A Summary of the 2016 James W. Freston Conference of the American Gastroenterological Association: Intestinal Metaplasia in the Esophagus and Stomach: Origins, Differences, Similarities and Significance
2017; Elsevier BV; Volume: 153; Issue: 1 Linguagem: Inglês
10.1053/j.gastro.2017.05.050
ISSN1528-0012
AutoresStuart J. Spechler, Juanita L. Merchant, Timothy C. Wang, Parakrama Chandrasoma, James G. Fox, Robert M. Genta, James R. Goldenring, Yoku Hayakawa, Ernst J. Kuipers, P. Kay Lund, Frank McKeon, Jason C. Mills, Robert D. Odze, Richard M. Peek, Thai H. Pham, Jianwen Que, Anil K. Rustgi, Nicholas J. Shaheen, Ramesh A. Shivdasani, Rhonda F. Souza, Peter Störz, Andrea Todisco, David H. Wang, Nicholas A. Wright,
Tópico(s)Gastric Cancer Management and Outcomes
ResumoMetaplasia, wherein 1 type of adult tissue replaces another, is a consequence of chronic inflammation.1Corbett J.L. Tosh D. Conversion of one cell type into another: implications for understanding organ development, pathogenesis of cancer and generating cells for therapy.Biochem Soc Trans. 2014; 42: 609-616Crossref PubMed Scopus (11) Google Scholar Presumably, metaplasias develop and persist because they are more adept than the native tissue at resisting injury from the underlying inflammatory condition. In the stomach, intestinal metaplasia develops in the setting of chronic Helicobacter pylori gastritis, whereas intestinal metaplasia in the esophagus results from chronic esophagitis caused by gastroesophageal reflux disease (GERD). Limited dialogue between investigators studying intestinal metaplasia in the stomach and those studying it in the esophagus has been a barrier to progress in understanding these conditions. The 2016 James W. Freston Conference of the American Gastroenterological Association was unique in bringing these groups together. Senior investigators delivered lectures on basic and clinical features of intestinal metaplasia in the esophagus and stomach, and young faculty and trainees gave oral and poster presentations. Robert Genta reviewed the histologic features of intestinal metaplasia, and Jason Mills provided a historical overview, noting that Rudolph Virchow coined the term "metaplasia" at the VIIIth International Medical Congress in Copenhagen in 1884. In 1900, the pathologist George Adami presciently contended that there are "mother" (stem) cells that regenerate normal tissue and, "under abnormal conditions, the fully differentiated functioning cells of certain tissues are capable of proliferation and giving rise to cells of like nature, but this is only after a preliminary reversion to a simpler, more embryonic type." Adami proposed that this process of dedifferentiation leading to increased proliferation might result in "glandular cancer."2Adami J.G. On growth and overgrowth and on the relationship between cell differentiation and proliferative capacity; its bearing upon the regeneration of tissues and the development of tumors, in "Festschrift" in Honor of Abraham Jacobi.in: Huber F. Sondern F.E. The Knickerbocker Press, New York1900: 422-432Google Scholar During the 1930s, developmental biologists largely abandoned Adami's concepts, instead embracing Conrad Waddington's notion that stem cell differentiation was unidirectional. However, recent evidence vindicates Adami, showing that differentiated cells can indeed contribute to metaplasia. Stuart Spechler reviewed how concepts about intestinal metaplasia have evolved. Early investigators thought intestinal epithelium in the stomach was congenital, and not until the 1930s did it become widely regarded as a metaplasia caused by gastritis.3Morson B.C. Intestinal metaplasia of the gastric mucosa.Br J Cancer. 