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• W2763014843 abstract "Although researchers have identified genetic alterations that contribute to development of esophageal adenocarcinoma, we know little about features of patients or environmental factors that mediate progression of chronic acid biliary reflux to Barrett’s esophagus and cancer. Increasing our understanding of the mechanisms by which normal squamous epithelium progresses to early-stage invasive cancer will help formulate rational surveillance guidelines and allow us to divest resources away from patients at low risk of malignancy. We review the cellular and genetic alterations that occur during progression of Barrett’s esophagus, based on findings from clinical studies and mouse models of disease. We review the features of the luminal and mucosal microenvironment of Barrett’s esophagus that promote, in a small proportion of patients, development of esophageal adenocarcinoma. Markers of clonal evolution can be used to determine patient risk for cancer and set surveillance intervals. Although researchers have identified genetic alterations that contribute to development of esophageal adenocarcinoma, we know little about features of patients or environmental factors that mediate progression of chronic acid biliary reflux to Barrett’s esophagus and cancer. Increasing our understanding of the mechanisms by which normal squamous epithelium progresses to early-stage invasive cancer will help formulate rational surveillance guidelines and allow us to divest resources away from patients at low risk of malignancy. We review the cellular and genetic alterations that occur during progression of Barrett’s esophagus, based on findings from clinical studies and mouse models of disease. We review the features of the luminal and mucosal microenvironment of Barrett’s esophagus that promote, in a small proportion of patients, development of esophageal adenocarcinoma. Markers of clonal evolution can be used to determine patient risk for cancer and set surveillance intervals. Trevor A. GrahamView Large Image Figure ViewerDownload Hi-res image Download (PPT)Marnix JansenView Large Image Figure ViewerDownload Hi-res image Download (PPT) Although esophageal adenocarcinoma (EAC) is rare in many parts of the world, its incidence has increased 4%−10% each year in developed countries since the 1970s.1Brown L.M. Devesa S.S. Chow W.H. Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age.J Natl Cancer Inst. 2008; 100: 1184-1187Crossref PubMed Scopus (0) Google Scholar Median survival times are short, chiefly because most patients are diagnosed with advanced-stage disease that is not curable.2Hur C. Miller M. Kong C.Y. et al Trends in esophageal adenocarcinoma incidence and mortality.Cancer. 2013; 119: 1149-1158Crossref PubMed Scopus (149) Google Scholar EAC prevalence, therefore, closely follows its incidence. Barrett’s esophagus (BE), defined as replacement of the squamous epithelial lining native to the esophagus by metaplastic columnar epithelium, is a well-established risk factor for EAC.3Quante M. Abrams J.A. Lee Y. et al Barrett esophagus: what a mouse model can teach us about human disease.Cell Cycle. 2012; 11: 4328-4338Crossref PubMed Scopus (18) Google Scholar Acid biliary reflux from the stomach leads to development of BE, the initial step in progression to EAC, which can be tracked by histologic and genetic changes.4Spechler S.J. Fitzgerald R.C. Prasad G.A. et al History, molecular mechanisms, and endoscopic treatment of Barrett's esophagus.Gastroenterology. 2010; 138: 854-869Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The increase in EAC incidence appears to be a result of the increased prevalence of BE.5Corley D.A. Kubo A. Levin T.R. et al Race, ethnicity, sex and temporal differences in Barrett's oesophagus diagnosis: a large community-based study, 1994−2006.Gut. 2009; 58: 182-188Crossref PubMed Scopus (0) Google Scholar The exact population prevalence of BE is difficult to establish because this disease does not produce symptoms and because of the weak association between reflux complaints and BE.6Rubenstein J.H. Shaheen N.J. Epidemiology, diagnosis, and management of esophageal adenocarcinoma.Gastroenterology. 