{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:05:22Z","timestamp":1790093122520,"version":"4.0.1"},"reference-count":111,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["101109731"],"award-info":[{"award-number":["101109731"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"award":["101109731"],"award-info":[{"award-number":["101109731"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Esophageal submucosal glands (SMGs) contribute to mucosal defense through bicarbonate, mucin, and reparative-factor secretion. Chronic reflux may impair these functions and remodel the glandular compartment, potentially linking SMG injury to reflux esophagitis, Barrett\u2019s esophagus (BE), and esophageal adenocarcinoma (EAC). Objective: To map the human, animal, and in vitro literature on the physiological and pathological roles of esophageal SMGs and to identify evidence gaps relevant to reflux injury, BE, EAC, and endoscopic therapy. Methods: This scoping review was reported in accordance with PRISMA-ScR. Embase, Web of Science, PubMed, and Google Scholar were searched from inception to 15 January 2025. Two reviewers independently screened records against prespecified eligibility criteria. The protocol was not registered. Results: The review included 97 full-text publications and 7 conference abstracts. The full-text set comprised 89 original studies and 8 reviews; review articles were used for context and citation tracing rather than counted as independent primary evidence. The mapped literature supports secretory and reparative functions of SMGs and documents injury-associated remodeling, including loss of mucinous acini and expansion of atrophic, oncocytic, or duct-like phenotypes. Marker expression, spatial continuity, and clonal observations are compatible with glandular participation in repair and Barrett-associated biology, but do not establish a unique cell of origin and lineage relationships remain unresolved. Conclusions: Esophageal SMGs occupy a plausible interface between mucosal protection and pathological plasticity. The most consequential gaps are the lack of longitudinal human evidence, source-resolved lineage information, standardized reporting of glandular phenotypes, and human models that reproduce reflux exposure and the stromal niche.<\/jats:p>","DOI":"10.3390\/cells15191727","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:28:43Z","timestamp":1790090923000},"page":"1727","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Dual Roles of Esophageal Submucosal Glands: Protection and Pathogenesis in Benign and Malignant Disease: A Scoping Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7190-9862","authenticated-orcid":false,"given":"Chun-Ting","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Medical Centre Rotterdam (Erasmus MC), Erasmus University Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"},{"name":"The Laboratory of Experimental Medicine and Pediatrics (LEMP), Antwerp University, Universiteitsplein 1, Wilrijk, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiel F. G.","family":"de Maat","sequence":"additional","affiliation":[{"name":"Department of Abdominal Surgery\/eSophageal Oncology Network Antwerp Region (SONAR), University Hospital Antwerp (UZA), Antwerp University, Drie Eikenstraat 655, Edegem, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4148-610X","authenticated-orcid":false,"given":"Ann","family":"Driessen","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Hospital Antwerp (UZA), Antwerp University, Drie Eikenstraat 655, Edegem, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8611-840X","authenticated-orcid":false,"given":"Michael","family":"Doukas","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medical Centre Rotterdam (Erasmus MC), Erasmus University Rotterdam, Dr. Molewaterplein 40, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bas P. L.","family":"Wijnhoven","sequence":"additional","affiliation":[{"name":"Department of Surgery, University Medical Centre Rotterdam (Erasmus MC), Erasmus University Rotterdam, Dr. Molewaterplein 40, Erasmus MC, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9112-6028","authenticated-orcid":false,"given":"Maikel P.","family":"Peppelenbosch","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Medical Centre Rotterdam (Erasmus MC), Erasmus University Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kausilia","family":"K. Krishnadath","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Hospital Antwerp (UZA), Antwerp University, Drie Eikenstraat 655, Edegem, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8279-1816","authenticated-orcid":false,"given":"Vincent T.","family":"Janmaat","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Medical Centre Rotterdam (Erasmus MC), Erasmus University Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"},{"name":"The Laboratory of Experimental Medicine and Pediatrics (LEMP), Antwerp University, Universiteitsplein 1, Wilrijk, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"ref_1","first-page":"A234","article-title":"Endoscopic detection of submucosal glands in the distal esophagus","volume":"128","author":"Rey","year":"2005","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1111\/nyas.13705","article-title":"The microscopic anatomy of the esophagus including the individual layers, specialized tissues, and unique components and their responses to injury","volume":"1434","author":"Zhang","year":"2018","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2818","DOI":"10.1111\/j.1572-0241.1999.1422_b.x","article-title":"Esophageal submucosal glands: Structure and function","volume":"94","author":"Long","year":"1999","journal-title":"Am. J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1002\/1097-0215(20001215)88:6<856::AID-IJC3>3.0.CO;2-D","article-title":"Mucin gene expression and cell differentiation in human normal, premalignant and malignant esophagus","volume":"88","author":"Guillem","year":"2000","journal-title":"Int. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/BF00492353","article-title":"Human oesophageal submucosal glands. Their detection mucin, enzyme and secretory protein content","volume":"86","author":"Hopwood","year":"1986","journal-title":"Histochemistry"},{"key":"ref_6","first-page":"38","article-title":"Systemic factors in esophageal mucosal protection","volume":"56","author":"Tobey","year":"1995","journal-title":"Digestion"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nrgastro.2014.181","article-title":"Barrett oesophagus: Lessons on its origins from the lesion itself","volume":"12","author":"McDonald","year":"2015","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1126\/science.abd1449","article-title":"Molecular phenotyping reveals the identity of Barrett\u2019s esophagus and its malignant transition","volume":"373","author":"Zhuang","year":"2021","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1053\/j.gastro.2019.03.072","article-title":"Pathogenesis and Cells of Origin of Barrett\u2019s Esophagus","volume":"157","author":"Que","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1093\/ajcp\/89.4.493","article-title":"Diagnostic value of cytopathology in Barrett esophagus and associated carcinoma","volume":"89","author":"Robey","year":"1988","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1007\/s10388-020-00758-1","article-title":"Submucosal gland neoplasms of the esophagus: An update and review","volume":"17","author":"Nie","year":"2020","journal-title":"Esophagus"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"467","DOI":"10.7326\/M18-0850","article-title":"PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation","volume":"169","author":"Tricco","year":"2018","journal-title":"Ann. Intern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R83","DOI":"10.1152\/ajpregu.00648.2010","article-title":"Ion transport mechanisms linked to bicarbonate secretion in the esophageal submucosal glands","volume":"301","author":"Nakhoul","year":"2011","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"G736","DOI":"10.1152\/ajpgi.00055.2004","article-title":"HCO3\u2212 secretion in the esophageal submucosal glands","volume":"288","author":"Nakhoul","year":"2005","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_15","first-page":"705","article-title":"Fine structure of squamous epitheilum and submucosal glands of human oesophagus","volume":"123","author":"Toner","year":"1977","journal-title":"J. Anat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/path.1526","article-title":"Distribution of laminins in the basement membranes of the upper gastrointestinal tract and Barrett\u2019s oesophagus","volume":"202","author":"Dave","year":"2004","journal-title":"J. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4011","DOI":"10.3748\/wjg.v20.i14.4011","article-title":"Immunohistochemical assessment of NY-ESO-1 expression in esophageal adenocarcinoma resection specimens","volume":"20","author":"Hayes","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.pathol.2019.12.002","article-title":"Role of submucosal glands in the development and progression of carcinoma in Barrett\u2019s oesophagus","volume":"52","author":"Johncilla","year":"2020","journal-title":"Pathology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/B978-0-323-40232-3.00004-2","article-title":"Chapter 4-Relevant Anatomic Relations of the Esophagus","volume":"Volume 1","author":"Lin","year":"2019","journal-title":"Shackelford\u2019s Surgery of the Alimentary Tract, 2 Volume Set"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/j.1365-2559.2012.04180.x","article-title":"Submucosal glands in the columnar-lined oesophagus: Evidence of an association with metaplasia and neosquamous epithelium","volume":"61","author":"Lorinc","year":"2012","journal-title":"Histopathology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3054","DOI":"10.1007\/s10620-006-9739-3","article-title":"Characterization of esophageal submucosal glands in pig tissue and cultures","volume":"52","author":"Nakhoul","year":"2007","journal-title":"Dig. Dis. