[Show abstract][Hide abstract] ABSTRACT: Although the prevalence of Barrett's esophagus (BE) is rising no data exist for racial minorities on prevalence in the general population. Minorities have a lower prevalence than Caucasians, and yet age, smoking, abdominal obesity, and Helicobacter pylori are all risk factors. Metabolic changes induced by adipocytokines and the apparently strong association between obesity, central adiposity, and BE may lead to reconsideration of some aspects of the natural history of BE. There is lack of experimental evidence on acid sensitivity and BE, which is hyposensitive compared to esophageal reflux disease. Reactive nitrogen and oxygen species lead to impaired expression of tumor suppressor genes, which can lead to cancer development; thus, antioxidants may be protective. Gastroesophageal reflux disease may be considered an immune-mediated disease starting at the submucosal layer; the cytokine profile of the mucosal immune response may explain the different outcome of gastroesophageal reflux.
Annals of the New York Academy of Sciences 09/2011; 1232(1):1 - 17. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The following on proton pump inhibitors and chemoprevention in Barrett's esophagus includes commentaries on normalization of esophageal refluxate; the effects of 5-HT4 agonists on EGF secretion and of lubripristone on chloride channels agents; the role of Campylobacter toxin production; the deleterious effects of unconjugated bile acids; the role of baclofen in nonacid reflux; the threshold for adequate esophageal acid exposure; the effects of proton pump inhibitor (PPI) therapy on normalization of esophageal pH and on cell proliferation; the role of the phenotype of cellular proliferation on the effects of PPI therapy; and the value of Symptom Index and Symptom Association Probability in the evaluation of potential response to treatment.
Annals of the New York Academy of Sciences 09/2011; 1232(1):93 - 113. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The following on molecular mechanisms of Barrett's esophagus and adenocarcinoma contains commentaries on the mechanism of bile and gastric acid induced damage; the roles of BMP-4 and CDX-2 in the development of intestinal metaplasia; the transcription factors driving intestinalization in Barrett's esophagus; the contribution of bone marrow to metaplasia and adenocarcinoma; activation and inactivation of transcription factors; and a novel study design targeting molecular pathways in Barrett's esophagus.
Annals of the New York Academy of Sciences 09/2011; 1232(1):381 - 391. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The following on prevalence and incidence of adenocarcinomas in Barrett's esphophagus (BE) includes commentaries on the mechanisms of a potential protective effect of proton pump inhibitors (PPIs) on progression of BE to high-grade dysplasia; evaluation of the role of PPIs in decreasing the risk of degeneration; the geographical variations of incidence of BE; the role of the nonmorphologic biomarkers; the relationship between length of BE and development of cancer; the confounding factors in incidence rates of BE; the role of the increase of cell differentiation and apoptosis induced by PPIs in the diminution of cancer risk; the frequency of occult neoplastic foci and unsuspected invasive cancer in surgical specimens; the influence on the indications of endoscopic therapy; the overestimation of regression in surgical series; attempts to evaluate the reasons for variations of cancer incidence in the literature; and progress in screening and surveillance for BE.
Annals of the New York Academy of Sciences 09/2011; 1232(1):230 - 247. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The following on endoscopic treatments of Barrett's esophagus includes commentaries on indications for endoscopic treatments; endo-luminal plication procedures; the cellular modifications induced by the endoscopic ablation therapies; eradication by banding without resection; the evaluation of complete ablation; recurrence after ablation; association of antireflux surgery; radiofrequency ablation; and nondysplastic Barrett's esophagus.
Annals of the New York Academy of Sciences 09/2011; 1232:140-55. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Apoptosis resistance is a hallmark of cancer cells. Typically, bile acids induce apoptosis. However during gastrointestinal (GI) tumorigenesis the cancer cells develop resistance to bile acid-induced cell death. To understand how bile acids induce apoptosis resistance we first need to identify the molecular pathways that initiate apoptosis in response to bile acid exposure. In this study we examined the mechanism of deoxycholic acid (DCA)-induced apoptosis, specifically the role of Na(+)/H(+) exchanger (NHE) and Na(+) influx in esophageal cells. In vitro studies revealed that the exposure of esophageal cells (JH-EsoAd1, CP-A) to DCA (0.2 mM-0.5 mM) caused lysosomal membrane perturbation and transient cytoplasmic acidification. Fluorescence microscopy in conjunction with atomic absorption spectrophotometry demonstrated that this effect on lysosomes correlated with influx of Na(+), subsequent loss of intracellular K(+), an increase of Ca(2+) and apoptosis. However, ethylisopropyl-amiloride (EIPA), a selective inhibitor of NHE, prevented Na(+), K(+) and Ca(2+) changes and caspase 3/7 activation induced by DCA. Ouabain and amphotericin B, two drugs that increase intracellular Na(+) levels, induced similar changes as DCA (ion imbalance, caspase3/7 activation). On the contrary, DCA-induced cell death was inhibited by medium with low a Na(+) concentrations. In the same experiments, we exposed rat ileum ex-vivo to DCA with or without EIPA. Severe tissue damage and caspase-3 activation was observed after DCA treatment, but EIPA almost fully prevented this response. In summary, NHE-mediated Na(+) influx is a critical step leading to DCA-induced apoptosis. Cells tolerate acidification but evade DCA-induced apoptosis if NHE is inhibited. Our data suggests that suppression of NHE by endogenous or exogenous inhibitors may lead to apoptosis resistance during GI tumorigenesis.