2015; 149: 302-317 e1Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Furthermore, the operative definition of BE is not consistent among expert guidelines, so the true prevalence is unclear.7Rubenstein J.H. The view of Barrett's esophagus from across the pond.Gastroenterology. 2014; 146: 1122-1123Abstract Full Text Full Text PDF PubMed Google Scholar Notwithstanding these caveats, population estimates of BE range from 1% to 5%.8Ronkainen J. Aro P. Storskrubb T. et al Prevalence of Barrett's esophagus in the general population: an endoscopic study.Gastroenterology. 2005; 129: 1825-1831Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 9Hayeck T.J. Kong C.Y. Spechler S.J. et al The prevalence of Barrett's esophagus in the US: estimates from a simulation model confirmed by SEER data.Dis Esophagus. 2010; 23: 451-457Crossref PubMed Scopus (69) Google Scholar Retrospective population-based studies found that rates of progression from BE to cancer range from 0.10% to 0.13% per year,10Hvid-Jensen F. Pedersen L. Drewes A.M. et al Incidence of adenocarcinoma among patients with Barrett's esophagus.N Engl J Med. 2011; 365: 1375-1383Crossref PubMed Scopus (639) Google Scholar, 11Bhat S. Coleman H.G. Yousef F. et al Risk of malignant progression in Barrett's esophagus patients: results from a large population-based study.J Natl Cancer Inst. 2011; 103: 1049-1057Crossref PubMed Scopus (325) Google Scholar indicating that BE is mostly a long-term benign condition.12Esserman L.J. Thompson I.M. Reid B. et al Addressing overdiagnosis and overtreatment in cancer: a prescription for change.Lancet Oncol. 2014; 15: e234-e242Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar Many patients in surveillance programs are therefore needlessly exposed to the risks and negative effects of routine screening. The flip side to this argument is that BE is an underdiagnosed condition because >85% of patients with newly diagnosed EAC have no history of either BE or heartburn complaints.6Rubenstein J.H. Shaheen N.J. Epidemiology, diagnosis, and management of esophageal adenocarcinoma.Gastroenterology. 2015; 149: 302-317 e1Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 13Cooper S.C. El-Agib A. Dar S. et al Endoscopic surveillance for Barrett's oesophagus: the patients' perspective.Eur J Gastroenterol Hepatol. 2009; 21: 850-854Crossref PubMed Scopus (11) Google Scholar For this reason, the clinical return (and cost−benefit) of BE surveillance programs is subject to scrutiny. Trials such as the British Barrett’s Oesophagus Surveillance Study and the BarrettNET registry (in Munich, Germany), comprising >5000 patients to be followed for more than 10 years, aim to compare all-cause and disease-specific mortality between patients who have been randomly assigned to groups that will undergo endoscopic surveillance every 2 years vs patients with a more conservative clinical follow-up. It is hoped that findings from these studies will provide some guidance on this issue.14Old O. Moayyedi P. Love S. et al Barrett's Oesophagus Surveillance versus Endoscopy at Need Study (BOSS): protocol and analysis plan for a multicentre randomized controlled trial.J Med Screen. 2015; 22: 158-164Crossref PubMed Google Scholar The sample size and length of follow-up of these trials are clear indications of the complexity and magnitude of this endeavor. In BE, the inflammatory microenvironment and somatic genomic alterations in stem cell populations are believed to mediate progression to EAC. We review the mechanisms by which these factors promote carcinogenesis based on findings from clinical studies15Stachler M.D. Taylor-Weiner A. Peng S. et al Paired exome analysis of Barrett's esophagus and adenocarcinoma.Nat Genet. 2015; 47: 1047-1055Crossref PubMed Scopus (72) Google Scholar, 16Dulak A.M. Stojanov P. Peng S. et al Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity.Nat Genet. 2013; 45: 478-486Crossref PubMed Scopus (314) Google Scholar, 17McDonald S.A. Lavery D. Wright N.A. et al Barrett oesophagus: lessons on its origins from the lesion itself.Nat Rev Gastroenterol Hepatol. 