New Mechanisms of Barrett's Esophagus Development

Venera Rakhmetova 1, Agzhan Aldabergenova 2, Adina Beisenbekova 2, Madina Kalimullina 2, Madina Temirbek 2 *
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1 Department of Internal Medicine, NJSC “Astana Medical University”, Astana, Kazakhstan
2 Gastroenterology residency, NJSC “Astana Medical University”, Astana, Kazakhstan
* Corresponding Author
J CLIN MED KAZ, Volume 21, Issue 3, pp. 20-25.
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Author Contributions: Conceptualization, V. R.; methodology, A. B.; validation, V. R.; formal analysis, A. A.; investigation, M. K.; resources, A. A.; data curation, V. R.writing
– original draft preparation, M. T.; writing – review and editing, M. T.; visualization, A. B.; supervision, M. K.; project administration, V. R.; funding acquisition, V. R. All authors have
read and agreed to the published version of the manuscript.


Barrett's esophagus is a pathological condition that develops as a result of metaplastic transformation of the stratified squamous non-keratinized epithelium of the mucous membrane of the distal esophagus into columnar epithelium of the intestinal type[13]. The objective of this review was to furnish information on new hypotheses and mechanisms concerning the development of Barrett's esophagus, with the aim of identifying trends in this area and advancing understanding of the disease's pathogenesis for the prevention of esophageal adenocarcinoma.
A literary analysis of recent articles was conducted to investigate the mechanisms underlying the development of Barrett's esophagus.
During the review of extensive literature, in addition to the classic theory of esophageal cell replacement, new mechanisms of cell transdifferentiation and transcommitment were identified.
Much remains unknown, particularly regarding the originating cell population and the molecular events or stages through which Barrett's esophagus progresses to esophageal adenocarcinoma. These are crucial questions for researchers, the answers to which will significantly impact disease prevention and treatment. Despite the currently limited experimental model systems available for studying Barrett's esophagus and esophageal adenocarcinoma, innovations in tissue engineering and organotypic cell culture systems based on human cells offer great prospects as platforms for future investigations into the pathogenesis and progression of these diseases.


Rakhmetova V, Aldabergenova A, Beisenbekova A, Kalimullina M, Temirbek M. New Mechanisms of Barrett's Esophagus Development. J CLIN MED KAZ. 2024;21(3):20-5.