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1007\/s10620-007-0170-1","article-title":"The effect of tegaserod on esophageal submucosal glands bicarbonate and mucin secretion","volume":"53","author":"Tobey","year":"2008","journal-title":"Dig. Dis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"G180","DOI":"10.1152\/ajpgi.00036.2017","article-title":"Ductular and proliferative response of esophageal submucosal glands in a porcine model of esophageal injury and repair","volume":"313","author":"Kruger","year":"2017","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"G613","DOI":"10.1152\/ajpgi.00086.2019","article-title":"Lubiprostone protects esophageal mucosa from acid injury in porcine esophagus","volume":"318","author":"Kruger","year":"2020","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.jcmgh.2017.07.005","article-title":"Porcine esophageal submucosal gland culture model shows capacity for proliferation and differentiation","volume":"4","author":"Li","year":"2017","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/bjs.1800750208","article-title":"Experimental columnar metaplasia in the canine oesophagus","volume":"75","author":"Gillen","year":"1988","journal-title":"Br. J. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"30","DOI":"10.4993\/acrt.25.30","article-title":"The mechanism of esophageal stricture after endoscopic resection: Histological and biomechanical evaluation in a canine model","volume":"25","author":"Honda","year":"2017","journal-title":"Ann. Cancer Res. Ther."},{"key":"ref_28","first-page":"176","article-title":"Mechanisms of columnar metaplasia and squamous regeneration in experimental Barrett\u2019s esophagus","volume":"115","author":"Li","year":"1994","journal-title":"Surgery"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1093\/dote\/11.2.89","article-title":"Gastroesophageal reflux triggers proliferative activity of the submucosal glands in the canine esophagus","volume":"11","author":"Willems","year":"1998","journal-title":"Dis. Esophagus"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"G113","DOI":"10.1152\/ajpgi.2000.278.1.G113","article-title":"Lumen-to-surface pH gradients in opossum and rabbit esophagi: Role of submucosal glands","volume":"278","author":"Nakhoul","year":"2000","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/0016-5085(89)90635-5","article-title":"In vivo alkaline secretion by mammalian esophagus","volume":"97","author":"Hamilton","year":"1989","journal-title":"Gastroenterology"},{"key":"ref_32","first-page":"A244","article-title":"Vagal stimulation of opossum esophageal submucosal gland bicarbonate secretion","volume":"110","author":"Rossowski","year":"1996","journal-title":"Gastroenterology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1007\/s10620-005-2902-4","article-title":"Morphology and glycoconjugate content of opossum esophageal epithelium and glands: Regional heterogeneity and effects of acid-induced mucosal injury and recovery","volume":"50","author":"White","year":"2005","journal-title":"Dig. Dis. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"C171","DOI":"10.1152\/ajpcell.00226.2003","article-title":"Critical role of p63 in the development of a normal esophageal and tracheobronchial epithelium","volume":"287","author":"Daniely","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Straub, D., Elferink, R.P.J.O., Jansen, P.L.M., Bergman, J.J.G.H.M., Parikh, K., and Krishnadath, K.K. (2019). Glyco-conjugated bile acids drive the initial metaplastic gland formation from multi-layered glands through crypt-fission in a murine model. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0220050"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.acthis.2013.07.008","article-title":"Keratinization of the esophageal epithelium of domesticated mammals","volume":"116","author":"Meyer","year":"2014","journal-title":"Acta Histochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.jcmgh.2017.01.016","article-title":"Origin of Barrett\u2019s Epithelium: Esophageal Submucosal Glands","volume":"4","author":"Garman","year":"2017","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_38","first-page":"375","article-title":"Identification of Cftr and Slc26a6 in the Esophageal Submucosal Glands","volume":"57","author":"Doetjes","year":"2009","journal-title":"J. Investig. Med."