1955; 9: 365-376Crossref PubMed Scopus (144) Google Scholar In the 1970s, Japanese pathologists categorized intestinal metaplasia associated with gastric cancer as "complete" or "incomplete" based on how closely it resembled normal small intestine.4Kawachi T. Kurisu M. Numanyu N. et al.Precancerous changes in the stomach.Cancer Res. 1976; 36: 2673-2677PubMed Google Scholar In the 1980s, Jass and Filipe5Jass J.R. Filipe M.I. The mucin profiles of normal gastric mucosa, intestinal metaplasia and its variants and gastric carcinoma.Histochem J. 1981; 13: 931-939Crossref PubMed Scopus (162) Google Scholar used mucin immunohistochemistry to categorize 2 types of intestinal metaplasia in the stomach. Type I was histologically "complete," comprising absorptive cells and goblet cells expressing sialomucins. Type II was "incomplete," comprising goblet cells and gastric foveolar-like cells, and subcategorized as IIB if it expressed colonic-type sulfomucins, and as IIA if it did not. Esophageal researchers instead used terms like "specialized columnar epithelium" and "specialized intestinal metaplasia" to categorize the incomplete intestinal metaplasia of Barrett's esophagus. By the 1980s, it had become accepted that chronic reflux esophagitis resulted in intestinal metaplasia that predisposed to esophageal adenocarcinoma.6Spechler S.J. Goyal R.K. Barrett's esophagus.N Engl J Med. 1986; 315: 362-371Crossref PubMed Scopus (761) Google Scholar In the 1990s, Pelayo Correa proposed that chronic H pylori gastritis caused the intestinal metaplasia that predisposed to gastric adenocarcinoma.7Correa P. Human gastric carcinogenesis: a multistep and multifactorial process—first American Cancer Society Award Lecture on Cancer Epidemiology and Prevention.Cancer Res. 1992; 52: 6735-6740PubMed Google Scholar Ernst Kuipers reviewed data on cancer risk for intestinal metaplasia. Recent, population-based studies describe esophageal adenocarcinoma incidence rates for Barrett's esophagus in the range of 1.2 to 1.6 per 1,000 patient-years.8de Jonge P.J.F. van Blankenstein M. Looman C.W.N. et al.Risk of malignant progression in patients with Barrett's oesophagus: a Dutch nationwide cohort study.Gut. 2010; 59: 1030-1036Crossref PubMed Scopus (233) Google Scholar, 9Bhat 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 (514) Google Scholar, 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 (1025) Google Scholar Dr Kuipers debunked the popular notion that intestinal metaplasia in the stomach has a lower cancer risk than in Barrett's esophagus, noting a study of 97,837 Dutch patients with preneoplastic gastric lesions that found a gastric cancer incidence of 4 per 1000 patient-years,11de Vries A.C. van Grieken N.C.T. Looman C.W.N. et al.Gastric cancer risk in patients with premalignant gastric lesions: a nationwide cohort study in the Netherlands.Gastroenterology. 2008; 134: 945-952Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar with similar incidence rates found in cohorts from the United States and Sweden.12Song H. Ekheden I.G. Zheng Z. et al.Incidence of gastric cancer among patients with gastric precancerous lesions: observational cohort study in a low risk Western population.BMJ. 2015; 351: h3867Crossref PubMed Scopus (48) Google Scholar, 13Li D. Bautista M.C. Jiang S.-F. et al.Risks and predictors of gastric adenocarcinoma in patients with gastric intestinal metaplasia and dysplasia: A population-based study.Am J Gastroenterol. 2016; 111: 1104-1113Crossref PubMed Scopus (72) Google Scholar As in the esophagus, cancer risk in the stomach is proportional to the extent of intestinal metaplasia. Therefore, physicians should consider endoscopic surveillance for patients with extensive gastric intestinal metaplasia (involving both the antrum and the fundus).14Dinis-Ribeiro M. Areia M. de Vries A.C. et al.Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa.Endoscopy. 