PLoS ONE 08/2011; 6(8):e23835. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Barrett's esophagus (BE) is a premalignant condition, where normal squamous epithelium is replaced by intestinal epithelium. BE is associated with an increased risk of developing esophageal adenocarcinoma (EAC). However, the BE cell of origin is not clear. We hypothesize that BE tissue originates from esophageal squamous cells, which can differentiate to columnar cells as a result of repeated exposure to gastric acid and bile acids, two components of refluxate implicated in BE pathology. To test this hypothesis, we repeatedly exposed squamous esophageal HET1A cells to 0.2 mM bile acid (BA) cocktail at pH 5.5 and developed an HET1AR-resistant cell line. These cells are able to survive and proliferate after repeated 2-h treatments with BA at pH 5.5. HET1AR cells are resistant to acidification and express markers of columnar differentiation, villin, CDX2, and cytokeratin 8/18. HET1AR cells have increased amounts of reactive oxygen species, concomitant with a decreased level and activity of manganese superoxide dismutase compared with parental cells. Furthermore, HET1AR cells express proteins and activate signaling pathways associated with inflammation, cell survival, and tumorigenesis that are thought to contribute to BE and EAC development. These include STAT3, NF-κB, epidermal growth factor receptor (EGFR), cyclooxygenase-2, interleukin-6, phosphorylated mammalian target of rapamycin (p-mTOR), and Mcl-1. The expression of prosurvival and inflammatory proteins and resistance to cell death could be partially modified by inhibition of STAT3 signaling. In summary, our study shows that long-term exposure of squamous cells to BA at acidic pH causes the cells to display the same characteristics and markers as BE.
[Show abstract][Hide abstract] ABSTRACT: Barrett's oesophagus is a premalignant disease associated with oesophageal adenocarcinoma. The major goal of this study was to determine the mechanism responsible for bile acid-induced alteration in intracellular pH (pH(i)) and its effect on DNA damage in cells derived from normal oesophagus (HET1A) or Barrett's oesophagus (CP-A).
Cells were exposed to bile acid cocktail (BA) and/or acid in the presence/absence of inhibitors of nitric oxide synthase (NOS) or sodium-hydrogen exchanger (NHE). Nitric oxide (NO), pH(i) and DNA damage were measured by fluorescent imaging and comet assay. Expression of NHE1 and NOS in cultured cells and biopsies from Barrett's oesophagus or normal squamous epithelium was determined by RT-PCR, immunoblotting or immunohistochemistry.
A dose dependent decrease in pH(i) was observed in CP-A cells exposed to BA. This effect of BA is the consequence of NOS activation and increased NO production, which leads to NHE inhibition. Exposure of oesophageal cells to acid in combination with BA synergistically decreased pH(i). The decrease was more pronounced in CP-A cells and resulted in >2-fold increase in DNA damage compared to acid treatment alone. Examination of biopsies and cell lines revealed robust expression of NHE1 in Barrett's oesophagus but an absence of NHE1 in normal epithelium.
The results of this study identify a new mechanism of bile acid-induced DNA damage. We found that bile acids present in the refluxate activate immediately all three isoforms of NOS, which leads to an increased NO production and NHE inhibition. This consequently results in increased intracellular acidification and DNA damage, which may lead to mutations and cancer progression. Therefore, we propose that in addition to gastric reflux, bile reflux should be controlled in patients with Barrett's oesophagus.
Gut 09/2010; 59(12):1606-16. · 13.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Barrett's esophagus (BE) is a premalignant condition associated with the development of esophageal adenocarcinoma (EAC). Previous studies have implicated hydrophobic bile acids and gastric acid in BE and EAC pathogenesis. In this study, we tested the hypothesis that DNA damage, cytotoxicity and oxidative stress induced by bile acids and gastric acid can be attenuated by the cytoprotective, hydrophilic bile acid glycoursodeoxycholic acid (GUDCA). Non-dysplastic BE cells were exposed for 10 min to pH 4 and/or bile acid cocktail or to pH 4 and a modified cocktail consisting of a mixture of bile acids and GUDCA. DNA damage was evaluated by the comet assay; cell viability and proliferation were measured by trypan blue staining and the MTS assay; reactive oxygen species (ROS) were measured using hydroethidium staining; oxidative DNA/RNA damage was detected by immunostaining with antibody against 8-OH-dG; thiol levels were measured by 5-chloromethylfluorescein diacetate (CMFDA) staining; and the expression of antioxidant proteins was evaluated by western blotting. DNA damage and oxidative stress were significantly increased, while thiol levels were decreased in BE cells treated with pH 4 and bile acid cocktail compared with cells treated with pH 4 alone or untreated cells. Bile acids and low pH also significantly decreased cell proliferation. Expression of the antioxidant enzymes, MnSOD and CuZnSOD, was elevated in the cells treated with bile acids and low pH. When GUDCA was included in the medium, all these effects of pH 4 and bile acids were markedly reduced. In conclusion, treatment of BE cells with acidified medium and a bile acid cocktail at physiologically relevant concentrations induces DNA damage, cytotoxicity, and ROS. The cytoprotective bile acid, GUDCA, inhibits these deleterious effects by inhibiting oxidative stress.
Diseases of the Esophagus 07/2009; 23(2):83-93. · 2.06 Impact Factor