},{"key":"ref_39","first-page":"A542","article-title":"Immunolocalization of a Na+(HCO3\u2212)n cotransporter in esophageal submucosal glands","volume":"126","author":"Nakhoul","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1136\/gut.47.6.753","article-title":"Mucin gene expression in Barrett\u2019s oesophagus: An in situ hybridisation and immunohistochemical study","volume":"47","author":"Arul","year":"2000","journal-title":"Gut"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"365","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":"ref_42","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/0016-5085(94)90756-0","article-title":"Human esophageal secretion: Mucosal response to luminal acid and pepsin","volume":"106","author":"Namiot","year":"1994","journal-title":"Gastroenterology"},{"key":"ref_43","first-page":"1177","article-title":"Diminished luminal release of esophageal epidermal growth factor in patients with reflux esophagitis","volume":"89","author":"Rourk","year":"1994","journal-title":"Am. J. Gastroenterol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/nyas.13187","article-title":"Does the healing of the esophageal mucosa improve the function of the esophageal submucosal and salivary glands?","volume":"1380","author":"Sarosiek","year":"2016","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S152","DOI":"10.14309\/00000434-200709002-00097","article-title":"Gender-related difference in composition of secretion from esophageal submucosal mucous glands, in response to stimulation of serotonergic pathway, in patients with gastroesophageal reflux disease","volume":"102","author":"Majewski","year":"2007","journal-title":"Am. J. Gastroenterol."},{"key":"ref_46","first-page":"A405","article-title":"Tegaserod stimulates bicarbonate secretion by esophageal submucosal glands and protects against acid-pepsin injury in a pig model","volume":"130","author":"Tobey","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1097\/00000478-199802000-00013","article-title":"The histopathology of treated Barrett\u2019s esophagus: Squamous reepithelialization after acid suppression and laser and photodynamic therapy","volume":"22","author":"Biddlestone","year":"1998","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.14309\/ajg.0000000000001940","article-title":"An Endoscopic and Histologic Study on Healing of Radiofrequency Ablation Wounds in Patients With Barrett\u2019s Esophagus","volume":"117","author":"Konda","year":"2022","journal-title":"Am. J. Gastroenterol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.gie.2021.04.028","article-title":"Extension of early esophageal squamous cell neoplasia into ducts and submucosal glands and the role of endoscopic ablation therapy","volume":"94","author":"Overwater","year":"2021","journal-title":"Gastrointest. Endosc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S0016-5085(19)31680-4","article-title":"Cell proliferation in esophageal columnar epithelium (Barrett\u2019s esophagus)","volume":"75","author":"Herbst","year":"1978","journal-title":"Gastroenterology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1136\/thx.40.11.849","article-title":"Oesophageal intramural pseudodiverticulosis","volume":"40","author":"Sabanathan","year":"1985","journal-title":"Thorax"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s00428-014-1590-x","article-title":"Necrotizing sialometaplasia-like change of the esophageal submucosal glands is associated with Barrett\u2019s esophagus","volume":"465","author":"Braxton","year":"2014","journal-title":"Virchows Arch."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1111\/his.12707","article-title":"Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma","volume":"67","author":"Garman","year":"2015","journal-title":"Histopathology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.jcmgh.2014.10.001","article-title":"The Barrett\u2019s Gland in Phenotype Space","volume":"1","author":"McDonald","year":"2015","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_55","unstructured":"Fass, O. (2017). Bile Acid-Mediated Transdifferentiation of Stem Cells from the Deep Esophageal Glands, Harvard University."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"S207","DOI":"10.1016\/S0016-5085(18)31090-4","article-title":"Increased Gastrin Responsiveness after Injury in Esophageal Submucosal Glands","volume":"154","author":"Su","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4261","DOI":"10.1038\/s41467-018-06796-9","article-title":"Single cell RNA-seq reveals profound transcriptional similarity between Barrett\u2019s oesophagus and oesophageal submucosal glands","volume":"9","author":"Owen","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"S81","DOI":"10.1007\/s11605-009-1011-7","article-title":"The molecular pathogenesis of Barrett\u2019s esophagus: Common signaling pathways in embryogenesis metaplasia and neoplasia","volume":"14","author":"Peters","year":"2010","journal-title":"J. Gastrointest. Surg."