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History, Molecular Mechanisms, and Endoscopic Treatment of Barrett's Esophagus

2010; Elsevier BV; Volume: 138; Issue: 3 Linguagem: Inglês

10.1053/j.gastro.2010.01.002

1528-0012

Stuart J. Spechler, Rebecca C. Fitzgerald, Ganapathy A. Prasad, Kenneth K. Wang,

Helicobacter pylori-related gastroenterology studies

This report is an adjunct to the American Gastroenterological Association Institute's medical position statement and technical review on the management of Barrett's esophagus, which will be published in the near future. Those documents will consider a number of broad questions on the diagnosis, clinical features, and management of patients with Barrett's esophagus, and the reader is referred to the technical review for an in-depth discussion of those topics. In this report, we review historical, molecular, and endoscopic therapeutic aspects of Barrett's esophagus that are of interest to clinicians and researchers. This report is an adjunct to the American Gastroenterological Association Institute's medical position statement and technical review on the management of Barrett's esophagus, which will be published in the near future. Those documents will consider a number of broad questions on the diagnosis, clinical features, and management of patients with Barrett's esophagus, and the reader is referred to the technical review for an in-depth discussion of those topics. In this report, we review historical, molecular, and endoscopic therapeutic aspects of Barrett's esophagus that are of interest to clinicians and researchers. Barrett's esophagus is a condition named for the late Norman Rupert Barrett, an influential esophageal surgeon who was born in Adelaide, Australia, in 1903.1Lord R.V. Norman Barrett, “doyen of esophageal surgery”.Ann Surg. 1999; 229: 428-439Crossref PubMed Google Scholar Barrett worked for most of his career as a consultant surgeon at St. Thomas' Hospital in London. He was a pioneer in the field of thoracic surgery and a charismatic academic leader who served for more than 25 years as editor of Thorax. By all accounts, Norman Barrett was an outstanding surgeon, scholar, and teacher. However, Norman Barrett was not the first to describe the condition that now bears his name; in fact, his original contentions about the nature and pathogenesis of the condition were incorrect. The eponym “Barrett's esophagus” continues to evoke confusion and controversy, and authorities still dispute the definition of the disorder.2Vakil N. van Zanten S.V. Kahrilas P. et al.Global Consensus GroupThe Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus.Am J Gastroenterol. 2006; 101: 1900-1920Crossref PubMed Scopus (1216) Google Scholar To appreciate these controversies, it is helpful to consider some key events in the relatively brief history of Barrett's esophagus. In 1950, Barrett published a treatise proposing that the esophagus should be defined as “that part of the foregut, distal to the cricopharyngeal sphincter, which is lined by squamous epithelium.”3Barrett N.R. Chronic peptic ulcer of the oesophagus and “oesophagitis”.Br J Surg. 1950; 38: 175-182Crossref PubMed Google Scholar He commented on earlier reports describing patients with ulcerations in a tubular organ that grossly appeared to be the esophagus but had a distal, ulcerated portion lined by columnar epithelium. Because Barrett had defined the esophagus by its squamous lining, he argued that the ulcerated, columnar-lined viscus described in those reports was a tubular segment of stomach that had been tethered within the chest by a congenitally short esophagus. To support that contention, Barrett noted that the ulcerated columnar lining always was identified as “histologically gastric in type.” Barrett himself claimed that peptic ulcer of the esophagus was first reported in 1839 by the German pathologist Albers.3Barrett N.R. Chronic peptic ulcer of the oesophagus and “oesophagitis”.Br J Surg. 1950; 38: 175-182Crossref PubMed Google Scholar However, credit for describing the columnar-lined esophagus probably should go to Wilder Tileston, a pathologist who, while working in Boston in 1906, described 3 cases of “peptic ulcer of the