Roy","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1093\/carcin\/bgs233","article-title":"Helicobacter pylori and the BMP pathway regulate CDX2 and SOX2 expression in gastric cells","volume":"33","author":"Camilo","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/path.2369","article-title":"Key elements of the BMP\/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines","volume":"215","author":"Barros","year":"2008","journal-title":"J. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.15252\/embj.201490583","article-title":"Notch signaling regulates gastric antral LGR5 stem cell function","volume":"34","author":"Demitrack","year":"2015","journal-title":"EMBO J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1084\/jem.20101737","article-title":"Notch signaling in stomach epithelial stem cell homeostasis","volume":"208","author":"Kim","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1136\/gutjnl-2015-310811","article-title":"Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis","volume":"66","author":"Gifford","year":"2017","journal-title":"Gut"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e20200219","DOI":"10.1084\/jem.20200219","article-title":"Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy","volume":"218","author":"Loe","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.jcmgh.2018.09.007","article-title":"Active Kras Expression in Gastric Isthmal Progenitor Cells Induces Foveolar Hyperplasia but Not Metaplasia","volume":"7","author":"Choi","year":"2019","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e98311","DOI":"10.15252\/embj.201798311","article-title":"Regenerative proliferation of differentiated cells by mTORC 1-dependent paligenosis","volume":"37","author":"Willet","year":"2018","journal-title":"EMBO J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.devcel.2020.10.001","article-title":"MTORC1 and the Rebirth of Stemness","volume":"55","author":"Johnson","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"G133","DOI":"10.1152\/ajpgi.00325.2016","article-title":"NOTCH1 and NOTCH2 regulate epithelial cell proliferation in mouse and human gastric corpus","volume":"312","author":"Demitrack","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1172\/JCI30491","article-title":"Menetrier disease and gastrointestinal stromal tumors: Hyperproliferative disorders of the stomach","volume":"117","author":"Coffey","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","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":"ref_44","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1053\/j.gastro.2019.09.026","article-title":"Mouse Models of Human Gastric Cancer Subtypes With Stomach-Specific CreERT2-Mediated Pathway Alterations","volume":"157","author":"Seidlitz","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.coph.2016.09.003","article-title":"Hedgehog signaling in the stomach","volume":"31","author":"Konstantinou","year":"2016","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/labinvest.2012.148","article-title":"Sonic Hedgehog contributes to gastric mucosal restitution after injury","volume":"93","author":"Xiao","year":"2013","journal-title":"Lab. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1126\/science.2006419","article-title":"Cadherin cell adhesion receptors as a morphogenetic regulator","volume":"251","author":"Takeichi","year":"1991","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.jmb.2004.01.026","article-title":"Identification of new human cadherin genes using a combination of protein motif search and gene finding methods","volume":"337","author":"Hoeng","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1101\/gad.267103","article-title":"Canonical Wnt signals are essential for homeostasis of the intestinal epithelium","volume":"17","author":"Pinto","year":"2003","journal-title":"Genes Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1101\/gad.235473.113","article-title":"The R-spondin\/Lgr5\/Rnf43 module: Regulator of Wnt signal strength","volume":"28","author":"Peng","year":"2014","journal-title":"Genes Dev."},{"doi-asserted-by":"crossref","unstructured":"Fischer, A.-S., and Sigal, M. (2019). The Role of Wnt and R-spondin in the Stomach During Health and Disease. Biomedicines, 7.","key":"ref_51","DOI":"10.3390\/biomedicines7020044"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"a015081","DOI":"10.1101\/cshperspect.a015081","article-title":"Secreted and transmembrane wnt inhibitors and activators","volume":"5","author":"Cruciat","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1146\/annurev.bi.62.070193.002321","article-title":"Signalling by receptor tyrosine kinases","volume":"62","author":"Fantl","year":"1993","journal-title":"Annu. Rev. Biochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1007\/BF02213134","article-title":"Overexpression of transforming growth factor-alpha alters differentiation of gastric cell lineages","volume":"41","author":"Goldenring","year":"1996","journal-title":"Dig. Dis. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1016\/S0016-5085(97)70130-6","article-title":"Epidermal growth factor influences cell proliferation, glycoproteins, and lipase activity in human fetal stomach","volume":"112","author":"Tremblay","year":"1997","journal-title":"Gastroenterology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1002\/jez.1402580309","article-title":"Expression of epidermal growth factor (EGF) and the EGF receptor in human tissues","volume":"258","author":"Fukuyama","year":"1991","journal-title":"J. Exp. Zool."