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Volume: Barrett's Esophagus
Chapter: Diagnosis

What are the current alterations in gene expression coexisting with the phenotypic transformation of squamous epithelium into Barrett's mucosa?

J. Theisen, J.R. Siewert (Munich)

Barrett's esophagus is defined as a metaplastic change from squamous epithelium in the distal esophagus to a specialized intestinal epithelium with goblet cells. Chronic gastroesophageal reflux disease is the most significant risk factor for the development of Barrett's esophagus besides white race, male gender, and obesity. Its progression to esophageal adenocarcinoma follows a step-wise sequence from Barrett's esophagus through lowgrade-dysplasia, high-grade dysplasia and ultimately adenocarcinoma. Numerous studies have focused on the sequence Barrett's esophagus-adenocarcinoma whereas little is known about the factors leading to the development of intestinal metaplasia (IM). This is especially true for molecular alterations.

Since inflammation of the squamous epithelium always precedes the development of IM a constant damage and repair process leads to a regenerated inflamed epithelium containing immature squamous cells. This immature epithelium is then even more sensitive to acid or bile damage as seen in patients with chronic reflux disease. One theory of the development of Barrett's esophagus suggests an origin in the transition zone of esophageal and gastric junction epithelium. However, molecular evidence to prove this theory is missing.

Another theory is that with chronic inflammation and subsequent cell death/loss the height of the proliferative zone and the length of basal papillae increases in the squamous epithelium. This is accompanied by increased folding of the esophageal epithelium bringing stem cells into a more exposed position within the epithelial layer and more susceptible to potential toxic reflux material. The expression of epidermal growth factor in these areas underlines this theory. These stem cells undergo altered differentiation in response to continuous reflux. This leads to the expression of a glandular phenotype distinct from adjacent gastric mucosa cells. However, three metaplastic tissue types may arise, intestinal-type, fundic-type, or gastric-type. Currently it is unclear which molecular alterations are needed in order to compose intestinal-type metaplastic epithelium since this is the epithelial type carrying the risk of malignant degeneration [1]. The identification of clonal divergence in chromosomes 5,8,9,12,17, and 18 demonstrates a potential genetic control mechanism of phenotypic heterogeneity. Compared to the other epithelial types Barrett's epithelium has a higher proliferative index associated with the expression of cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase (iNOS) indicating a more pronounced and probably specialized proliferation. COX-2 and iNOS have been shown to be inducible by bile acids and gastric juice and are increasingly expressed in the metaplasiadysplasia-carcinoma sequence [2, 3].

In order to look for molecular alterations in the progression from squamous to metaplastic epithelium one may assume that specific squamous epithelial markers are being down regulated whereas specific glandular (intestinal) epithelial markers are being up regulated in the transition from squamous to IM. Such studies may even enhance the understanding of the origin of the metaplastic tissue.

Cytokeratins (CK) are characteristic cytoskeletal structural proteins representing certain epithelial profiles. Boch et al. compared cytokeratin profiles of squamous epithelium, Barrett's epithelium and the multilayered epithelium within Barrett's tissue. CK 4 and 13 were found to be present in squamous epithelium as specific markers for this type of epithelium whereas CK 8 and 19 represent glandular type epithelium. Both sets of CK were found within the multilayered epithelium suggesting that this epithelium may be the origin of Barrett's epithelium [4].

The heat-shock-protein (Hsp27) as a specific squamous epithelial marker has been shown to be down regulated in Barrett's tissue compared to its abundant expression in squamous epithelium. This is true as well for esophagin, a specific esophageal squamous marker.

Three members of specific glandular markers, trefoil-peptides, human spasmolytic polypeptide (hsp), and intestine specific transcription factors (CDX) have been shown to be over expressed in Barrett's tissue compared to squamous epithelial tissue providing evidence for the fact that the transition from squamous into Barrett's epithelium is possibly a response reaction to continuous inflammation involving differentiation and proliferation. The increased expression of COX-2, an enzyme involved in inflammation and carcinogenesis, in Barrett's epithelium underlines this theory. Furthermore in vivo studies have shown that COX-2 gene-expression is inducible by bile acids and gastric juice and may be a potential chemo preventive target.

Most presently published studies focused on single genes, enzymes, or proteins. By using differential display of mRNA more than a 1,000 gene products could be compared between squamous epithelium and Barrett's epithelium. This technology may identify a panel of genes involved in the transition from squamous epithelium into Barrett's metaplasia with potential therapeutic options.

This transition has not been the focus of interest in the past, even though early recognition of a potential progression to the premalignant lesion, Barrett's esophagus, may enable early preventive treatment.


1. Jankowski JA, Wright NA, Meltzer SJ, et al. Molecular evolution of the metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. Am J Pathol 1999;154:965-973.

2. Theisen J, Danenberg K, DeMeester TR, et al. Effect of acid and bile salts on COX-2 gene expression on an esophageal adenocarcinoma cell line. Gastroenterology 1999;40:3333(A).

3. Lord RV, Danenberg K, Peters JP, et al. Increased COX-2 and iNOS expression and decreased COX-1 expression in Barrett' s esophagus and Barrett's associated adenocarcinoma. Gastroenterology 1999;40:2109(A).

4. Boch JA, Shields HM, Antonioli DA, et al. Distribution of cytokeratin markers in Barrett's specialized columnar epithelium. Gastroenterology 1997;112:760-765.

Publication date: August 2003 OESO©2015