oesophagus” and noted “the close resemblance of the mucous membrane about the ulcer to that normally found in the stomach.”4Tileston W. Peptic ulcer of the oesophagus.Am J Med Sci. 1906; 132: 240-265Crossref Google Scholar Tileston wrote that “the first requisite for the formation of the peptic ulcer of the oesophagus is an insufficiency of the cardia” (ie, gastroesophageal reflux). Thus, almost a half-century before Barrett, Tileston described the columnar-lined esophagus and correctly attributed the pathogenesis of the associated ulceration to gastroesophageal reflux. In 1953, Allison and Johnstone described 7 patients who had reflux esophagitis involving an “oesophagus lined with gastric mucous membrane.”5Allison P.R. Johnstone A.S. The oesophagus lined with gastric mucous membrane.Thorax. 1953; 8: 87-101Crossref PubMed Google Scholar In this report, they refuted Barrett's contention that the tubular, intrathoracic, columnar-lined viscus was stomach. They noted that, unlike the stomach, the columnar-lined organ lacked a peritoneal covering, harbored islands of squamous epithelium, and had submucosal glands and a muscularis propria typical of the esophagus. In deference to Barrett, the editor of the journal to which they had submitted their report, Allison and Johnstone suggested that ulcerations in the columnar-lined esophagus should be called “Barrett's ulcers.” Barrett eventually accepted Allison and Johnstone's arguments and, in a report published in 1957, suggested that the condition should be called “lower oesophagus lined by columnar epithelium.”6Barrett N.R. The lower esophagus lined by columnar epithelium.Surgery. 1957; 41: 881-894PubMed Google Scholar Whether justified or not, the eponym “Barrett's esophagus” has been retained. In another influential report published in Thorax in 1961, an Australian surgeon named John Hayward elaborated his opinions on the histologic features of the distal esophagus.7Hayward J. The lower end of the oesophagus.Thorax. 1961; 16: 36-41Crossref PubMed Google Scholar He contended that the distal 1 to 2 cm of the esophagus is normally lined by a mucus-secreting, junctional epithelium (also called gastric cardia-type epithelium). Hayward argued that “… if squamous epithelium joined gastric epithelium of fundal [acid-secreting] type directly, it would be liable to digestion at the junction. The buffer zone of junctional epithelium, which does not secrete acid or pepsin but is resistant to them, has to be interposed.” Hayward provided no data to support his contentions, and Barrett remarked that Hayward's report contained “a lot of nonsense.”1Lord R.V. Norman Barrett, “doyen of esophageal surgery”.Ann Surg. 1999; 229: 428-439Crossref PubMed Google Scholar Nevertheless, Barrett published the report essentially unaltered, and it has had substantial influence on the course of studies on Barrett's esophagus. The histology of the columnar-lined esophagus remains a controversial issue to this day. Barrett, and virtually all of the investigators who wrote about the condition before he did, described an acid-secreting, gastric type of columnar epithelium lining the esophagus.3Barrett N.R. Chronic peptic ulcer of the oesophagus and “oesophagitis”.Br J Surg. 1950; 38: 175-182Crossref PubMed Google Scholar In 1951, Bosher and Taylor were the first to describe intestinal-type goblet cells in the columnar-lined esophagus.8Bosher L.H. Taylor F.H. Heterotopic gastric mucosa in the esophagus with ulceration and stricture formation.J Thorac Surg. 1951; 21: 306-312PubMed Google Scholar In 1952, Morson and Belcher reported a patient who had an adenocarcinoma in an esophageal mucosa that had “atrophic changes with a tendency towards intestinal type containing many goblet cells.”9Morson B.C. Belcher J.R. Adenocarcinoma of the esophagus and ectopic gastric mucosa.Br J Cancer. 