2015; 12: 50-60Crossref PubMed Google Scholar, 18Lavery D.L. Martinez P. Gay L.J. et al Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus.Gut. 2016; 65: 907-913Crossref PubMed Scopus (8) Google Scholar, 19et al Cancer Genome Atlas Research Network, Analysis Working Group: Asan UniversityIntegrated genomic characterization of oesophageal carcinoma.Nature. 2017; 541: 169-175Crossref PubMed Scopus (75) Google Scholar and mouse models of BE.20Quante M. Bhagat G. Abrams J.A. et al Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia.Cancer Cell. 2012; 21: 36-51Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 21Wang X. Ouyang H. Yamamoto Y. et al Residual embryonic cells as precursors of a Barrett's-like metaplasia.Cell. 2011; 145: 1023-1035Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar The adaptive nature of BE indicates that forces of natural selection act on tissue-specific stem cells, causing changes that lead to tumorigenesis. The seemingly straightforward histopathologic definition of BE as a metaplastic condition, whereby the native squamous epithelium of the distal esophagus is replaced with columnar epithelium belies a far more complex microscopic process. Biopsies from patients contain a range of columnar phenotypes. Despite emphasis on the cellular composition of the epithelium, the BE segment is organized, like all mucosal layers of the gastrointestinal tract, into a quasi-repetitive arrangement of glands. Every gland is maintained by a unique population of stem cells and can therefore be thought of as a singularly evolving unit within the mucosal sheet. These metaplastic glandular units have a variety of appearances. However, morphologies of the various types of glandular units do not vary within or among patients—they often resemble gland types found elsewhere in the gastrointestinal tract, in either healthy individuals or patients with gastrointestinal disease. The gland phenotype most commonly associated with BE has a mixed epithelial lining comprising scattered goblet cells against a background of columnar cells with properties that are indistinguishable from gastric foveolar cells (Figure 1A and B). This dual pattern of epithelial differentiation is reflected in its mucin core peptide and expression pattern of trefoil factor (TFF), with goblet cells producing the intestinal type mucin (mucin 2, oligomeric mucus/gel-forming, MUC2), as well as TFF3, whereas foveolar cells produce the gastric type mucin (MUC5AC) and TFF1.22Lavery D.L. Nicholson A.M. Poulsom R. et al The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands.Gut. 2014; 63: 1854-1863Crossref PubMed Scopus (17) Google Scholar These MUC proteins contain abundant oligosaccharide side chains, which allow these proteins to bind copious amounts of water after secretion into the gut lumen. These MUC proteins further self-aggregate, which creates a viscoelastic gel that coats the underlying epithelium.23Dixon J. Strugala V. Griffin S.M. et al Esophageal mucin: an adherent mucus gel barrier is absent in the normal esophagus but present in columnar-lined Barrett's esophagus.Am J Gastroenterol. 2001; 96: 2575-2583Crossref PubMed Google Scholar This peculiar pattern of mixed gastric and intestinal lineage differentiation has been widely described as specialized epithelium or specialized metaplasia, or, simply, intestinal metaplasia. Older publications referred to this as type II or type III incomplete intestinal metaplasia—terms that are now obsolete.24Reis C.A. David L. Correa P. et al Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression.Cancer Res. 1999; 59: 1003-1007PubMed Google Scholar In crypts in the small intestine and colon, stem cells reside strictly at the base of the gland and move up along the crypt (and villus) as they differentiate and mature. In BE glands, alternatively, the stem cell compartment is located about one-third up the height of the gland; mature cell lineages show bi-directional flow from this stem cell compartment toward the lumen, as well as toward the base of the gland. This was demonstrated in a study of patients with EAC scheduled for esophageal