2012; 44: 74-94Crossref PubMed Scopus (538) Google Scholar, 15Sugano K. Tack J. Kuipers E.J. et al.Kyoto global consensus report on Helicobacter pylori gastritis.Gut. 2015; 64: 1353-1367Crossref PubMed Scopus (940) Google Scholar Surveillance can lead to early detection of gastric cancer and improved survival, but data showing that endoscopists miss 1 out of 9 early cancers suggest that recognition of these early lesions needs improvement.16Menon S. Trudgill N. How commonly is upper gastrointestinal cancer missed at endoscopy? A meta-analysis.Endosc Int Open. 2014; 2: E46-E50Crossref PubMed Google Scholar Robert Odze explained that Barrett's metaplasia has (1) a surface/crypt epithelial compartment with columnar cells exhibiting variable degrees of gastric and intestinal differentiation, and (2) an underlying glandular compartment composed of mucus glands, oxyntic glands, or both. Although goblet cells have been considered the sine qua non for Barrett's intestinal metaplasia, Dr Odze noted that esophageal nongoblet columnar epithelium also expresses transcription factors of intestinal differentiation.17Hahn 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 (124) Google Scholar Furthermore, goblet cells can be missed by biopsy sampling error,18Harrison 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 (195) Google Scholar and nongoblet esophageal cells can be mistaken for goblet cells, resulting in false-negative and false-positive Barrett's diagnoses, respectively.19Naini B.V. Souza R.F. Odze R.D. Barrett's Esophagus: A comprehensive and contemporary review for pathologists.Am J Surg Pathol. 2016; 40: e45-e66Crossref PubMed Scopus (73) Google Scholar Nongoblet esophageal columnar epithelium can exhibit DNA content abnormalities,20Liu 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 (153) Google Scholar and a recent report found an inverse association between goblet cell density in Barrett's metaplasia and risk of esophageal adenocarcinoma.21Srivastava A. Golden K.L. Sanchez C.A. et al.High goblet cell count is inversely associated with ploidy abnormalities and risk of adenocarcinoma in Barrett's esophagus.PLoS One. 2015; 10: e0133403Crossref PubMed Scopus (18) Google Scholar Dr Odze noted that it is inaccurate to call esophageal nongoblet columnar epithelium "cardiac epithelium," because it is the underlying mucus gland compartment that identifies mucosa as cardiac type (not the surface/crypt epithelium). He concluded that goblet cells are not a consistent, sensitive, or specific biomarker for Barrett's esophagus or its cancer risk. Nicholas Shaheen explained why it is difficult to estimate the cancer risk for cardiac mucosa without goblet cells. Despite the high prevalence of this mucosal type in the general population,22Nakanishi Y. Saka M. Eguchi T. et al.Distribution and significance of the oesophageal and gastric cardiac mucosae: a study of 131 operation specimens.Histopathology. 2007; 51: 515-519Crossref PubMed Scopus (38) Google Scholar, 23Robertson E.V. Derakhshan M.H. Wirz A.A. et al.Central obesity in asymptomatic volunteers is associated with increased intrasphincteric acid reflux and lengthening of the cardiac mucosa.Gastroenterology. 2013; 145: 730-739Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar studies on its cancer risk have focused largely on patients with GERD symptoms who have cardiac mucosa extending above the gastric folds into the esophagus. It is unclear if their cancer risk differs from asymptomatic individuals with cardiac epithelium at a normally positioned Z-line. Furthermore, some studies have found a cancer risk similar to that for Barrett's patients, whereas others have shown a much lower cancer risk.24Chandrasoma P. Wijetunge S. DeMeester S. et al.Columnar-lined esophagus without intestinal metaplasia has no proven risk of adenocarcinoma.Am J Surg Pathol. 2012; 36: 1-7Crossref PubMed Scopus (55) Google Scholar, 25Bhat 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 (480) Google Scholar, 26Takubo 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: 65-74Crossref PubMed Scopus (172) Google Scholar, 27Kelty 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 (150) Google Scholar The reasons for these discrepancies are unclear, but may include inadequate biopsy sampling (misclassifying patients as intestinal metaplasia-negative),28Pereira A.D. Chaves P. Columnar-lined oesophagus without intestinal metaplasia: results from a cohort with a mean follow-up of 7 years.Aliment Pharmacol Ther. 2012; 36: 282-289Crossref PubMed Scopus (23) Google Scholar, 29Gatenby P.A.C. Ramus J.R. Caygill C.P.J. et al.Relevance of the detection of intestinal metaplasia in non-dysplastic columnar-lined oesophagus.Scand J Gastroenterol. 