Menke, V.

Myo9B is associated with an increased risk of Barrett's esophagus and esophageal adenocarcinoma (Article)

2012-12-01T00:00:00Z

Background. Reflux esophagitis (RE) and Barrett's esophagus (BE) are predisposing factors for development of esophageal adenocarcinoma (EAC), the solid tumor with the fastest rising incidence in the Western world. This RE-BE-EAC cascade involves multiple host factors and consequently multiple genes. Polymorphisms in the 3′ region of myosin IXB (Myo9B) are associated with chronic inflammatory gastrointestinal disorders like celiac disease and ulcerative colitis, assuming that variation in Myo9B influences the intestinal permeability. Aim. To determine esophageal expression and the genetic variation of the Myo9B gene in the RE-BE-EAC cascade. Methods. DNA from 886 Caucasian participants (198 non-reflux controls, 305 RE, 254 BE, 129 EAC) was collected for the determination of the Myo9B gene polymorphism (rs2305764). Esophageal Myo9B expression was determined on biopsies from normal, RE, BE and EAC epithelium. Results. Genotype G/G was more common in BE (p = 0.032) and EAC (p = 0.046), but not in RE (p = 0.126) compared with the control group. Cytoplasmic Myo9B expression was determined in RE, BE and EAC, but most prominent in epithelial cells of BE and EAC. Conclusions. Genetic variation of Myo9B may play a role in the etiology of BE and EAC by increasing the permeability of the epithelial barrier.

Barrett's esophagus: Origin, development and options for therapeutic intervention (Doctoral Thesis)

2012-10-26T00:00:00Z

Barrett’s esophagus (BE) consists of a metaplasia in which the normal squamous cells lining the esophagus are replaced by a mixture of gastric and intestinal lining cells. The intestinal-type lining cells are often referred to as specialized columnar cells and include e.g. goblet cells. For a number of years, some scientists thought that there were two types of BE; one in which the normal lining was replaced with gastric type cells only, and the second in which intestinal cells were present. Presently, intestinal metaplasia is required for the diagnosis of BE because intestinal metaplasia is the only type of esophageal columnar epithelium that clearly predisposes to malignancy. BE is a complication of chronic gastroesophageal reflux disease (GERD), primarily in white men. GERD is a disease in which there is reflux of acidic fluid from the stomach and bile contents from the duodenum into the esophagus. It most commonly causes heartburn, but many patients do not have any symptoms.

Functional single-nucleotide polymorphism of epidermal growth factor is associated with the development of Barrett's esophagus and esophageal adenocarcinoma (Article)

2012-01-01T00:00:00Z

Reflux esophagitis (RO) and Barrett's esophagus (BO) can cause esophageal adenocarcinoma (OAC). The esophageal mucosa in the RO-BO-OAC cascade is chronically exposed to gastro-esophageal reflux. Epidermal growth factor (EGF) has an important role in the protection and repair of mucosal damage, and non-physiologic levels are associated with gastrointestinal tumors. The aim is to determine the functional effect of EGF gene polymorphisms on RO, BO and OAC development. A cohort of 871 unrelated Dutch Caucasians consisted of 198 healthy controls, 298 RO patients, 246 BO patients and 129 OAC patients. The frequency of the EGF-production-associated 5′UTR A61G polymorphism was determined in these four groups. EGF immunohistochemistry was performed on BO biopsies. EGF expression was significantly lower in the G/G genotype compared with the A/G (P0.008) and A/A (P0.002) group. The G/G genotype was significantly more prevalent in RO (odds ratios (OR)2.6; 95% confidence intervals (95% CI): 1.3-5.2), BO (OR3.0; 95% CI: 1.5-6.2) and OAC (OR4.1; 95% CI: 1.8-9.7) than in controls. The G allele is associated with reduced EGF expression and increased risk for RO, BO and OAC development. This indicates that reduced mucosal protection resulting from genetically decreased EGF expression enhances esophageal tumor development.

Expression, localization and polymorphisms of the nuclear receptor PXR in Barrett's esophagus and esophageal adenocarcinoma (Article)

2011-10-06T00:00:00Z

Background: The continuous exposure of esophageal epithelium to refluxate may induce ectopic expression of bile-responsive genes and contribute to the development of Barrett's esophagus (BE) and esophageal adenocarcinoma. In normal physiology of the gut and liver, the nuclear receptor Pregnane × Receptor (PXR) is an important factor in the detoxification of xenobiotics and bile acid homeostasis. This study aimed to investigate the expression and genetic variation of PXR in reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma.Methods: PXR mRNA levels and protein expression were determined in biopsies from patients with adenocarcinoma, BE, or RE, and healthy controls. Esophageal cell lines were stimulated with lithocholic acid and rifampicin. PXR polymorphisms 25385C/T, 7635A/G, and 8055C/T were genotyped in 249 BE patients, 233 RE patients, and 201 controls matched for age and gender.Results: PXR mRNA levels were significantly higher in adenocarcinoma tissue and columnar Barrett's epithelium, compared to squamous epithelium of these BE patients (P < 0.001), and RE patients (P = 0.003). Immunohistochemical staining of PXR showed predominantly cytoplasmic expression in BE tissue, whereas nuclear expression was found in adenocarcinoma tissue. In cell lines, stimulation with lithocholic acid did not increase PXR mRNA levels, but did induce nuclear translocation of PXR protein. Genotyping of the PXR 7635A/G polymorphism revealed that the G allele was significantly more prevalent in BE than in RE or controls (P = 0.037).Conclusions: PXR expresses in BE and adenocarcinoma tissue, and showed nuclear localization in adenocarcinoma tissue. Upon stimulation with lithocholic acid, PXR translocates to the nuclei of OE19 adenocarcinoma cells. Together with the observed association of a PXR polymorphism and BE, this data implies that PXR may have a function in prediction and treatment of esophageal disease.

Conversion of metaplastic Barrett's epithelium into post-mitotic goblet cells by γ-secretase inhibition (Article)

2010-01-01T00:00:00Z

Barrett's esophagus (BE) affects approximately 2% of the Western population and progresses to esophageal adenocarcinoma (EAC) in 0.5% of these patients each year. In BE, the stratified epithelium is replaced by an intestinal-type epithelium owing to chronic gastroduodenal reflux. Since selfrenewal of intestinal crypts is driven by Notch signaling, we investigated whether this pathway was active in the proliferative crypts of BE. Immunohistochemistry confirmed the presence of an intact and activated Notch signaling pathway in metaplastic BE epithelium, but not in the normal human esophagus. Similar observations were made in two well-known human Barrett's-derived EAC cell lines, OE33 and SKGT-5. We then sought to investigate the effects of Notch inhibition by systemic treatment with a γ-secretase inhibitor in a well-validated rodent model for BE. As we have shown previously in normal intestinal epithelium, Notch inhibition converted the proliferative Barrett's epithelial cells into terminally differentiated goblet cells, whereas the squamous epithelium remained intact. These data imply that local application of γ-secretase inhibitors may present a simple therapeutic strategy for this increasingly common pre-malignant condition.