resection. Patients were given an infusion of a thymidine analogue at different time points before surgery.22Lavery D.L. Nicholson A.M. Poulsom R. et al The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands.Gut. 2014; 63: 1854-1863Crossref PubMed Scopus (17) Google Scholar Tracing the distribution of this indelible label in daughter cell populations confirmed bi-directional migration within BE glands and showed that cell migration toward the glandular base compartment of the gland occurred much more slowly than toward the superficial crypt compartment of the gland. The label had been all but lost from the superficial crypt population in little over a week, whereas nondividing cells that contained the thymidine analogue were detected for as long as 10 weeks after label infusion in the gland base population.25Quante M. Marrache F. Goldenring J.R. et al TFF2 mRNA transcript expression marks a gland progenitor cell of the gastric oxyntic mucosa.Gastroenterology. 2010; 139: 2018-2027 e2Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar The mucous base of the BE gland is lined by a population of columnar cells that express MUC6 and also secrete bicarbonate (HCO3−). This buffers the caustic refluxate and, together with the mucinous gel that covers the metaplastic mucosa, protects the lining of the distal esophagus. It is important to be aware of this functional compartmentalization to understand the unique functional properties of the BE gland.26McDonald S.A. Graham T.A. Lavery D.L. et al The Barrett's gland in phenotype space.Cell Mol Gastroenterol Hepatol. 2015; 1: 41-154Abstract Full Text Full Text PDF PubMed Google Scholar Expression of LGR5, a marker of stem cells, about one-third up the height of the gland, provides support for this location of the stem cell niche.22Lavery D.L. Nicholson A.M. Poulsom R. et al The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands.Gut. 2014; 63: 1854-1863Crossref PubMed Scopus (17) Google Scholar LGR5 messenger RNA is detected at the junction of the MUC5AC+ and TFF1+ cells and the MUC6+ and TFF2+ cells, the origin of the bi-directional cell flux and site of maximum proliferative activity (shown by immunohistochemical analysis for Ki-67, see Figure 1). These observations help us to understand the cells and their functions in the BE gland. It is important to note that this bi-directional compartmentalization is not unique to the metaplastic esophagus—it resembles the basic architecture of the pyloric gland in the normal gastric antrum. There are a small numbers of other gland types, which together constitute the metaplastic mosaic of the columnar esophagus (see Figure 2). Best studied of these is the cardiac gland (also transitional gland or non-goblet columnar gland). In essence, the epithelial lining and bi-directional architecture of the cardiac-type gland are identical to those of the BE gland, except for an absence of goblet cells in these glands. This makes the cardiac gland the simplest, in terms of differentiated epithelial cell types, of all BE gland types. The cardiac gland contains only MUC5AC+ and TFF1+ foveolar cells along the superficial crypt compartment and MUC6+ and TFF2+ cells along the mucous base. These glands have been studied extensively because they are the type most commonly found in biopsies of patients with short-segment BE and in biopsies from patients with columnar metaplasia of the neodistal esophagus after esophageal resection. This gland type may be the earliest detected during development of BE. It is also indistinguishable, in terms of glandular architecture and cell composition, from reparative glands (known as pseudopyloric metaplasia) found in, for example, terminal ileitis in patients with Crohn’s disease. The remaining gland types are variations on a theme. The cardiac-type gland may show oxyntic differentiation in the form of scattered parietal cells, at which point the gland is essentially comparable to similar glands found in the transitional mucosa of the gastric incisura or gastric pylorus (see Figure 2). Contrary to common belief, parietal cells are not restricted to corpus mucosa and are abundant