2008; 43: 524-530Crossref PubMed Scopus (119) Google Scholar small study sample sizes, and short durations of follow-up. Dr Shaheen concluded that, presently, no blanket recommendation for surveillance of patients with cardiac mucosa is advisable. Parakrama Chandrasoma presented his controversial contention that cardiac mucosa without goblet cells is never normal and always metaplastic, irrespective of whether it is found above or below the endoscopically identified gastroesophageal junction. He cited a study showing that cardiac mucosa exhibits the same morphologic and molecular features irrespective of its location,30Derakhshan M.H. Robertson E.V. Lee Y.Y. et al.In healthy volunteers, immunohistochemistry supports squamous to columnar metaplasia as mechanism of expansion of cardia, aggravated by central obesity.Gut. 2015; 64: 1705-1714Crossref PubMed Scopus (24) Google Scholar and discussed reasons to believe that cardiac mucosa represents a squamous-to-columnar metaplasia of the esophagus caused by GERD.31Chandrasoma P.T. Histologic definition of gastro-esophageal reflux disease.Curr Opin Gastroenterol. 2013; 29: 460-467Crossref PubMed Scopus (18) Google Scholar Endoscopists demarcate the gastroesophageal junction at the top of gastric folds, but Dr Chandrasoma argued that this is an unreliable landmark in GERD patients in whom the distal esophagus has dilated and developed rugal-like folds easily mistaken for gastric folds.32Robertson E.V. Derakhshan M.H. Wirz A.A. et al.Central obesity in asymptomatic volunteers is associated with increased intrasphincteric acid reflux and lengthening of the cardiac mucosa.Gastroenterology. 2013; 145: 730-739Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 33Chandrasoma P. Wijetunge S. Ma Y. et al.The dilated distal esophagus: a new entity that is the pathologic basis of early gastroesophageal reflux disease.Am J Surg Pathol. 2011; 35: 1873-1881Crossref PubMed Scopus (29) Google Scholar Dr Chandrasoma proposed that the finding of cardiac mucosa might be used as an objective, histologic marker for the presence of GERD. Anil Rustgi explained that the esophagus has a prototypical stratified squamous epithelium with proliferative basal cells abutting the basement membrane. These basal cells undergo lineage allocation as they migrate toward the epithelial surface, becoming early differentiated suprabasal cells and terminally differentiated superficial squamous cells that ultimately desquamate. Experiments performed by Dr Veronique Giroux have identified a murine esophageal progenitor cell population.34Giroux V. Lento A. Islam M. et al.Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration.J Clin Invest. 2017 May 8; ([Epub ahead of print])Crossref PubMed Scopus (55) Google Scholar Using genetic in vivo lineage tracing, she found that the keratin 15 (Krt15) promoter marked a long-lived basal cell population capable of allocating all stages of differentiation, and that genetic depletion of Krt15 lineage-labeled cells resulted in decreased proliferation and epithelial atrophy. Radioresistant Krt15+ cells fostered regeneration following radiation-induced esophageal injury, and Krt15+ cells in 3-dimensional organoids exhibited enhanced clonogenicity. Dr Rustgi concluded that this Krt15+ long-lived progenitor cell population might constitute an esophageal stem cell population. Expanding on his earlier discussion that metaplasias can develop when mature cells dedifferentiate and proliferate, Jason Mills discussed the contribution of factors like the basic helix–loop–helix transcription factor MIST1 to this process.35Lo H.G. Jin R.U. Sibbel G. et al.A single transcription factor is sufficient to induce and maintain secretory cell architecture.Genes Dev. 2017; 31: 154-171Crossref PubMed Scopus (48) Google Scholar Increased expression of these factors can scale up a cell's energy use toward maintaining an elaborate secretory apparatus (differentiated status), whereas decreased expression can scale down these processes as the cell