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1053\/j.gastro.2005.03.019","article-title":"Evidence for repatterning of the gastric fundic epithelium associated with Menetrier\u2019s disease and TGFalpha overexpression","volume":"128","author":"Nomura","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"109069","DOI":"10.1016\/j.celrep.2021.109069","article-title":"mTOR signaling regulates gastric epithelial progenitor homeostasis and gastric tumorigenesis via MEK1-ERKs and BMP-Smad1 pathways","volume":"35","author":"Li","year":"2021","journal-title":"Cell Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/nrgastro.2018.5","article-title":"Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer","volume":"15","author":"Mills","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1080\/15548627.2020.1857080","article-title":"Autophagy repurposes cells during paligenosis","volume":"17","author":"Miao","year":"2021","journal-title":"Autophagy"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1146\/annurev-physiol-061121-035954","article-title":"Paligenosis: Cellular Remodeling During Tissue Repair","volume":"84","author":"Brown","year":"2022","journal-title":"Annu Rev. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1038\/ng1430","article-title":"BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt\u2013\u03b2-catenin signaling","volume":"36","author":"He","year":"2004","journal-title":"Nature Genet."},{"key":"ref_63","first-page":"323","article-title":"Notch as a Driver of Gastric Epithelial Cell Proliferation","volume":"Volume 3","author":"Demitrack","year":"2017","journal-title":"CMGH"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1053\/j.gastro.2009.11.002","article-title":"Loss of parietal cell expression of Sonic hedgehog induces hypergastrinemia and hyperproliferation of surface mucous cells","volume":"138","author":"Xiao","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1053\/j.gastro.2010.08.047","article-title":"Intracellular calcium release and protein kinase C activation stimulate sonic hedgehog gene expression during gastric acid secretion","volume":"139","author":"Zavros","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1113\/jphysiol.2011.220681","article-title":"Hedgehog signalling in gut development, physiology and cancer","volume":"590","author":"Merchant","year":"2012","journal-title":"J. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1053\/j.gastro.2014.05.006","article-title":"Indian Hedgehog mediates gastrin-induced proliferation in stomach of adult mice","volume":"147","author":"Feng","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"101737","DOI":"10.1016\/j.bpg.2021.101737","article-title":"Molecular modelling of the gastric barrier response, from infection to carcinogenesis","volume":"50\u201351","author":"Traulsen","year":"2021","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1751-2980.2011.00550.x","article-title":"The gastric precancerous cascade","volume":"13","author":"Correa","year":"2012","journal-title":"J. Dig. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1136\/jcp.55.5.352","article-title":"Foveolar hyperplasia at the gastric cardia: Prevalence and associations","volume":"55","author":"Voutilainen","year":"2002","journal-title":"J. Clin. Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1097\/00000478-199610000-00001","article-title":"Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994","volume":"20","author":"Dixon","year":"1996","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.humpath.2004.12.008","article-title":"Staging and grading of chronic gastritis","volume":"36","author":"Rugge","year":"2005","journal-title":"Hum. Pathol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1046\/j.1365-2559.2001.01221.x","article-title":"Morphometric assessment of gastric antral atrophy: Comparison with visual evaluation","volume":"39","author":"Ruiz","year":"2001","journal-title":"Histopathology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/BF01600253","article-title":"Helicobacter colonization and histopathological profile of chronic gastritis in patients with or without dyspepsia, mucosal erosion and peptic ulcer: A morphological approach to the study of ulcerogenesis in man","volume":"420","author":"Fiocca","year":"1992","journal-title":"Virchows Arch. A"},{"key":"ref_75","first-page":"gmr.15027358","article-title":"Role of the IL-11\/STAT3 signaling pathway in human chronic atrophic gastritis and gastric cancer","volume":"15","author":"Wang","year":"2016","journal-title":"Genet. Mol. Res."},{"key":"ref_76","first-page":"273","article-title":"STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer (Review)","volume":"19","author":"Katoh","year":"2007","journal-title":"Int. J. Mol. Med."