1952; 6: 127-130Crossref PubMed Google Scholar Still other investigators described cardia-type epithelium in Barrett's esophagus.10Pedersen S.A. Hage E. Nielsen P.A. et al.Barrett's syndrome: morphological and physiological characteristics.Scand J Thorac Cardiovasc Surg. 1971; 6: 191-205Crossref Scopus (3) Google Scholar This confusing situation was clarified somewhat in 1976, when Paull et al reported a systematic study of 11 patients with Barrett's esophagus who had esophageal biopsy specimens taken above the lower esophageal sphincter using manometric guidance.11Paull 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 Those patients were found to have as many as 3 types of columnar epithelia lining the distal esophagus: (1) a junctional (cardia-type) epithelium that comprised mucus-secreting cells, (2) a gastric fundic-type epithelium with parietal and chief cells, and (3) intestinal-type metaplasia, which the authors called specialized columnar epithelium, with prominent goblet cells. The 3 epithelial types occupied different zones in the columnar-lined esophagus, with intestinal-type metaplasia adjacent to squamous epithelium in the most proximal segment, followed by cardia-type epithelium, with gastric fundic-type epithelium lining the most distal esophageal segment. By the 1970s, it was well established that Barrett's esophagus was associated with severe gastroesophageal reflux disease (GERD) and hiatal hernia,12Burgess J.N. Payne W.S. Andersen H.A. et al.Barrett esophagus: the columnar-epithelial-lined lower esophagus.Mayo Clin Proc. 1971; 46: 728-734PubMed Google Scholar, 13Naef A.P. Savary M. Ozzello L. Columnar-lined lower esophagus: an acquired lesion with malignant predisposition: report on 140 cases of Barrett's esophagus with 12 adenocarcinomas.J Thorac Cardiovasc Surg. 1975; 70: 826-834PubMed Google Scholar, 14Borrie J. Goldwater L. Columnar cell-lined esophagus: assessment of etiology and treatment: a 22 year experience.J Thorac Cardiovasc Surg. 1976; 71: 825-834PubMed Google Scholar conditions that can obscure the endoscopic landmarks used to identify the gastroesophageal junction. Endoscopists intent on collecting biopsy samples from the distal esophagus of patients with these disorders could mistakenly take those specimens from the proximal stomach, resulting in a spurious diagnosis of Barrett's esophagus lined by gastric-type epithelium. Further complicating diagnostic issues, Hayward had contended that even the normal esophagus could be lined by up to 2 cm of cardia-type epithelium.7Hayward J. The lower end of the oesophagus.Thorax. 1961; 16: 36-41Crossref PubMed Google Scholar Therefore, analysis of biopsy samples from this “normal” columnar mucosa also might result in a spurious diagnosis of Barrett's esophagus. These factors created major problems for investigators, because accurate diagnostic criteria are a prerequisite for a meaningful study of a disease. In the early 1980s, investigators intent on avoiding the problem of spurious diagnoses established diagnostic criteria for Barrett's esophagus based on an arbitrary extent of esophageal columnar lining above the gastroesophageal junction. For example, Skinner et al chose 3 cm as the extent of esophageal columnar lining required for patients to be enrolled in studies of Barrett's esophagus.15Skinner D.B. Walther B.C. Riddell R.H. et al.Barrett's esophagus: comparison of benign and malignant cases.Ann Surg. 1983; 198: 554-565Crossref PubMed Google Scholar These arbitrary, investigative criteria were eventually used by clinicians as diagnostic criteria. As a result, endoscopists often dismissed columnar epithelium limited to the distal few centimeters of the esophagus as normal and obtained biopsy specimens to confirm a diagnosis of Barrett's esophagus only when columnar lining extended some arbitrary distance (eg, >3 cm) above the gastroesophageal junction. Furthermore, endoscopists sought to identify Barrett's esophagus almost exclusively in patients who had symptoms and endoscopic signs of severe GERD. By adhering to such diagnostic guidelines, physicians minimized the problem of misdiagnosis but failed to identify short segments of metaplastic epithelium in the distal esophagus. By the 1980s, it was well established that adenocarcinoma was associated with Barrett's esophagus.16Adler R.H. The lower esophagus lined by columnar epithelium: its association with hiatal hernia, ulcer, stricture, and tumor.J Thorac Cardiovasc Surg. 1963; 45: 13-32PubMed Google Scholar, 17Hawe A. Payne W.S. Weiland L.H. Adenocarcinoma in the columnar epithelial lined lower (Barrett) esophagus.Thorax. 