undergoes dedifferentiation and reversion to a proliferative state. Dr Mills also discussed evidence that quiescent, differentiated cells are recruited back into the cell cycle during metaplasia via an evolutionarily conserved, invariant sequence of steps. Each step can be blocked by pharmacologic inhibitors or by genetic modifications in mice. Yoku Hayakawa discussed his observation that Mist1 messenger RNA is expressed, not only in gastric chief cells, but also in quiescent stem cells in the isthmus of gastric corpus glands.36Hayakawa Y. Ariyama H. Stancikova J. et al.Mist1 expressing gastric stem cells maintain the normal and neoplastic gastric epithelium and are supported by a perivascular stem cell niche.Cancer Cell. 2015; 28: 800-814Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar Chief cell ablation experiments suggest that it is Mist1+ isthmus stem cells (not Mist1+ chief cells) that are responsible for long-term lineage tracing in the gastric corpus. With the induction of mutant Kras, Mist1+ isthmus stem cells serve as the cell of origin for intestinal metaplasia, and give rise to both intestinal-type and diffuse-type gastric cancers when they lose Apc and E-cadherin, respectively. Dr Hayakawa concluded that Mist1+ stem cells in the isthmus of gastric glands likely are the main source of metaplasia and cancers in the stomach. Kay Lund described a Sox9-EGFP reporter mouse model that identifies intestinal epithelial cell subtypes by their levels of Sox9-EGFP expression. These include (1) "actively cycling" intestinal epithelial stem cells (IESC; Sox9-EGFPLow), (2) IESC progenitors (Sox9-EGFPSublow), (3) enteroendocrine cells (Sox9-EGFPHigh), and (4) differentiated enterocytes, Paneth cells, and goblet cells (Sox9-EGFPNegative). After intestinal injury, a reserve population of Sox9-EGFPHigh cells is activated to fuel expansion of Sox9-EGFPLow IESC during regeneration.37Van Landeghem L. Santoro A.M. Krebs A.E. et al.Activation of two distinct Sox9-EGFP expressing intestinal stem cell populations during crypt regeneration after irradiation.Am J Physiol Gastrointest Liver Physiol. 2012; 302: G1111-G1132Crossref PubMed Scopus (112) Google Scholar IESC exhibit enrichment of insulin-like growth factor 1 receptor (IGF1R) and insulin receptor isoform-A, and sustained insulin receptor signaling seems to protect against adenomas, perhaps by inhibiting IGF1R signaling.38Andres S.F. Simmons J.G. Mah A.T. et al.Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation.J Cell Sci. 2013; 126: 5645-5656Crossref PubMed Scopus (48) Google Scholar, 39Santoro M.A. Andres S.F. Galanko J.A. et al.Reduced insulin-like growth factor I receptor and altered insulin receptor isoform mRNAs in normal mucosa predict colorectal adenoma risk.Cancer Epidemiol Biomarkers Prev. 2014; 23: 2093-2100Crossref PubMed Scopus (13) Google Scholar MicroRNA (miR375), which has been linked both to cancer and IGF1R regulation, is enriched in IESC and can limit their proliferation.40Peck B.C. Mah A.T. Pitman W.A. et al.Functional transcriptomics in diverse intestinal epithelial cell types reveals robust MicroRNA sensitivity in intestinal stem cells to microbial status.J Biol Chem. 2017; 292: 2586-2600Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Dr Lund concluded that maintained expression and function of insulin receptors might regulate IESC and prevent adenomas, potentially by inhibiting IGF1R, and that miR375 could be a new target to limit IESC proliferation and tumor growth. Peter Storz discussed how studies on pancreatic acinar-to-ductal metaplasia (ADM) might be applied to intestinal metaplasia in the esophagus and stomach. In the pancreas, inflammatory macrophages produce factors such as tumor necrosis factor, IL-6, and RANTES that contribute to ADM development.41Lesina M. Kurkowski M.U. Ludes K. et al.Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer.Cancer Cell. 2011; 19: 456-469Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar, 42Liou G.Y. Doppler H. Necela B. et al.Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-kappaB and MMPs.J Cell Biol. 2013; 202: 563-577Crossref PubMed Scopus (174) Google Scholar This ADM becomes irreversible when it acquires an oncogenic KRas mutation, and neoplastic progression occurs in synergy with inflammation.43Guerra C. Collado M. Navas C. et al.Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence.Cancer Cell. 2011; 19: 728-739Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar Nonneoplastic ADM is associated predominantly with inflammatory macrophages, but alternatively activated macrophages, which can drive fibrosis and lesion growth, become more plentiful as neoplasia develops.44Storz P. Acinar cell plasticity and development of pancreatic ductal adenocarcinoma.Nat Rev Gastroenterol Hepatol. 2017; 14: 296-304Crossref PubMed Scopus (147) Google Scholar Interleukins released by cells in precancerous ADM lesions initiate this phenotypic switch in macrophage populations. Thus, using the pancreas as an example, Dr Storz implicated inflammation and inflammatory macrophages as initiators and drivers of the metaplasia–neoplasia sequence. David Wang reviewed unique anatomic features of the mice and rats used in metaplasia studies, noting that these rodents have a forestomach lined by squamous epithelium and an esophagus that lacks submucosal glands. The rodent esophagus joins stomach at the junction between squamous-lined forestomach and distal glandular stomach, and the squamocolumnar junction has a distinctive "first fundic gland" containing cells that express stem cell markers including LGR5 and DCLK-1.45Quante 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 (32) Google Scholar, 46Nam K.T. O'Neal R. Lee Y.S. et al.Gastric tumor development in Smad3-deficient mice initiates from forestomach/glandular transition zone along the lesser curvature.Lab Invest. 2012; 92: 883-895Crossref PubMed Scopus (27) Google Scholar Jianwen Que reviewed mechanisms controlling normal gastroesophageal embryonic development. Around embryonic days 9.5-11.0, live imaging reveals a saddle-like structure that separates esophagus and stomach from trachea and lung.47Que J. The initial establishment and epithelial morphogenesis of the esophagus: a new model of tracheal-esophageal separation and transition of simple columnar into stratified squamous epithelium in the developing esophagus.Wiley Interdiscip Rev Dev Biol. 2015; 4: 419-430Crossref PubMed Scopus (32) Google Scholar Genetic models suggest that transcription factors (eg, SOX2, NKX2.1) and signaling molecules (eg, Noggin, Wnt2/2b) are critical for establishing esophagus from foregut,48Zhang Y. Jiang M. Kim E. et al.Development and stem cells of the esophagus.Semin Cell Dev Biol. 2016 Dec 19; ([Epub ahead of print])Google Scholar after which esophageal lining changes from columnar into squamous epithelium under control of transcription factors like p63 and SOX2. A p63 gene deletion prevents this epithelial change, and SOX2 down-regulation causes esophageal progenitor cells to differentiate abnormally into mucin-secreting cells.48Zhang Y. Jiang M. Kim E. et al.Development and stem cells of the esophagus.Semin Cell Dev Biol. 2016 Dec 19; ([Epub ahead of print])Google Scholar, 49Que J. Okubo T. Goldenring J.R. et al.Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm.Development. 2007; 134: 2521-2531Crossref PubMed Scopus (386) Google Scholar Bmp signaling in the esophagus also is required for normal development of squamous epithelium.50Jiang M. Ku W.Y. Zhou Z. et al.BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis.J Clin Invest. 2015; 125: 1557-1568Crossref PubMed Scopus (66) Google Scholar In the stomach, multiple signaling pathways (eg, Bmp, Notch, Wnt) and transcription factors (eg, BARX1, NKX2.5, and GATA3) mediate the development of gastric glandular epithelia. Ramesh Shivdasani discussed how cellular identity is influenced by thousands of distant enhancers that regulate gene transcription, dictated by chromatin structure.51Kim T.H. Shivdasani R.A. Stomach development, stem cells and disease.Development. 