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1053\/j.gastro.2022.07.045","article-title":"The Ephrin B2 Receptor Tyrosine Kinase Is a Regulator of Proto-oncogene MYC and Molecular Programs Central to Barrett\u2019s Neoplasia","volume":"163","author":"Venkitachalam","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1097\/00000478-200105000-00002","article-title":"Phenotypic characteristics of a distinctive multilayered epithelium suggests that it is a precursor in the development of Barrett\u2019s esophagus","volume":"25","author":"Glickman","year":"2001","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1078\/0344-0338-00465","article-title":"Different patterns of cytokeratin expression in Barrett\u2019s esophagus\u2014What is beyond?","volume":"199","author":"Mandys","year":"2003","journal-title":"Pathol. Res. Pract."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.humpath.2005.01.012","article-title":"Islands of squamous epithelium and their surrounding mucosa in columnar-lined esophagus: A pathognomonic feature of Barrett\u2019s esophagus?","volume":"36","author":"Takubo","year":"2005","journal-title":"Hum. Pathol."},{"key":"ref_63","first-page":"S55","article-title":"On the histogenesis of Barrett\u2019s oesophagus: A three dimensional study of the relationship between oesophageal gland ducts, Barrett\u2019s oesophagus and associated squamous islands","volume":"91","author":"Coad","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1111\/his.12604","article-title":"Hyperplasia of the submucosal glands of the columnar-lined oesophagus","volume":"66","author":"Lorinc","year":"2015","journal-title":"Histopathology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1097\/PAS.0000000000000623","article-title":"Histologic Features Associated With Columnar-lined Esophagus in Distal Esophageal and Gastroesophageal Junction (GEJ) Biopsies From GERD Patients: A Community-based Population Study","volume":"40","author":"Soucy","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1053\/j.gastro.2021.12.271","article-title":"Clonal Transitions and Phenotypic Evolution in Barrett\u2019s Esophagus","volume":"162","author":"Evans","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1136\/gut.2007.143339","article-title":"Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett\u2019s oesophagus","volume":"57","author":"Leedham","year":"2008","journal-title":"Gut"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1136\/gutjnl-2011-301174","article-title":"Barrett\u2019s metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor","volume":"61","author":"Nicholson","year":"2012","journal-title":"Gut"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1158\/1078-0432.CCR-05-1810","article-title":"Neosquamous epithelium does not typically arise from Barrett\u2019s epithelium","volume":"12","author":"Paulson","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/ajcp\/70.1.1","article-title":"Adenocarcinoma complicating columnar epithelium-lined (Barrett\u2019s) esophagus","volume":"70","author":"Haggitt","year":"1978","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_71","first-page":"551","article-title":"Pericentriolar material analyses in normal esophageal mucosa, Barrett\u2019s metaplasia and adenocarcinoma","volume":"25","author":"Segat","year":"2010","journal-title":"Histol. Histopathol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.gie.2017.06.024","article-title":"Subsquamous intestinal metaplasia is common in treatment-naive Barrett\u2019s esophagus","volume":"87","author":"Bartel","year":"2018","journal-title":"Gastrointest. Endosc."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.gie.2018.02.036","article-title":"Response","volume":"88","author":"Bartel","year":"2018","journal-title":"Gastrointest. Endosc."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1053\/j.gastro.2023.08.039","article-title":"Genetic Defect in Submucosal Gland-Associated Caveolin-3: A New Paradigm in Esophageal Adenocarcinoma Risk","volume":"165","author":"Garman","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1136\/jcp.48.6.539","article-title":"Expression of HLA-ABC, HLA-DR and intercellular adhesion molecule-1 in oesophageal carcinoma","volume":"48","author":"Rockett","year":"1995","journal-title":"J. Clin. Pathol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1053\/j.gastro.2021.05.057","article-title":"Hybrid stomach-intestinal chromatin states underlie human Barrett\u2019s