1973; 28: 511-514Crossref PubMed Google Scholar, 18Haggitt R.C. Tryzelaar J. Ellis F.H. et al.Adenocarcinoma complicating columnar epithelium-lined (Barrett's) esophagus.Am J Clin Pathol. 1978; 70: 1-5Crossref PubMed Google Scholar When reports of esophageal adenocarcinomas in patients with Barrett's esophagus provided a description of the associated Barrett's epithelium, they almost invariably identified that epithelium as intestinal-type metaplasia, usually with dysplastic features.19Haggitt R.C. Dean P.J. Adenocarcinoma in Barrett's epithelium.in: Spechler S.J. Goyal R.K. Barrett's esophagus: pathophysiology, diagnosis, and management. Elsevier, New York1985: 153-166Google Scholar By the late 1980s, intestinal metaplasia was widely regarded as both the most common type of Barrett's epithelium and the epithelial type associated with cancer development.20Reid B.J. Weinstein W.M. Barrett's esophagus and adenocarcinoma.Annu Rev Med. 1987; 38: 477-492Crossref PubMed Google Scholar, 21Reid B.J. Weinstein W.M. Lewin K.J. et al.Endoscopic biopsy can detect high-grade dysplasia or early adenocarcinoma in Barrett's esophagus without grossly recognizable neoplastic lesions.Gastroenterology. 1988; 94: 81-90PubMed Google Scholar Barrett's esophagus had little clinical importance outside of its malignant predisposition, and intestinal metaplasia was distinct in its histologic appearance (and, unlike the gastric types of Barrett's epithelia, clearly abnormal when located at the gastroesophageal junction). Consequently, some researchers chose to define Barrett's esophagus by the presence of intestinal metaplasia.22Reid B.J. Barrett's esophagus and esophageal adenocarcinoma.Gastroenterol Clin North Am. 1991; 20: 817-834PubMed Google Scholar, 23Weinstein W.M. Ippoliti A.F. The diagnosis of Barrett's esophagus: goblets, goblets, goblets.Gastrointest Endosc. 1996; 44: 91-95Abstract Full Text Full Text PDF PubMed Google Scholar This diagnostic criterion, arguably based more on convenience than on science, also was adopted into clinical practice. An esophageal biopsy specimen showing intestinal-type metaplasia had become virtually a sine qua non for the diagnosis of Barrett's esophagus by the early 1990s.22Reid B.J. Barrett's esophagus and esophageal adenocarcinoma.Gastroenterol Clin North Am. 1991; 20: 817-834PubMed Google Scholar Nevertheless, in the early 1990s, most endoscopists would not take esophageal biopsy specimens to seek a diagnosis of Barrett's esophagus unless their patients had GERD with some minimal extent of esophageal columnar lining (eg, at least 3 cm). That practice was challenged in 1994, when Spechler et al showed that 18% of consecutive patients in a general endoscopy unit who had columnar epithelium that involved <3 cm of the distal esophagus also had intestinal metaplasia.24Spechler S.J. Zeroogian J.M. Antonioli D.A. et al.Prevalence of metaplasia at the gastro-oesophageal junction.Lancet. 1994; 344: 1533-1536Abstract PubMed Scopus (458) Google Scholar Furthermore, they showed that symptoms and endoscopic signs of GERD were not reliable markers for intestinal metaplasia in the distal esophagus. Numerous subsequent studies confirmed that short segments of intestinal metaplasia frequently line the distal esophagus of individuals with no signs or symptoms of GERD.25Spechler S.J. The columnar lined oesophagus: a riddle wrapped in a mystery inside an enigma.Gut. 1997; 41: 710-711Crossref PubMed Google Scholar, 26Rex D.K. Cummings O.W. Shaw M. et al.Screening for Barrett's esophagus in colonoscopy patients with and without heartburn.Gastroenterology. 2003; 125: 1670-1677Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 27Ronkainen 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 (407) Google Scholar Since the late 1990s, therefore, Barrett's esophagus has been categorized as long segment (when the metaplastic epithelium extends at least 3 cm above the gastroesophageal junction) or short segment (when there is <3 cm of metaplastic epithelium lining the esophagus).28Sharma P. Morales T.G. Sampliner R.E. Short segment Barrett's esophagus The need for standardization of the definition and of endoscopic criteria.Am J Gastroenterol. 