Elsevier

The Lancet

Volume 356, Issue 9247, 16 December 2000, Pages 2079-2085
The Lancet

Seminar
Barrett's metaplasia

https://doi.org/10.1016/S0140-6736(00)03411-5Get rights and content

Summary

The rate of oesophageal adenocarcinoma is increasing in the western world and has a poor prognosis mainly because individuals present at a late stage. Attempts to intervene at an early stage of tumour progression have not proven cost effective, although lesions identified during surveillance programmes have a better prognosis. As a consequence, there has been renewed interest in strategies that might prevent the precursor lesion Barrett's oesophagus. Furthermore, there is an improved understanding of genetic and environmental interactions necessary for the clonal expansion and propagation of metaplastic premalignant lesions. Clearly, three mechanisms promote cancer progression—inheritance of germ-line mutations or polymorphisms, sporadic mutagenesis, and local epigenetic alterations. Locally produced cytokines and bile acids in the refluxate create a microenvironment that sets the scene for metaplastic transformation of the oesophageal epithelium, mainly by directly affecting metaplastic stem cells.

Section snippets

Oesophageal stem cells

Barrett's metaplasia consists of a simple columnar epithelium that is folded to form glandular invaginations in the mucosa. Cells that are shed from the epithelial surface into the lumen are replaced from below by new cells as a result of stem-cell division. Stem cells can self-renew (clonogenic) and produce indefinite numbers of differentiated progeny. These progeny, termed transit amplifying cells or daughter cells, can undergo a finite number of divisions, but each time they divide they lose

Clonal expansion

After the initial selection or generation of a metaplastic stem cell, clonal expansion takes place, which depends on the control of stem-cell number per gland. The number of stem cells is usually highly controlled so that the production of new cells does not upset homoeostatic balance. However, knowledge of stem-cell biology in the intestine has shown that any abnormality in stem-cell division causes extreme alterations in glandular organisation, structure, and function (figure 2).22 Usually

Role of bile acids

Gastro-oesophageal reflux of acid and bile are the predominant initiating factors in Barrett's metaplasia, although the precise mechanism of cytotoxicity is unclear. Partly regressed metaplastic mucosa might be induced by ablation of acid (and bile) reflux with either proton pump inhibitors or antireflux surgery.32 However, a series of in-vitro experiments showed that intermittent exposure to acid causes epithelial changes, which could be interpreted as selecting poorly differentiated cells

Mucosal inflammmation

Mixed inflammatory cell infiltrate is a common feature of acid and bile damage to the native oesophageal mucosa, especially around the stem-cell rich areas of the basal mucosal compartment and papillae.41, 42 This infiltrate is initially composed of acute inflammatory cells. Subsequently T lymphocytes become more numerous, especially in tissues in which metaplastic foci develop.42 Once duodenal gastro-oesophageal reflux disease is corrected by powerful acid suppressing drugs Barrett's

Conclusion

The process of initiation, clonal expansion, and aberrant epithelial biology explains not only why cancer evolution is a multistage process but also why there is a long lag phase between initiation of metaplastic change and cancer development. A combination of aberrant biology, site of origin, and resistance to environmentally induced apoptosis could explain the heterogeneity and malignant potential of metaplastic cells. We suggest that during the initiation phase of Barrett's metaplasia, there

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      Gastro-oesophageal reflux is one of the main risk factors for Barrett's oesophagus, in which a portion of the oesophagus that is usually lined with squamous epithelium undergoes metaplastic change to become columnar mucosa. Barrett's oesophagus is a complex, genetically predisposed, premalignant condition6 that affects 2% of the adult population in western countries and can progress to adenocarcinoma, following the sequence oesophagitis-metaplasia-dysplasia-adenocarcinoma.7,8 Surveillance of Barrett's oesophagus to detect early stage cancer has been associated with only a modest improvement in the outlook of oesophageal adenocarcinoma.9

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