metaplasia","volume":"161","author":"Singh","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1136\/gutjnl-2015-310748","article-title":"Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett\u2019s oesophagus","volume":"65","author":"Lavery","year":"2016","journal-title":"Gut"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1158\/2159-8290.CD-22-0824","article-title":"Single-Cell RNA Sequencing Unifies Developmental Programs of Esophageal and Gastric Intestinal Metaplasia","volume":"13","author":"Zhuang","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1002\/1097-0142(19850801)56:3<514::AID-CNCR2820560318>3.0.CO;2-D","article-title":"Glandular or mucus-secreting components in squamous cell carcinoma of the esophagus","volume":"56","author":"Kuwano","year":"1985","journal-title":"Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/nyas.13108","article-title":"Rare tumors of esophageal squamous mucosa","volume":"1381","author":"Tripathi","year":"2016","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_81","first-page":"399","article-title":"Submucosal gland differentiation and implications in esophageal basaloid squamous cell carcinomas","volume":"39","author":"Nie","year":"2024","journal-title":"Histol. Histopathol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.4240\/wjgs.v15.i5.1000","article-title":"Modified endoscopic submucosal tunnel dissection for large esophageal submucosal gland duct adenoma: A case report","volume":"15","author":"Chen","year":"2023","journal-title":"World J. Gastrointest. Surg."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1111\/dote.12442","article-title":"Esophageal submucosal gland duct adenoma: A clinicopathological and immunohistochemical study with a review of the literature","volume":"29","author":"Nie","year":"2016","journal-title":"Dis. Esophagus"},{"key":"ref_84","first-page":"962","article-title":"Endoscopic findings of esophageal gland duct adenoma resected by endoscopic submucosal dissection Commentary","volume":"92","author":"Othman","year":"2020","journal-title":"Gastrointest. Endosc."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1038\/ajg.2015.337","article-title":"Corrigendum: A Novel Case of an Unusual Esophageal Submucosal Tumor: An Esophageal Submucosal Gland Duct Hamartoma","volume":"110","author":"Yorita","year":"2015","journal-title":"Am. J. Gastroenterol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Zhu, Z., Qin, B., Wang, B., Liu, K., Hu, X., Chen, B., Yao, X., Ma, Y., and Wang, Z. (2021). Whole-Exome Sequencing of Esophageal Submucosal Gland Duct Adenocarcinoma. Preprint, in press.","DOI":"10.21203\/rs.3.rs-791813\/v1"},{"key":"ref_87","first-page":"1","article-title":"Roles of Cl\u2212\/HCO3\u2212 anion exchanger 2 in the physiology and pathophysiology of the digestive system (Review)","volume":"24","author":"Wang","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1111\/his.12719","article-title":"The immunophenotypic relationship between the submucosal gland unit, columnar metaplasia and squamous islands in the columnar-lined oesophagus","volume":"67","author":"Lorinc","year":"2015","journal-title":"Histopathology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s10388-004-0016-2","article-title":"Submucosal adenoma of the esophagus: Case report and review of the literature","volume":"1","author":"Hayashi","year":"2004","journal-title":"Esophagus"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.gie.2014.09.004","article-title":"Is it justified to ablate flat-type esophageal squamous cancer? An analysis of endoscopic submucosal dissection specimens of lesions meeting the selection criteria of radiofrequency studies","volume":"80","author":"Jansen","year":"2014","journal-title":"Gastrointest. Endosc."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"S2289","DOI":"10.14309\/01.ajg.0001043136.59406.2f","article-title":"An Incidental Case of Esophageal Submucosal Gland Duct Adenoma","volume":"119","author":"Maurer","year":"2024","journal-title":"Am. J. Gastroenterol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1097\/00000478-199510000-00009","article-title":"Esophageal submucosal gland duct adenoma","volume":"19","author":"Rouse","year":"1995","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.gastrohep.2020.08.009","article-title":"Submucosal gland adenocarcinoma of the esophagus. A rare non-Barrett\u2019s associated tumor","volume":"44","author":"Guerrero","year":"2021","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/1097-0142(20000715)89:2<248::AID-CNCR7>3.0.CO;2-Q","article-title":"Significance of involvement by squamous cell carcinoma of the ducts of esophageal submucosal glands. Analysis of 201 surgically resected superficial squamous cell carcinomas","volume":"89","author":"Tajima","year":"2000","journal-title":"Cancer"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1002\/1097-0142(19930415)71:8<2435::AID-CNCR2820710802>3.0.CO;2-A","article-title":"Adenoma