1998; 93: 1033-1036PubMed Google Scholar Thus, 5 decades after the publication of Norman Barrett's treatise, the diagnostic criteria for Barrett's esophagus had evolved from an esophagus lined extensively by gastric epithelium in patients with severe GERD to an esophagus lined by any extent of intestinal epithelium in patients who might not have GERD. A recent issue of contention is whether the presence of gastric cardia-type epithelium in the distal esophagus warrants a diagnosis of Barrett's esophagus.29Riddell R.H. Odze R.D. Definition of Barrett's esophagus: time for a rethink—is intestinal metaplasia dead?.Am J Gastroenterol. 2009; 104: 2588-2594Crossref PubMed Scopus (83) Google Scholar Recent guidelines from the British Society of Gastroenterology specifically state that only “columnar lined oesophagus on histology” (ie, cardia- or intestinal-type epithelium) is needed for the diagnosis of Barrett's esophagus.30Playford R.J. New British Society of Gastroenterology (BSG) guidelines for the diagnosis and management of Barrett's oesophagus.Gut. 2006; 55: 442Crossref PubMed Scopus (170) Google Scholar Data indicate that cardia-type epithelium is not normal, as Hayward had contended, but rather a metaplastic lining that develops as a consequence of GERD.31Chandrasoma P. Pathophysiology of Barrett's esophagus.Semin Thorac Cardiovasc Surg. 1997; 9: 270-278PubMed Google Scholar Histochemical and genetic studies of cardia-type epithelium have revealed molecular abnormalities, similar to those found in intestinal metaplasia, that could predispose patients to carcinogenesis,32Liu W. Hahn H. Odze R.D. et al.Metaplastic esophageal columnar epithelium without goblet cells shows DNA content abnormalities similar to goblet cell-containing epithelium.Am J Gastroenterol. 2009; 104: 816-824Crossref PubMed Scopus (87) Google Scholar, 33Hahn H.P. Blount P.L. Ayub K. et al.Intestinal differentiation in metaplastic, nongoblet columnar epithelium in the esophagus.Am J Surg Pathol. 2009 Apr 9; ([Epub ahead of print])Google Scholar and recent clinical studies support the concept that cardia-type epithelium has malignant potential.34Takubo K. Aida J. Naomoto Y. et al.Cardiac rather than intestinal-type background in endoscopic resection specimens of minute Barrett adenocarcinoma.Hum Pathol. 2009; 40: 65-74Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 35Kelty C.J. Gough M.D. Van Wyk Q. et al.Barrett's oesophagus: intestinal metaplasia is not essential for cancer risk.Scand J Gastroenterol. 2007; 42: 1271-1274Crossref PubMed Scopus (78) Google Scholar, 36Gatenby P.A. Ramus J.R. Caygill C.P. et al.Relevance of the detection of intestinal metaplasia in non-dysplastic columnar-lined oesophagus.Scand J Gastroenterol. 2008; 43: 524-530Crossref PubMed Scopus (68) Google Scholar This issue and others related to diagnostic criteria for Barrett's esophagus are discussed in detail in the AGA Institute's technical review on Barrett's esophagus, which recommends that Barrett's esophagus should now be defined as “the condition in which any extent of metaplastic columnar epithelium that predisposes to cancer development replaces the stratified squamous epithelium that normally lines the distal esophagus.” Physicians should consider how and when the diagnostic criteria for Barrett's esophagus changed when evaluating reports on the disorder. Short-segment Barrett's esophagus was not widely recognized until 1994,24Spechler S.J. Zeroogian J.M. Antonioli D.A. et al.Prevalence of metaplasia at the gastro-oesophageal junction.Lancet. 1994; 344: 1533-1536Abstract PubMed Scopus (458) Google Scholar and the vast majority of studies reported before that year included patients with only long-segment disease. More recent studies, however, include a substantial proportion of patients with short-segment Barrett's esophagus. Patients with short- and long-segment Barrett's esophagus can differ considerably in the severity of their associated GERD and risk of developing esophageal adenocarcinoma. It is therefore not appropriate to extrapolate the results of older studies on the epidemiology and natural history of Barrett's esophagus to patients with short-segment disease. Long-segment Barrett's esophagus is associated with GERD, and the epithelial metaplasia characteristic of Barrett's esophagus is widely regarded as a consequence of GERD (Figure 1A and B). Early investigators proposed that Barrett's esophagus developed from gastric columnar cells that migrated from the stomach into the esophagus to reconstitute GERD-damaged squamous epithelium.5Allison P.R. Johnstone A.S. The oesophagus lined with gastric mucous membrane.Thorax. 