in normal pyloric mucosa.27Choi E. Roland J.T. Barlow B.J. et al Cell lineage distribution atlas of the human stomach reveals heterogeneous gland populations in the gastric antrum.Gut. 2014; 63: 1711-1720Crossref PubMed Scopus (0) Google Scholar Mature chief cells are also found in these glands, which contain the complete complement of cell types normally found in the gastric body and fundus, although the irregular packing of these glands indicates that this is non-native, post-inflammatory mucosa. In many patients, these glands are found in the context of anatomic features of the esophagus, such as submucosal gland complexes, so these fundic-type glands develop as part of the metaplastic mosaic. It is important to determine whether these metaplastic oxyntic glands develop from cardiac glands and, if so, whether they are true stem-cell derived metaplasias or a manifestation of varying levels of oxyntic gland differentiation. Varying levels of differentiation of these archetypal gastric glands have important implications for the temporal dynamics of glandular metaplasia in the atrophic stomach. Some glands have mature intestinal differentiation, with Paneth cells at the base and enterocytes along the superficial crypt compartment (Figure 2). These are the only glands that completely lack gastric mucin core proteins; they are also the most rare of the gland types described. However, tissues from some patients have high levels of Paneth cell differentiation. Remarkably, the distribution of these gland phenotypes is not random—they appear in recurrent temporal and spatial patterns along the BE segment. Intestinal phenotypes are found more proximally at the squamocolumnar junction, whereas cardiac and oxyntocardiac gland phenotypes are proportionally more common around the gastroesophageal junction.28Paull A. Trier J.S. Dalton M.D. et al The histologic spectrum of Barrett's esophagus.N Engl J Med. 1976; 295: 476-480Crossref PubMed Google Scholar, 29Harrison R. Perry I. Haddadin W. et al Detection of intestinal metaplasia in Barrett's esophagus: an observational comparator study suggests the need for a minimum of eight biopsies.Am J Gastroenterol. 2007; 102: 1154-1161Crossref PubMed Scopus (133) Google Scholar, 30Going J.J. Fletcher-Monaghan A.J. Neilson L. et al Zoning of mucosal phenotype, dysplasia, and telomerase activity measured by telomerase repeat assay protocol in Barrett's esophagus.Neoplasia. 2004; 6: 85-92PubMed Google Scholar For example, Harrison et al29Harrison R. Perry I. Haddadin W. et al Detection of intestinal metaplasia in Barrett's esophagus: an observational comparator study suggests the need for a minimum of eight biopsies.Am J Gastroenterol. 2007; 102: 1154-1161Crossref PubMed Scopus (133) Google Scholar found that intestinal differentiation was almost twice as common in proximal biopsies taken near the squamocolumnar junction compared to the biopsies collected from the gastroesophageal junction, with a clear stepwise gradient in between. The density of glands containing intestinal differentiation correlates with the pH gradient along the BE segment; the less acidic the local average pH (closer to the squamocolumnar junction), the higher the proportion of glands with goblet cell differentiation.31Theodorou D. Ayazi S. DeMeester S.R. et al Intraluminal pH and goblet cell density in Barrett's esophagus.J Gastrointest Surg. 2012; 16: 469-474Crossref PubMed Scopus (0) Google Scholar The functional significance of this spatial distribution of gland phenotypes is unclear. We proposed that this distribution in gland types could result from local selection for cells that can survive in the harsh environment of the acid biliary refluxate at the distal esophagus.26McDonald S.A. Graham T.A. Lavery D.L. et al The Barrett's gland in phenotype space.Cell Mol Gastroenterol Hepatol. 