accompanied by superficial squamous cell carcinoma of the esophagus","volume":"71","author":"Takubo","year":"1993","journal-title":"Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"E237","DOI":"10.1055\/s-2008-1077680","article-title":"Early adenocarcinoma originating in submucosal gland of thoracic esophagus presenting as submucosal tumor","volume":"40","author":"Wang","year":"2008","journal-title":"Endoscopy"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"6860","DOI":"10.1038\/s41598-020-62668-7","article-title":"Risk factors and pathological characteristics for intraductal tumor spread of submucosal gland in early esophageal squamous cell neoplasia","volume":"10","author":"Wang","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/ajg.2013.238","article-title":"Clonal selection and persistence in dysplastic Barrett\u2019s esophagus and intramucosal cancers after failed radiofrequency ablation","volume":"108","author":"Zeki","year":"2013","journal-title":"Am. J. Gastroenterol."},{"key":"ref_99","unstructured":"Attwood, S.E.A. (1993, January 1\u20134). What factors are evidenced by study of the mucins of the esophageal glands during esophagitis. Proceedings of the 4th OESO World Congress on the Esophageal Mucosa, Unesco, Paris, France."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1053\/j.gastro.2012.06.044","article-title":"A combination of esomeprazole and aspirin reduces tissue concentrations of prostaglandin E(2) in patients with Barrett\u2019s esophagus","volume":"143","author":"Falk","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/S0140-6736(18)31388-6","article-title":"Esomeprazole and aspirin in Barrett\u2019s oesophagus (AspECT): A randomised factorial trial","volume":"392","author":"Jankowski","year":"2018","journal-title":"Lancet"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Fuchs, K.H., Kafetzis, I., Hann, A., and Meining, A. (2024). Hiatal Hernias Revisited-A Systematic Review of Definitions, Classifications, and Applications. Life, 14.","DOI":"10.3390\/life14091145"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1007\/s00464-009-0811-x","article-title":"Differential regulation of MMP-2 in the gastrohepatic ligament of the gastroesophageal junction","volume":"24","author":"Melman","year":"2010","journal-title":"Surg. Endosc."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1053\/j.gastro.2010.01.048","article-title":"Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett\u2019s metaplasia","volume":"138","author":"Wang","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3855","DOI":"10.1002\/jcp.26136","article-title":"Basal progenitor cells bridge the development, malignant cancers, and multiple diseases of esophagus","volume":"233","author":"Lin","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1177\/26345161241242757","article-title":"Origins of the Glandular Mucosae in the Gastro-Esophageal Junction\u2014A Study in a South Asian Population With Low Incidence of Esophageal Adenocarcinoma","volume":"4","author":"Wijetunge","year":"2024","journal-title":"Foregut"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1038\/s41467-021-23641-8","article-title":"HOXA13 in etiology and oncogenic potential of Barrett\u2019s esophagus","volume":"12","author":"Janmaat","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jcmgh.2017.01.015","article-title":"The Esophageal Squamous Epithelial Cell\u2014Still a Reasonable Candidate for the Barrett\u2019s Esophagus Cell of Origin?","volume":"4","author":"Wang","year":"2017","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.jcmgh.2018.01.011","article-title":"Esophageal 3D culture systems as modeling tools in esophageal epithelial pathobiology and personalized medicine","volume":"5","author":"Whelan","year":"2018","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.gastha.2023.03.009","article-title":"Epithelial-Stromal Interactions in Barrett\u2019s Esophagus Modeled in Human Organ Chips","volume":"2","author":"Shimshoni","year":"2023","journal-title":"Gastro Hep Adv."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/s41592-021-01344-8","article-title":"Lineage recording in human cerebral organoids","volume":"19","author":"He","year":"2022","journal-title":"Nat. Methods"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1727\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:33:59Z","timestamp":1790091239000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1727"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":111,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cells15191727"],"URL":"https:\/\/doi.org\/10.3390\/cells15191727","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]}}}