},{"doi-asserted-by":"crossref","unstructured":"Wang, Z., Si, X., Xu, A., Meng, X., Gao, S., Qi, Y., Zhu, L., Li, T., Li, W., and Dong, L. (2013). Activation of STAT3 in human gastric cancer cells via interleukin (IL)-6-type cytokine signaling correlates with clinical implications. PLoS ONE, 8.","key":"ref_77","DOI":"10.1371\/journal.pone.0075788"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1136\/gut.2005.077917","article-title":"Gastric mucosal hyperplasia via upregulation of gastrin induced by persistent activation of gastric innate immunity in major histocompatibility complex class II deficient mice","volume":"55","author":"Fukui","year":"2006","journal-title":"Gut"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.bbrc.2008.09.031","article-title":"Induction of follistatin precedes gastric transformation in gastrin deficient mice","volume":"376","author":"Kang","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"657","DOI":"10.3109\/00365521.2015.1019918","article-title":"Chronic gastritis","volume":"50","author":"Sipponen","year":"2015","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.bbadis.2012.05.002","article-title":"A new mouse model for studying EGFR-dependent gastric polyps","volume":"1822","author":"Dahlhoff","year":"2012","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"dmm035071","DOI":"10.1242\/dmm.035071","article-title":"Plasticity of differentiated cells in wound repair and tumorigenesis, part I: Stomach and pancreas","volume":"11","author":"Burclaff","year":"2018","journal-title":"Dis. Models Mech."},{"key":"ref_83","doi-asserted-by":"crossref","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":"ref_84","first-page":"639","article-title":"Identification of a metaplastic cell lineage associated with human gastric adenocarcinoma","volume":"79","author":"Schmidt","year":"1999","journal-title":"Lab. Investig."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1053\/j.gastro.2020.08.027","article-title":"Single-Cell Transcriptional Analyses Identify Lineage-Specific Epithelial Responses to Inflammation and Metaplastic Development in the Gastric Corpus","volume":"159","author":"Bockerstett","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_86","doi-asserted-by":"crossref","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":"ref_87","doi-asserted-by":"crossref","first-page":"16085","DOI":"10.1074\/jbc.M112.445551","article-title":"The hyaluronic acid receptor CD44 coordinates normal and metaplastic gastric epithelial progenitor cell proliferation","volume":"288","author":"Khurana","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1136\/gutjnl-2011-300539","article-title":"IL-11 is a parietal cell cytokine that induces atrophic gastritis","volume":"61","author":"Howlett","year":"2012","journal-title":"Gut"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1053\/j.gastro.2008.12.003","article-title":"The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development","volume":"136","author":"Howlett","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1053\/j.gastro.2005.06.068","article-title":"Differential regulation of gastric tumor growth by cytokines that signal exclusively through the coreceptor gp130","volume":"129","author":"Howlett","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.molmed.2012.07.006","article-title":"Gastric intestinal metaplasia revisited: Function and regulation of CDX2","volume":"18","author":"Barros","year":"2012","journal-title":"Trends Mol. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1136\/gut.2010.222323","article-title":"CDX2 autoregulation in human intestinal metaplasia of the stomach: Impact on the stability of the phenotype","volume":"60","author":"Barros","year":"2011","journal-title":"Gut"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/modpathol.2009.135","article-title":"CDX2 expression in the intestinal-type gastric epithelial neoplasia: Frequency and significance","volume":"23","author":"Park","year":"2010","journal-title":"Mod. Pathol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1158\/0008-5472.CAN-15-2272","article-title":"Cdx2 Expression and Intestinal Metaplasia Induced by H. pylori Infection of Gastric Cells Is Regulated by NOD1-Mediated Innate Immune Responses","volume":"76","author":"Asano","year":"2016","journal-title":"Cancer Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1007\/s10620-016-4048-y","article-title":"Follow-Up Study on CDX1 and CDX2 mRNA Expression in Noncancerous Gastric Mucosae After Helicobacter pylori Eradication","volume":"61","author":"Shin","year":"2016","journal-title":"Dig. Dis. Sci."},{"unstructured":"World Health Organization (2022, January 20). Global Cancer Observatory, Stomach Cancer Fact Sheet. Available online: https:\/\/gco.iarc.fr\/.","key":"ref_96"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/apm.1965.64.1.31","article-title":"The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma","volume":"64","year":"1965","journal-title":"Acta Pathol. Microbiol. Scand."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.gtc.2013.01.002","article-title":"Gastric Cancer: Overview","volume":"42","author":"Correa","year":"2013","journal-title":"Gastroenterol. Clin. N. Am."