  • Que J, Garman KS, Souza RF, Spechler SJ.Pathogenesis and Cells of Origin of Barrett's Esophagus. Gastroenterology. 2019; 157(2): 349–364.
  • Chen H, Fang Y, Tevebaugh W, Orlando RC, Shaheen NJ and Chen X. Mechanism of Barrett’s Esophagus. Dig Dis Sci. 2011; 56(12): 3405–3420.
  • Wijnhoven BP, Hussey DJ, Watson DI, Tsykin A, Smith CM, Michael MZ. MicroRNA profiling of Barrett’s oesophagus and oesophageal adenocarcinoma. Br J Surg. 2010; 97: 853–61.
  • Spehler SY, Sousa RF. Esophagus Barretta. N Engl J Med. 2014; 371: 836-45.
  • Shaheen NJ, Falk GW, Iyer PG, Gerson LB; American College of Gastroenterology. ACG Clinical Guideline: Diagnosis and Management of Barrett's Esophagus. Am J Gastroenterol 2016; 111:30–50.
  • Wang J, Qin R, Ma Y, et al. Differential gene expression in normal esophagus and Barrett’s esophagus. J Gastroenterol. 2009; 44: 897–911.
  • Bass AJ, Watanabe H, Mermel CH, et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet. 2009; 41: 1238–42.
  • Mutoh H, Sashikawa M, Sugano K. Sox2 expression is maintained while gastric phenotype is completely lost in Cdx2-induced intestinal metaplastic mucosa. Differentiation. 2010; 81: 92–8.
  • Sherwood RI, Chen TY, Melton DA. Transcriptional dynamics of endodermal organ forquanmation. Dev Dyn. 2009; 238: 29–42.
  • Benoit YD, Pare F, Francoeur C, et al. Cooperation between HNF-1alpha, Cdx2, and GATA-4 in initiating an enterocytic differentiation program in a normal human intestinal epithelial progenitor cell line. Am J Physiol Gastrointest Liver Physiol. 2010; 298: G504–17.
  • Kazumori H, Ishihara S, Kinoshita Y. Roles of caudal-related homeobox gene Cdx1 in oesophageal epithelial cells in Barrett’s epithelium development. Gut. 2009; 58: 620–8.
  • Verzi MP, Shin H, Ho LL, Liu XS, Shivdasani RA. Essential and redundant functions of Caudal family proteins in activating adult intestinal genes. Mol Cell Biol. 2011: 31(10): 2026–2039.
  • Domyan ET, Ferretti E, Throckmorton K, Mishina Y, Nicolis SK, Sun X. Signaling through BMP receptors promotes respiratory identity in the foregut via repression of Sox2. Development. 2011; 138: 971–81.
  • Rodriguez P, Da Silva S, Oxburgh L, Wang F, Hogan BL, Que J. BMP signaling in the development of the mouse esophagus and forestomach. Development. 2010; 137: 4171–6.
  • Yamanaka Y, Shiotani A, Fujimura Y, et al. Expression of Sonic hedgehog (SHH) and CDX2 in the columnar epithelium of the lower oesophagus. Dig Liver Dis. 2011; 43 :54–9.
  • Wang DH, Clemons NJ, Miyashita T, et al. Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett’s metaplasia. Gastroenterology. 2010; 138: 1810–22.
  • Lao-Sirieix P, Fitzgerald RC. Role of the micro-environment in Barrett’s carcinogenesis. Biochem Soc Trans. 2010; 38: 327–30.
  • Menke V, van Es JH, de Lau W, et al. Conversion of metaplastic Barrett’s epithelium into post-mitotic goblet cells by gamma-secretase inhibition. Dis Model Mech. 2010; 3: 104–10.
  • Quante M, Abrams JA, Marrache F, Wang TC. Barrett’s esophagus correlates with increased putative gastrointestinal stem cell markers DCLK1 and CCK2R in a IL1b mouse model and in humans. Gastroenterology. 2010; 138 (5): S-128-S-128.
  • Bansal A, Lee IH, Hong X, et al. Feasibility of MicroRNAs as Biomarkers for Barrett’s Esophagus Progression: A Pilot Cross-Sectional, Phase 2 Biomarker Study. Am J Gastroenterol. 2011; 106(6): 1055-1063.
  • Fassan M, Volinia S, Palatini J, et al. MicroRNA expression profiling in human Barrett’s carcinogenesis. Int J Cancer. 2010.
  • Wijnhoven BP, Hussey DJ, Watson DI, Tsykin A, Smith CM, Michael MZ. MicroRNA profiling of Barrett’s oesophagus and oesophageal adenocarcinoma. Br J Surg. 2010; 97: 853–61.
  • Gudas LJ, Wagner JA. Retinoids regulate stem cell differentiation. J Cell Physiol. 2011; 226: 322–30.
  • Hu D, Wan Y. Regulation of Kruppel-like factor 4 by the anaphase promoting complex pathway is involved in TGF-beta signaling. J Biol Chem. 2011; 286: 6890–901.
  • Kazumori H, Ishihara S, Takahashi Y, Amano Y, Kinoshita Y. Roles of Kruppel-like factor 4 in oesophageal epithelial cells in Barrett’s epithelium development. Gut. 2011; 60: 608–17.
  • Zheng H, Pritchard DM, Yang X et al. KLF4 gene expression is inhibited by the notch signaling pathway that controls goblet cell differentiation in mouse gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol. 2009; 296: G490–8.
  • Van DH, Sousa RF. Transcription: the way to Barrett’s metaplasia. Adv Exp Med Biol. 2016; 908: 183-212.
  • Jin RU, Mills JC. Are gastric and esophageal metaplasia relatives,the case for Barrett's stemming from SPEM. Dig Dis Sci. 2018; 63: 2028–2041.
  • Lizhe Zhuang & Rebecca C. Fitzgerald Origins in the oesophagus. Nature. 2017; 550: 463–464.
  • Jiang M, Li H, Zhang Y et al. Transitional basal cells at the squamous-columnar junction generate Barrett’s oesophagus. Nature. 2017; 550: 529–533.
  • Asanuma K, Huo X, Agoston A, Zhang X, Yu C, Cheng E, Zhang Q, Dunbar KB, Pham TH, Wang DH, Iijima K, Shimosegawa T, Odze RD, Spechler SJ, Souza RF: In oesophageal squamous cells, nitric oxide causes s-nitrosylation of akt and blocks Sox2 (sex determining region y-box 2) expression. Gut 2015.
  • Kusaka G, Uno K, Iijima K, Shimosegawa T. Role of nitric oxide in the pathogenesis of Barrett’s-associated carcinogenesis. World J Gastrointest Pathophysiol. 2016 Feb 15; 7(1): 131–137.
  • Fujiya T, Asanuma K, Koike T, Okata T, Saito M, Asano N, Imatani A, Masamune A. Nitric oxide could promote development of Barrett's esophagus by S-nitrosylation-induced inhibition of Rho-ROCK signaling in esophageal fibroblasts. Am J Physiol Gastrointest Liver Physiol. 2022; 322 (1): G107-G116.
  • Wang DH. Souza RF. Transcommitment: paving the way to Barrett's metaplasia. Adv Exp Med Biol. 2016; 908: 183-21.