Bile salts induce or blunt cell proliferation in Barrett's esophagus in an acid-dependent fashion

Kaur, Baljeet; Ouatu-Lascar, Rodica; Fitzgerald, RC; Omary, MB

doi:10.1016/s0016-5085(98)80691-4

Cited by 26 publications

(38 citation statements)

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“…Overall, these data suggest a particular susceptibility of the metaplastic cells of Barrett's mucosa to DNA damage. Coupled with the increase in cell proliferation observed with exposure to bile salts and acid (22), the presence of increased DNA damage may lead to a cellular environment that is prone to the genetic alterations (e.g., p16 loss of heterozygosity and promoter methylation, TP53 mutation), seen as metaplasia progresses to dysplasia and adenocarcinoma (1)(2)(3).…”

Section: Discussionmentioning

confidence: 99%

Risk Factors, DNA Damage, and Disease Progression in Barrett's Esophagus

Olliver

Hardie²,

Gong³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Esophageal adenocarcinoma develops on a background of Barrett's esophagus. A number of risk factors have been linked to both conditions, including gastroesophageal reflux and smoking. However, the molecular mechanisms by which these factors influence disease progression remain unclear. One possibility is that risk factors generate promutagenic DNA damage in the esophagus. The comet assay was used to measure DNA damage in esophageal (Barrett's and squamous) and gastric mucosa of Barrett's patients with (n = 24) or without (n = 50) associated adenocarcinoma or high-grade dysplasia in comparison with control patients (squamous mucosa) without Barrett's esophagus (n = 64). Patients completed a questionnaire detailing exposure to some of the known risk factors for Barrett's esophagus and adenocarcinoma. In Barrett's esophagus patients, DNA damage was higher in Barrett's mucosa compared with normal esophageal and gastric mucosa (P < 0.001). In addition, the highest quartile of DNA damage in Barrett's mucosa was associated with an increased risk (odds ratio, 9.4; 95% confidence interval, 1.1-83.4; P = 0.044) of developing adenocarcinoma or highgrade dysplasia compared with DNA damage levels in the lowest quartile. Smoking was associated with higher DNA damage in squamous epithelium in all patient groups (P < 0.01) and in Barrett's mucosa (P < 0.05) in Barrett's esophagus patients only. In controls only, current reflux was associated with higher DNA damage, whereas anti-inflammatory drug use resulted in lower levels. Collectively, these data imply a genotoxic insult to the premalignant Barrett's mucosa that may explain the genetic instability in this tissue and the progression to adenocarcinoma. There is an indication for a role for smoking in inducing DNA damage in esophageal mucosa but an understanding of the role of reflux requires further investigation. (Cancer Epidemiol Biomarkers Prev 2005;14 (3):620 -5)

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Section: Discussionmentioning

confidence: 99%

Risk Factors, DNA Damage, and Disease Progression in Barrett's Esophagus

Olliver

Hardie²,

Gong³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…More recently, this technique was used to study explants of intestinal metaplasia, obtained from a Barrett's esophagus. [21][22][23] Culturing esophageal adenocarcinoma or squamous cell carcinoma has not been described previously. In our hands, we obtained a good viability of the cultured esophageal biopsies, which contained normal squamous epithelium, intestinal metaplasia and squamous cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Gene therapy for esophageal carcinoma: the use of an explant model to test adenoviral vectors ex vivo

Marsman¹,

Buskens²,

Wesseling³

et al. 2004

Cancer Gene Ther

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Adenoviral gene therapy might be a promising therapeutic strategy for esophageal carcinoma. However, adenoviral transduction efficacy in vivo is still limited. This efficacy can be improved by the insertion of an Arg-Gly-Asp (RGD) peptide in the HI-loop of the viral fiber knob. Indeed in established esophageal cell lines, we observed an up to six-fold improved transduction using the RGDtargeted adenovirus. Established cell lines, however, are easily transformed and do not represent the more complex in vivo histology and anatomy. Therefore, we set up an esophageal explant model using esophageal biopsies from patients. Viability is a limiting factor for this system. Cultured squamous epithelium, intestinal metaplasia and squamous cell carcinoma had a sufficient viability to study adenoviral transduction. Viability of the cultured adenocarcinoma biopsies was poor. Adenoviral transduction in the explant model was poor and was localized in particular cells. The transduction of the nontargeted and RGD-targeted adenovirus was similar in localization and efficacy. In conclusion, we established an esophageal explant system to test the transduction of adenoviral vectors ex vivo. The transduction was limited and localized in specific cells. RGD-targeted adenovirus did not show an improved transduction in this system.

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“…Previous attempts have been restricted to explants culture of esophageal mucosa (Fitzgerald et al, 1996;Kaur et al, 2000) or short-term primary cultures (Compton et al, 1998;Banks-Schlegel and Harris, 1983;Banks-Schlegel and Green, 1981) limited by the rapid death of the culture or immortalized cell lines, where the genetic regulation is altered by the immortalization process (Rheinwald and Becket, 1980;Stoner et al, 1982;Stoner et al, 1991; Palanca-Wessels et al, 1998; Mothersill and Seymour,…”

Section: Introductionmentioning

confidence: 99%

Chronic acid exposure leads to activation of thecdx2intestinal homeobox gene in a long-term culture of mouse esophageal keratinocytes

Marchetti

Caliot

Pringault

2003

Journal of Cell Science

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To explore mechanisms whereby Malpighian keratinocytes can transdifferentiate into an intestinal-like epithelium, as observed in the early steps of Barrett's esophagus (BE) development, long-standing cultures of esophageal keratinocytes derived from normal mouse esophageal explants were developed. These cells were able to form multilayers and to differentiate on filter support by the formation of differentiated layers of basal cells(cytokeratine 14 positive) on which secondary suprabasal cell layers(cytokeratine 4 positive) spontaneously developed. Thus, these cultured cells,referred to as P3E6, reproduced, at least in part, the proliferation and stratification pattern existing in the normal esophagus. Because chronic exposure to acid pH is known to be a critical factor for BE development,culture medium at pH 3.5 was added into the apical chamber of cell cultures. This led to a decrease in the overall number of cells but it did not affect cell proliferation. Furthermore, external acid environment triggered expression of the GFP reporter gene fused downstream of the cdx2 intestinal homeogene regulatory sequences in P3E6 transfected cells. Expression of the endogenous CDX2 protein, detected by western blot and immunocytochemical analysis, correlated with promoter activation. These findings demonstrate that chronic exposure of esophageal keratinocytes to acid pH induces transcription of cdx2, an intestinal specific homeobox gene known to play a critical role in the differentiation and maintenance of intestinal epithelial functions. The results suggest that chronic acid exposure can modify the fate of P3E6 esophageal keratinocytes towards an intestinal program. This can be a key step in the development of intestinal metaplasia often observed in esophagus-cardia junction.

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Bile salts induce or blunt cell proliferation in Barrett's esophagus in an acid-dependent fashion

Cited by 26 publications

References 0 publications

Risk Factors, DNA Damage, and Disease Progression in Barrett's Esophagus

Risk Factors, DNA Damage, and Disease Progression in Barrett's Esophagus

Gene therapy for esophageal carcinoma: the use of an explant model to test adenoviral vectors ex vivo

Chronic acid exposure leads to activation of thecdx2intestinal homeobox gene in a long-term culture of mouse esophageal keratinocytes

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