Reflux-induced apoptosis of the esophageal mucosa is inhibited in Barrett’s epithelium

Wetscher, Gerold J.; Schwelberger, H. G.; Unger, Andreas; Offner, Felix; Profanter, Christoph; Glaser, K.; Klingler, Antón; Gadenstaetter, Michael; Klingler, Paul J.

doi:10.1016/s0002-9610(98)00258-x

Cited by 36 publications

(27 citation statements)

References 20 publications

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“…An increase has been found in the apoptotic rate with increasing histologic severity in intestinal metaplasia/dysplasia and carcinoma, 18 whereas others found few apoptotic cells in Barrett's high-grade dysplasia and adenocarcinoma. 28,29 The Fas/APO-1 (CD95) gene encodes a transmembrane protein that is involved in apoptosis. Loss of its expression during carcinogenesis can result in interruption of the apoptotic pathway.…”

Section: Apoptosismentioning

confidence: 99%

Molecular Biology of Barrett’s Adenocarcinoma

Wijnhoven

Tilanus²,

Dinjens³

2001

Annals of Surgery

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ObjectiveTo review the current knowledge on the genetic alterations involved in the development and progression of Barrett's esophagus-associated neoplastic lesions. Summary Background DataBarrett's esophagus (BE) is a premalignant condition in which the normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. BE predisposes patients to the development of esophageal adenocarcinoma. Endoscopic surveillance can detect esophageal adenocarcinomas when they are early and curable, but most of the adenocarcinomas are detected at an advanced stage. Despite advances in multimodal therapy, the prognosis for invasive esophageal adenocarcinoma is poor. A better understanding of the molecular evolution of the Barrett's metaplasia to dysplasia to adenocarcinoma sequence may allow improved diagnosis, therapy, and prognosis. MethodsThe authors reviewed data from the published literature to address what is known about the molecular changes thought to be important in the pathogenesis of BE-associated neoplastic lesions. ResultsThe progression of Barrett's metaplasia to adenocarcinoma is associated with several changes in gene structure, gene expression, and protein structure. Some of the molecular alterations already showed promise as markers for early cancer detection or prognostication. Among these, alterations in the p53 and p16 genes and cell cycle abnormalities or aneuploidy appear to be the most important and well-characterized molecular changes. However, the exact sequence of events is not known, and probably multiple molecular pathways interact and are involved in the progression of BE to adenocarcinoma. ConclusionsFurther research into the molecular biology of BE-associated adenocarcinoma will enhance our understanding of the genetic events critical for the initiation and progression of Barrett's adenocarcinoma, leading to more effective surveillance and treatment.Since 1970, the incidence of adenocarcinomas of the esophagus has increased in many countries at a rate that exceeds that of any other malignancy.

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Section: Apoptosismentioning

confidence: 99%

Molecular Biology of Barrett’s Adenocarcinoma

Wijnhoven

Tilanus²,

Dinjens³

2001

Annals of Surgery

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“…Another example is Barrett's esophagus, a metaplastic alteration of the esophageal mucosa that occurs in response to chronic gastroesophageal reflux (Riegman et al, 2001;McManus et al, 2004). Bclx L expression is upregulated in the Barrett's mucosa when compared to its levels in the surrounding esophageal mucosa (Dvorakova et al, 2004), and whereas the apoptotic index is low in the Barrett's mucosa, apoptosis is prominent in the surrounding mucosa (Wetscher et al, 1998). Therefore, it is likely that the upregulation of Bcl-x L expression in the Barrett's mucosa is a protective mechanism.…”

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confidence: 99%

A moderate reduction of Bcl-xL expression protects against tumorigenesis; however, it also increases susceptibility to tissue injury

et al. 2005

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“…Duodeno-gastro-esophageal re¯ux is supposed to play a role in the pathogenesis of Barrett's epithelium (Wetcher et al, 1998;Polkowski et al, 1999;Schrump and Nguyen, 1999). Chen et al (2000) suggested the important role of oxidative damage in the carcinogenesis of Barrett's carcinoma in a rat model.…”

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Mutations in the mitochondrial DNA D-Loop region occur frequently in adenocarcinoma in Barrett's esophagus

et al. 2002

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Mitochondrial DNA (mtDNA) is known for high mutation rates caused by lack of protective histones, ine cient DNA repair systems, and continuous exposure to mutagenic e ects of oxygen radicals. We examined the frequency of mutations in the mtDNA D-Loop region in 20 patients with Barrett's carcinoma and associated Barrett's epithelium by automated DNA sequencing. Mutations were detected in eight of 20 (40%) patients in tumor and/or tumor-associated Barrett's epithelium. In six of eight positive cases, the mutations were detected only in the tumor, one of eight showed mutations in tumor and Barrett's epithelium, and one of eight only in Barrett's epithelium. The degree of dysplasia in Barrett's epithelium was classi®ed low-grade in one and high grade in the two specimens. There was no association of mtDNA D-Loop mutations with histopathological stage of disease or tumor grading. We present the ®rst study of frequent occurrence of mutations in the mtDNA D-Loop regions in adenocarcinomas in Barrett's esophagus. Furthermore, this study supports the hypothesis that oxidative damage might be a mechanism for the induction of adenocarcinoma in Barrett's esophagus. Since mutations were identi®ed in tumor-associated dysplastic Barrett's epithelium, they also might become a marker for the malignant potential of Barrett's epithelium.

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Reflux-induced apoptosis of the esophageal mucosa is inhibited in Barrett’s epithelium

Cited by 36 publications

References 20 publications

Molecular Biology of Barrett’s Adenocarcinoma

Molecular Biology of Barrett’s Adenocarcinoma

A moderate reduction of Bcl-xL expression protects against tumorigenesis; however, it also increases susceptibility to tissue injury

Mutations in the mitochondrial DNA D-Loop region occur frequently in adenocarcinoma in Barrett's esophagus

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