Gastroenterology

Gastroenterology

Volume 142, Issue 7, June 2012, Pages 1424-1430
Gastroenterology

Reviews and Perspectives
Imaging and Advanced Technology
Cellular Origin of Barrett's Esophagus: Controversy and Therapeutic Implications

https://doi.org/10.1053/j.gastro.2012.04.028Get rights and content

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Cellular Origin of Barrett's Metaplasia

It is estimated that between 1% and 2% of the US population has Barrett's esophagus, translating to an enormous figure of 3–4 million individuals nationwide with a heightened risk for lethal esophageal adenocarcinoma. Given the frequent acquisition of this metaplasia, it would seem a robust mechanism for its generation exists and at this point would have been well scrutinized and defined. In contrast with these expectations, the origins of Barrett's has gone through multiple renditions without

Origins of Barrett's Revisited

The weaknesses in the 3 models for the cell of origin of Barrett's esophagus and their limited predictive value signaled the need for additional models. We had previously cloned the p63 gene encoding a p53-like transcription factor and demonstrated that its expression was specific to stem cells of stratified epithelia including epidermis, esophagus, as well as mammary and prostate glands. In the functional characterization of the p63 gene, we generated p63 knockout (p63ko) mice and human

Acknowledgments

The authors thank the members of the Xian-McKeon, Crum, and Ho laboratories for helpful discussions and support. This work was supported by the National Cancer Institute and General Medical Sciences of the NIH (RO1-GM083348 and R21CA124688), the European Research Council, the Genome Institute of Singapore, and the Biomedical Research Council and the National Medical Research Council, Singapore.

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    Every mammal appears to have 1 or 2 pyloric-type glands at the gastroesophageal squamocolumnar junction.140 It is thought that cells from these cardia glands can migrate proximally to replace squamous esophageal cells in the face of severe damage via refluxed acid and bile.108,141–143 Interestingly, proximal cardia glands vary widely in abundance among the human population, and autopsy and biopsy series of children have shown the naïve cardia may be only a few millimeters.

  • SPT6 loss permits the transdifferentiation of keratinocytes into an intestinal fate that resembles Barrett's metaplasia

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    BE develops when the non-keratinized stratified squamous epithelium in the lower esophagus is replaced by a single layer of “intestine-like” cells after a prolonged phase of injury due to chronic acid reflux (Figure 1C). The origin of BE remains widely debated; theories include a direct origin from the esophageal stratified squamous epithelium or by proximal migration and subsequent intestinalization of the gastric epithelium (Zhang and Wang, 2018; Que et al., 2019; Xian et al., 2012; Gindea et al., 2014, Mcdonald et al., 2015). Alternative proposals include a niche cell at the squamocolumnar junction, or cells lining the esophageal gland ducts, or circulating bone-marrow-derived cells (Que et al., 2019).

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    However, future laboratory-based studies are clearly required to assess possible functional effects. Recent evidence has suggested that Barrett’s esophagus may represent the outgrowth of a residual embryonic epithelial cell population, rather than squamous-to-columnar trans-differentiation of resident stratified epithelium.51,52 In this context, it is intriguing to consider the possibility that the observed interaction between rs4930068 and GERD in relation to risk of BE might in part reflect alterations in the expression level of ASCL2, a transcription factor with known roles in both development and cancer.

  • Mechanisms of esophageal adenocarcinoma formation and approaches to chemopreventive intervention

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    Alterations in p16 are early lesions found in >85% of Barrett’s segments whereas p53 lesions appear later in BE progression in the background of p16 lesions [52]. Identification of the cell of origin of SIM has proved to be very challenging; consensus has yet to emerge [53]. The importance of identifying the putative cell of origin is that it would shed light on the natural course of gastroesophageal reflux sequelae.

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Conflicts of interest The author discloses no conflicts.

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