2015; 1: 41-154Abstract Full Text Full Text PDF PubMed Google Scholar The soluble component of bile acids, which acts as a detergent and solubilizes lipid cell membranes through micelle formation, could be responsible for this environment. Studies of bile salt solubility found it to be greatest at intermediate luminal pH ranges seen most proximally, whereas bile acids are insoluble and therefore incapable of forming micelles at lower pH ranges in the distal esophagus.31Theodorou D. Ayazi S. DeMeester S.R. et al Intraluminal pH and goblet cell density in Barrett's esophagus.J Gastrointest Surg. 2012; 16: 469-474Crossref PubMed Scopus (0) Google Scholar, 32Bechi P. Cianchi F. Mazzanti R. et al Reflux and pH: ‘alkaline’ components are not neutralized by gastric pH variations.Dis Esophagus. 2000; 13: 51-55Crossref PubMed Scopus (8) Google Scholar In vitro studies have shown that solubilized duodenal bile salts are a strong inducer of CDX2 expression and goblet cell differentiation.33Ghatak S. Reveiller M. Toia L. et al Bile acid at low pH reduces squamous differentiation and activates EGFR signaling in esophageal squamous cells in 3-D culture.J Gastrointest Surg. 2013; 17: 1723-1731Crossref PubMed Scopus (2) Google Scholar, 34Clemons N.J. Wang D.H. Croagh D. et al Sox9 drives columnar differentiation of esophageal squamous epithelium: a possible role in the pathogenesis of Barrett's esophagus.Am J Physiol Gastrointest Liver Physiol. 2012; 303: G1335-G1346Crossref PubMed Scopus (0) Google Scholar, 35Bajpai M. Liu J. Geng X. et al Repeated exposure to acid and bile selectively induces colonic phenotype expression in a heterogeneous Barrett's epithelial cell line.Lab Invest. 2008; 88: 643-651Crossref PubMed Scopus (0) Google Scholar The pH gradient along the BE segment could therefore create a proximal–distal gradient of bile salt solubility, which could determine the relative proportion of specific gland phenotypes along the length of the esophagus. Temporal analysis of gland phenotype distribution is complicated because, in most patients, the BE segment is static over time and does not expand (or contract) despite years, or in some cases decades, of endoscopic follow-up evlaluations36Moawad F.J. Young P.E. Gaddam S. et al Barrett's oesophagus length is established at the time of initial endoscopy and does not change over time: results from a large multicentre cohort.Gut. 2015; 64: 1874-1880Crossref PubMed Scopus (4) Google Scholar—even in patients with continued esophageal exposure to acid biliary reflux.37Cameron A.J. Lomboy C.T. Barrett's esophagus: age, prevalence, and extent of columnar epithelium.Gastroenterology. 1992; 103: 1241-1245Abstract Full Text PDF PubMed Google Scholar However, patients that have undergone cardia-esophagectomy because of esophageal cancer lose normal sphincter function, which provokes severe gastroesophageal reflux. Consequently, about half of these patients develop columnar mucosa in the remnant distal esophagus de novo. Longitudinal studies found that the length of columnar mucosa increases over time and histopathologic analyses demonstrated that the glandular phenotype changes from purely cardiac-type mucosa to BE glands with intestinal differentiation.38Hamilton S.R. Yardley J.H. Regnerative of cardiac type mucosa and acquisition of Barrett mucosa after esophagogastrostomy.Gastroenterology. 1977; 72: 669-675Abstract Full Text PDF PubMed Google Scholar, 39O'Riordan J.M. Tucker O.N. Byrne P.J. et al Factors influencing the development of Barrett's epithelium in the esophageal remnant postesophagectomy.Am J Gastroenterol. 2004; 99: 205-211Crossref PubMed Scopus (0) Google Scholar, 40Castillo D. Puig S. Iglesias M. et al Activation of the BMP4 pathway and early expression of CDX2 characterize non-specialized columnar metaplasia in a human model of Barrett's esophagus.J Gastrointest Surg. 2012; 16 (discussion 237): 227-237Crossref PubMed Scopus (0) Google Scholar These observations indicate that the mucous cardiac-type gland is the earliest gland phenotype that develops in the reflux-damaged distal esophagus; it might change to either an intestinal (goblet cells and Paneth cells) or gastric (parietal and chief cells) lineage differentiation (Figure 2). In support of this model, some studies have shown cardiac-type glands to undergo early intestinalization, with submaximal levels of villin and CDX2 expression.41Hahn H.P. Blount P.L. Ayub K. et al Intestinal differentiation in metaplastic, nongoblet columnar epithelium in the esophagus.Am J Surg Pathol. 