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/nature13480","article-title":"Comprehensive molecular characterization of gastric adenocarcinoma","volume":"513","author":"Bass","year":"2014","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e71","DOI":"10.1093\/nar\/gkv1507","article-title":"TCGAbiolinks: An R\/Bioconductor package for integrative analysis of TCGA data","volume":"44","author":"Colaprico","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1101\/gr.239244.118","article-title":"Maftools: Efficient and comprehensive analysis of somatic variants in cancer","volume":"28","author":"Mayakonda","year":"2018","journal-title":"Genome Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"53839","DOI":"10.18632\/oncotarget.17809","article-title":"The role of Notch signaling in gastric carcinoma: Molecular pathogenesis and novel therapeutic targets","volume":"8","author":"Yao","year":"2017","journal-title":"Oncotarget"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1038\/ng.982","article-title":"Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer","volume":"43","author":"Wang","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.stem.2018.09.016","article-title":"A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening","volume":"23","author":"Yan","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1186\/s12967-019-1941-0","article-title":"Mutational landscape of gastric cancer and clinical application of genomic profiling based on target next-generation sequencing","volume":"17","author":"Cai","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/nature07935","article-title":"Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche","volume":"459","author":"Sato","year":"2009","journal-title":"Nature"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41596-018-0080-z","article-title":"Generation of human antral and fundic gastric organoids from pluripotent stem cells","volume":"14","author":"Broda","year":"2019","journal-title":"Nat. Protoc."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nature13863","article-title":"Modelling human development and disease in pluripotent stem-cell-derived gastric organoids","volume":"516","author":"McCracken","year":"2014","journal-title":"Nature"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3710836","DOI":"10.1155\/2016\/3710836","article-title":"Three-Dimensional Gastrointestinal Organoid Culture in Combination with Nerves or Fibroblasts: A Method to Characterize the Gastrointestinal Stem Cell Niche","volume":"2016","author":"Pastula","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.stem.2021.10.010","article-title":"Functional human gastrointestinal organoids can be engineered from three primary germ layers derived separately from pluripotent stem cells","volume":"29","author":"Eicher","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/s41467-021-21162-y","article-title":"Genomic aberrations after short-term exposure to colibactin-producing E. coli transform primary colon epithelial cells","volume":"12","author":"Iftekhar","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.cobme.2019.12.010","article-title":"Microphysiological System Design: Simplicity Is Elegance","volume":"13","author":"Hinman","year":"2020","journal-title":"Curr. Opin. Biomed. Eng."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"15240","DOI":"10.1021\/acs.analchem.9b04217","article-title":"Photopatterned Membranes and Chemical Gradients Enable Scalable Phenotypic Organization of Primary Human Colon Epithelial Models","volume":"91","author":"Hinman","year":"2019","journal-title":"Anal. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"015006","DOI":"10.1088\/1758-5090\/ab446e","article-title":"An in vitro intestinal platform with a self-sustaining oxygen gradient to study the human gut\/microbiome interface","volume":"12","author":"Kim","year":"2019","journal-title":"Biofabrication"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.jcmgh.2017.10.007","article-title":"Formation of Human Colonic Crypt Array by Application of Chemical Gradients Across a Shaped Epithelial Monolayer","volume":"5","author":"Wang","year":"2018","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/s41596-020-00419-8","article-title":"In vitro generation of self-renewing human intestinal epithelia over planar and shaped collagen hydrogels","volume":"16","author":"Hinman","year":"2021","journal-title":"Nat. Protoc."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/s41586-020-2724-8","article-title":"Homeostatic mini-intestines through scaffold-guided organoid morphogenesis","volume":"585","author":"Nikolaev","year":"2020","journal-title":"Nature"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41563-020-00803-5","article-title":"Recapitulating macro-scale tissue self-organization through organoid bioprinting","volume":"20","author":"Brassard","year":"2021","journal-title":"Nat. Mater."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"108819","DOI":"10.1016\/j.celrep.2021.108819","article-title":"Human gastrointestinal epithelia of the esophagus, stomach, and duodenum resolved at single-cell resolution","volume":"34","author":"Busslinger","year":"2021","journal-title":"Cell Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3632\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:44:00Z","timestamp":1760136240000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3632"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,26]]},"references-count":119,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["ijms23073632"],"URL":"https:\/\/doi.org\/10.3390\/ijms23073632","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,3,26]]}}}