1953; 8: 87-101Crossref PubMed Google Scholar This hypothesis did not account for the intestinal metaplasia typical of Barrett's esophagus, however. The prevailing hypothesis now is that Barrett's esophagus forms when GERD damages the esophageal squamous epithelium, thereby exposing multipotential stem cells in the basal layers to refluxed gastric juice that stimulates abnormal differentiation.37Jankowski 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, 38Pera M. Pera M. Experimental Barrett's esophagus and the origin of intestinal metaplasia.Chest Surg Clin North Am. 2002; 12: 25-37Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 39Seery J.P. Stem cells of the oesophageal epithelium.J Cell Sci. 2002; 115: 1783-1789Crossref PubMed Google Scholar These progenitor cells may also be present in the ducts of esophageal mucosal glands.40Glickman J.N. Chen Y.Y. Wang H.H. et al.Phenotypic characteristics of a distinctive multilayered epithelium suggests that it is a precursor in the development of Barrett's esophagus.Am J Surg Pathol. 2001; 25: 569-578Crossref PubMed Scopus (126) Google Scholar One recent study has suggested that circulating stem cells of bone marrow origin might contribute to the development of Barrett's esophagus.41Sarosi G. Brown G. Jaiswal K. et al.Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett's esophagus.Dis Esophagus. 2008; 21: 43-50PubMed Google Scholar Although the progenitor cell for Barrett's esophagus remains unknown, metaplasias must arise from changes in cellular gene expression and, in Barrett's esophagus, those changes appear to be induced by GERD. Recent studies have reported molecular events in esophageal squamous epithelium that might be triggered by gastroesophageal reflux to cause Barrett's metaplasia. In esophageal squamous cell lines, for example, acid and bile induce the expression of caudal homeobox genes such as CDX1 and CDX2.42Hu Y. Williams V.A. Gellersen O. et al.The pathogenesis of Barrett's esophagus: secondary bile acids upregulate intestinal differentiation factor CDX2 expression in esophageal cells.J Gastrointest Surg. 2007; 11: 827-834Crossref PubMed Scopus (39) Google Scholar, 43Kazumori H. Ishihara S. Kinoshita Y. Roles of caudal-related homeobox gene Cdx1 in oesophageal epithelial cells in Barrett's epithelium development.Gut. 2009; 58: 620-628Crossref PubMed Scopus (34) Google Scholar, 44Pera M. Pera M. de Bolos C. et al.Duodenal-content reflux into the esophagus leads to expression of Cdx2 and Muc2 in areas of squamous epithelium in rats.J Gastrointest Surg. 2007; 11: 869-874Crossref PubMed Scopus (25) Google Scholar, 45Wong N.A. Wilding J. Bartlett S. et al.CDX1 is an important molecular mediator of Barrett's metaplasia.Proc Natl Acad Sci U S A. 2005; 102: 7565-7570Crossref PubMed Scopus (75) Google Scholar The word homeobox originates from the Greek homeosis, meaning a shift in structural development; homeobox genes encode transcription factors that regulate cell differentiation during embryogenesis. In adult cells, alterations in homeobox genes might alter cellular phenotypic features.46Beck F. The role of Cdx genes in the mammalian gut.Gut. 2004; 53: 1394-1396Crossref PubMed Scopus (46) Google Scholar, 47Souza R.F. Krishnan K. Spechler S.J. Acid, bile, and CDX: the ABCs of making Barrett's metaplasia.Am J Physiol Gastrointest Liver Physiol. 2008; 295: G211-G218Crossref PubMed Scopus (91) Google Scholar Homeobox gene expression in adult cells can be regulated epigenetically, such as through alterations in gene promoter methylation, or via cell signaling pathways regulated by factors such as bone morphogenetic proteins (BMPs) or fibroblast growth factors.45Wong N.A. Wilding J. Bartlett S. et al.CDX1 is an important molecular mediator of Barrett's metaplasia.Proc Natl Acad Sci U S A. 2005; 102: 7565-7570Crossref PubMed Scopus (75) Google Scholar, 48Liu T. Zhang X. So C.K. et al.Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells.Carcinogenesis. 2007; 28: 488-496Crossref PubMed Scopus (88) Google Scholar Compared with normal esophageal squamous epithelium, BMP4 expression is increased in Barrett's metaplasia; in a rat model of reflux-induced Barrett's esophagus, BMP4 expression is increased in the stroma that underlies the Barrett's metaplasia.49Milano F. van Baal J.W. Buttar N.S. et al.Bone morphogenetic protein 4 expressed in esophagitis induces a columnar phenotype in esophageal squamous cells.Gastroenterology. 2007; 132: 2412-2421Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Cultures of human esophageal squamous cells treated with BMP4 express cytokeratins that are characteristic of columnar cells.49Milano F. van Baal J.W. Buttar N.S. et al.Bone morphogenetic protein 4 expressed in esophagitis induces a columnar phenotype in esophageal squamous cells.Gastroenterology. 2007; 132: 2412-2421Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Bile acids, at neutral and acidic pH levels, cause a cancer cell line to express CDX2 through ligand-dependent transactivation of the epidermal growth factor receptor.50Avissar N.E. Toia L. Hu Y. et al.Bile acid alone, or in combination with acid, induces CDX2 expression through activation of the epidermal growth factor receptor (EGFR).J Gastrointest Surg. 2009; 13: 212-222Crossref PubMed Scopus (16) Google Scholar It was therefore proposed that GERD induces the expression of Cdx genes through BMP4 and, perhaps, epidermal growth factor receptor activation and that GERD-induced Cdx expression might partially mediate the development of Barrett's metaplasia.47Souza R.F. Krishnan K. Spechler S.J. Acid, bile, and CDX: the ABCs of making Barrett's metaplasia.Am J Physiol Gastrointest Liver Physiol. 2008; 295: G211-G218Crossref PubMed Scopus (91) Google Scholar Tumor initiation is the process in which cells are changed so that they are able to form tumors. Although GERD clearly plays a role in the pathogenesis of Barrett's metaplasia, it is not clear whether gastroesophageal reflux can initiate tumor formation in the metaplastic cells. Studies have shown that esophageal cells exposed to acid develop DNA double-strand breaks that might contribute to tumor initiation.51Clemons N.J. McColl K.E. Fitzgerald R.C. Nitric oxide and acid induce double-strand DNA breaks in Barrett's esophagus carcinogenesis via distinct mechanisms.Gastroenterology. 2007; 133: 1198-1209Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 52Zhang H.Y. Hormi-Carver K. Zhang X. et al.In benign Barrett's epithelial cells, acid exposure generates reactive oxygen species that cause DNA double strand breaks.Cancer Res. 2009; 69: 9083-9089Crossref PubMed Scopus (32) Google Scholar In addition, deoxycholic acid (a bile acid) induces DNA damage in a dose-dependent but nonlinear fashion.53Jenkins G.J. D'Souza F.R. Suzen S.H. et al.Deoxycholic acid at neutral and acid pH, is genotoxic to oesophageal cells through the induction of ROS: the potential role of anti-oxidants in Barrett's oesophagus.Carcinogenesis. 2007; 28: 136-142Crossref PubMed Scopus (63) Google Scholar, 54Jenkins G.J. Cronin J. Alhamdani A. et al.The bile acid deoxycholic acid has a non-linear dose response for DNA damage and possibly NF-kappaB activation in oesophageal cells, with a mechanism of action involving ROS.Mutagenesis. 2008; 23: 399-405Crossref PubMed Scopus (33) Google Scholar These DNA injuries appear to be mediated by reactive oxygen species, so antioxidants could have chemopreventive effects in patients with Barrett's esophagus. In addition to its potential role in initiating tumor development, GERD might also promote the growth of established neoplasms in Barrett's esophagus (a process called tumor promotion). Acid and bile exposure alter Barrett's cell kinetics55Fitzgerald R.C. Omary M.B. Triadafilopoulos G. Dynamic effects of acid on Barrett's esophagus An ex vivo proliferation and differentiation model.J Clin Invest. 1996; 98: 2120-2128Crossref PubMed Google Scholar, 56Fitzgerald R. Omary M. Triadafilopoulos G. Altered s