2009; 33: 1006-1015Crossref PubMed Scopus (99) Google Scholar, 42Srivastava A. Appelman H. Goldsmith J.D. et al The use of ancillary stains in the diagnosis of Barrett esophagus and Barrett esophagus-associated dysplasia: recommendations from the Rodger C. Haggitt Gastrointestinal Pathology Society.Am J Surg Pathol. 2017; 41: e8-e21Crossref PubMed Scopus (0) Google Scholar Studies have shown clonal ancestry of canonical specialized BE glands and non-intestinalized cardiac-type glands—these various phenotypes do not develop independently, but arise via phenotypic variation within glands derived from a common ancestor.18Lavery D.L. Martinez P. Gay L.J. et al Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus.Gut. 2016; 65: 907-913Crossref PubMed Scopus (8) Google Scholar Progression from cardiac-type glands to intestinalized epithelium was demonstrated in a mouse model of BE (EBV-L2-IL1B mice). These mice overexpress interleukin 1β (IL1B) in the esophageal and squamous forestomach epithelium, and develop spontaneous esophagitis that progresses to metaplasia at the gastroesophageal junction and adenocarcinoma with older age.20Quante M. Bhagat G. Abrams J.A. et al Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia.Cancer Cell. 2012; 21: 36-51Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar Addition of bile acids (0.2% deoxycholic acid) to their drinking water accelerates onset of intestinal metaplasia and tumorigenesis. Metaplastic esophageal tissues from these mice have increased levels of TFF2, CCKBR, MUC5AC, CDX2, and K19 compared to esophageal tissues of control mice. In EBV-L2-IL1B mice, bile acids led to demethylation of gene promotor regions, leading to increased expression of IL6, CDX2, and Notch,43Jankowski J.A. Wright N.A. Meltzer S.J. et al Molecular evolution of the metaplasia-dysplasia-adenocarcinoma sequence in the esophagus.Am J Pathol. 1999; 154: 965-973Abstract Full Text Full Text PDF PubMed Google Scholar, 44Kazumori H. Ishihara S. Rumi M.A. et al Bile acids directly augment caudal related homeobox gene Cdx2 expression in oesophageal keratinocytes in Barrett's epithelium.Gut. 2006; 55: 16-25Crossref PubMed Scopus (0) Google Scholar promoting commitment to the intestinal cell lineage. The earliest morphologic manifestation of glandular differentiation in the distal esophagus therefore appears to be the simple cardiac-type gland, which can evolve with time into either an intestinal or gastric cell glandular phenotype. What promotes columnar transformation of the distal esophagus when acid biliary reflux first hits the naïve squamous mucosa of the distal esophagus? This is a question of great contention and one on which opinion is sharply divided. Several models have been proposed, but 2 models have (arguably) been studied most. The transdifferentiation model proposes that squamous stem cells with chronic exposure to the corrosive effects of acid-biliary reflux slowly change their differentiation lineage, down-regulating the native squamous expression program and up-regulating a columnar cell expression program via up-regulation of lineage-determining factors, such as SOX9.34Clemons N.J. Wang D.H. Croagh D. et al Sox9 drives columnar differentiation of esophageal squamous epithelium: a possible role in the pathogenesis of Barrett's esophagus.Am J Physiol Gastrointest Liver Physiol. 2012; 303: G1335-G1346Crossref PubMed Scopus (0) Google Scholar, 45Huo X. Zhang X. Yu C. et al Aspirin prevents NF-kappaB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus.Gut. 2017 Apr 25; (pii: gutjnl-2016–313584) ([Epub ahead of print])https://doi.org/10.1136/gutjnl-2016-313584Crossref Google Scholar, 46Minacapelli C.D. Bajpai M. Geng X. et al Barrett's metaplasia develops from cellular reprograming of esop" @default.
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• W2763014843 date "2018-01-01" @default.
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• W2763014843 title "Insights Into the Pathophysiology of Esophageal Adenocarcinoma" @default.
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