Pathogenesis and Cells of Origin of Barrett's Esophagus

Que, Jianwen; Garman, Katherine S.; Souza, Rhonda F.; Spechler, Stuart J.

doi:10.1053/j.gastro.2019.03.072

Cited by 118 publications

(107 citation statements)

References 110 publications

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“…In SCCs, smoking cigarettes and drinking alcohol are the most well-known risk factors 70,80 . GERD is a strong risk factor for Barrett's adenocarcinoma; 68,72,81 however, GERD is also associated with an increased risk of SCC 74 . These same risk factors are also associated with Cox-2 overexpression; 74,82 thus, Cox-2 has long been considered a molecular target for esophageal cancer prevention [83][84][85] .…”

Section: The Role Of Cox-2 In Esophageal Tumorsmentioning

confidence: 99%

New insights into the functions of Cox-2 in skin and esophageal malignancies

2020

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Understanding the cellular and molecular mechanisms of tumor initiation and progression for each cancer type is central to making improvements in both prevention and therapy. Identifying the cancer cells of origin and the necessary and sufficient mechanisms of transformation and progression provide opportunities for improved specific clinical interventions. In the last few decades, advanced genetic manipulation techniques have facilitated rapid progress in defining the etiologies of cancers and their cells of origin. Recent studies driven by various groups have provided experimental evidence indicating the cellular origins for each type of skin and esophageal cancer and have identified underlying mechanisms that stem/progenitor cells use to initiate tumor development. Specifically, cyclooxygenase-2 (Cox-2) is associated with tumor initiation and progression in many cancer types. Recent studies provide data demonstrating the roles of Cox-2 in skin and esophageal malignancies, especially in squamous cell carcinomas (SCCs) occurring in both sites. Here, we review experimental evidence aiming to define the origins of skin and esophageal cancers and discuss how Cox-2 contributes to tumorigenesis and differentiation.

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Section: The Role Of Cox-2 In Esophageal Tumorsmentioning

confidence: 99%

New insights into the functions of Cox-2 in skin and esophageal malignancies

2020

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“…In summary, considerable debate continues on the cell of origin of Barrett's oesophagus, 82,83 though it is widely accepted that it is the requisite precursor lesion for the development of OAC. At least four candidate founder cells present themselves: basal cells of the squamous epithelium, stem cells of submucosal ducts, stem cells of the proximal stomach and transitional cells at the SCJ.…”

Section: Alisonmentioning

confidence: 99%

The cellular origins of cancer with particular reference to the gastrointestinal tract

Alison

2020

Int J Experimental Path

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Summary Stem cells or their closely related committed progenitor cells are the likely founder cells of most neoplasms. In the continually renewing and hierarchically organized epithelia of the oesophagus, stomach and intestine, homeostatic stem cells are located at the beginning of the cell flux, in the basal layer of the oesophagus, the isthmic region of gastric oxyntic glands and at the bottom of gastric pyloric‐antral glands and colonic crypts. The introduction of mutant oncogenes such as KrasG12D or loss of Tp53 or Apc to specific cell types expressing the likes of Lgr5 and Mist1 can be readily accomplished in genetically engineered mouse models to initiate tumorigenesis. Other origins of cancer are discussed including ‘reserve’ stem cells that may be activated by damage or through disruption of morphogen gradients along the crypt axis. In the liver and pancreas, with little cell turnover and no obvious stem cell markers, the importance of regenerative hyperplasia associated with chronic inflammation to tumour initiation is vividly apparent, though inflammatory conditions in the renewing populations are also permissive for tumour induction. In the liver, hepatocytes, biliary epithelial cells and hepatic progenitor cells are embryologically related, and all can give rise to hepatocellular carcinoma and cholangiocarcinoma. In the exocrine pancreas, both acinar and ductal cells can give rise to pancreatic ductal adenocarcinoma (PDAC), although the preceding preneoplastic states are quite different: acinar‐ductal metaplasia gives rise to pancreatic intraepithelial neoplasia culminating in PDAC, while ducts give rise to PDAC via. mucinous cell metaplasia that may have a polyclonal origin.

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“…[1] A serious consequence of chronic GERD and its associated inflammatory and cellular stress is development of Barrett's esophagus (BE), a condition in which a metaplastic columnar epithelium with gastric and intestinal features replaces the normal stratified squamous esophageal epithelium. [2][3][4][5][6][7] BE, estimated to affect 5.6% of American adults, is most alarming because it is a significant risk factor for esophageal adenocarcinoma (EAC), an aggressive and deadly cancer with a five-year survival rate of only 19% that has increased in incidence by more than 400% since 1975. [3,4,8,9] Esophageal cancer is most often diagnosed after symptoms have appeared, marking an advanced stage of the disease.…”

Section: Introductionmentioning

confidence: 99%

“…Several mechanisms to explain BE have been proposed, but none have yet been definitively proven in human disease. [4][5][6][7] One possibility is that reflux-induced tissue damage and inflammation cause cellular reprogramming of esophageal stem/progenitor cells. [11][12][13][14] Cells residing in submucosal esophageal glands have also been identified as a possible BE origin.…”

Section: Introductionmentioning

confidence: 99%

GATA4, expressed in Barrett’s esophagus and esophageal adenocarcinoma, can block squamous epithelial cell gene expression in human esophageal cells

Stavniichuk

DeLaForest

Thompson

et al. 2020

Preprint

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Metaplasia often involves a change from one cell type to another that was present during organogenesis. The embryonic esophagus is initially lined by columnar cells that are replaced by squamous cells, and metaplasia in Barrett's esophagus (BE) involves a change from squamous to columnar cells in the setting of gastroesophageal reflux.Here, we explored the effect of ectopic expression of the essential developmental transcription factor GATA4 on squamous epithelial cell gene expression using human esophageal squamous epithelial cells. We found that GATA4 protein, although absent in mature human esophageal squamous epithelium, was present in BE and esophageal adenocarcinoma (EAC). Moreover, acid and bile induced GATA4 mRNA in esophageal squamous epithelial cells. Ectopic GATA4 expression in esophageal squamous epithelial cells generally compromised squamous cell marker gene expression, although the extent varied between cell lines studied. We observed GATA4 occupancy in the p63, KRT5, and KRT15 gene promoters, suggesting that GATA4 can directly repress expression of typical squamous epithelial cell marker genes. Overall, our data suggest a mechanism whereby GATA4 expression in abnormal esophageal cells, possibly induced by reflux, supports a columnar metaplastic cell identity by repressing expression of key genes required to program stratified squamous epithelial cell identity.

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Pathogenesis and Cells of Origin of Barrett's Esophagus

Cited by 118 publications

References 110 publications

New insights into the functions of Cox-2 in skin and esophageal malignancies

New insights into the functions of Cox-2 in skin and esophageal malignancies

The cellular origins of cancer with particular reference to the gastrointestinal tract

GATA4, expressed in Barrett’s esophagus and esophageal adenocarcinoma, can block squamous epithelial cell gene expression in human esophageal cells

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