2016; 143: 554-565Crossref PubMed Scopus (92) Google Scholar, 52Garber M. Yosef N. Goren A. et al.A high-throughput chromatin immunoprecipitation approach reveals principles of dynamic gene regulation in mammals.Mol Cell. 2012; 47: 810-822Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar His laboratory has mapped the enhancer landscape in Barrett's esophagus and in normal esophageal, gastric, and intestinal mucosae, elucidating how Barrett's metaplasia reflects an intestinal enhancer signature and lacks vestiges of an esophageal enhancer signature. In studies on tissue-specific enhancers delineated during mouse organogenesis, the Shivdasani laboratory has found that, although thousands of enhancers specific to adult esophageal and intestinal epithelia are fully demarcated by birth, those regions of chromatin appear equally poised for activation in both mucosal primordia early in development. Dr Shivdasani anticipates that these studies will help to elucidate the chromatin basis of intestinal metaplasia in esophagus and stomach. David Wang explained how transcommitment, the molecular reprogramming of a progenitor cell, is a possible mechanism whereby cells native to the esophagus could give rise to Barrett's metaplasia. Transcommitment of squamous epithelial progenitor cells into intestinal-type columnar cells likely requires a stepwise process that includes the down-regulation of squamous transcription factors, and sequential upregulation of columnar, intestinal, and mucus-associated transcription factors. Dr Wang also described potential roles for Hedgehog and downstream bone morphogenetic protein (BMP)-4 signaling pathways in regulating these transcription factors.53Wang D.H. Clemons N.J. Miyashita T. et al.Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett's metaplasia.Gastroenterology. 2010; 138: 1810-1822Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 54Hedgehog signaling regulates Foxa2 in esophageal embryogenesis and Barrett's metaplasia.J Clin Invest. 2014; 124: 3767-3780Crossref PubMed Scopus (66) Google Scholar Andrea Todisco explained that BMP signaling, which targets gastric epithelial cells in mice with Helicobacter gastritis, has important antiinflammatory actions and effects on gastrointestinal cell growth and differentiation.55Shinohara M. Mao M. Keeley T.M. et al.Bone morphogenetic protein signaling regulates gastric epithelial cell development and proliferation in mice.Gastroenterology. 2010; 139: 2050-2060Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 56Takabayashi H. Shinohara M. Mao M. et al.Anti-inflammatory activity of bone morphogenetic protein signaling pathways in stomachs of mice.Gastroenterology. 2014; 147: 396-406Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Mice genetically engineered to express noggin (a BMP inhibitor) in the stomach exhibit decreased parietal cell numbers, increased epithelial cell proliferation, and development of spasmolytic polypeptide-expressing metaplasia (SPEM).55Shinohara M. Mao M. Keeley T.M. et al.Bone morphogenetic protein signaling regulates gastric epithelial cell development and proliferation in mice.Gastroenterology. 2010; 139: 2050-2060Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 56Takabayashi H. Shinohara M. Mao M. et al.Anti-inflammatory activity of bone morphogenetic protein signaling pathways in stomachs of mice.Gastroenterology. 2014; 147: 396-406Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Noggin-expressing mice also show enhanced Helicobacter-induced inflammation and epithelial cell proliferation, accelerated dysplasia development, and increased expression of STAT3 and AID (molecules implicated in gastric tumorigenesis).56Takabayashi H. Shinohara M. Mao M. et al.Anti-inflammatory activity of bone morphogenetic protein signaling pathways in stomachs of mice.Gastroenterology. 2014; 147: 396-406Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar In isolated canine gastric epithelial cells, BMP4, BMP2, and BMP7 inhibit expression of IL8, a proinflammatory chemokine.56Takabayashi H. Shinohara M. Mao M. et al.Anti-inflammatory activity of bone morphogenetic protein signa
Referência(s)