Duodenoesophageal reflux induces esophageal adenocarcinoma without exogenous carcinogen

Fein, Martin; Peters, Jeffrey H.; Chandrasoma, Para; Ireland, Adrian P.; Öberg, Stefan; Ritter, Manfred; Bremner, Cedric G.; Hagen, Jeffrey A.; DeMeester, Tom R.

doi:10.1016/s1091-255x(98)80021-8

Cited by 129 publications

(142 citation statements)

References 20 publications

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“…As with the intestinal epithelium, the Barrett's epithelium contains proliferative crypt-like compartments. To investigate whether Notch signaling was active in the proliferative cells of BE, we studied histology in human biopsy specimens, analyzed Barrett's-derived EAC cell lines and performed Notch inhibition on a well-validated rat model for BE (Fein et al, 1998;Levrat et al, 1962;Sato et al, 2002;van den Boogert et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Conversion of metaplastic Barrett’s epithelium into post-mitotic goblet cells by γ-secretase inhibition

Menke¹,

Lau

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARYBarrett'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 -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 -secretase inhibitors may present a simple therapeutic strategy for this increasingly common pre-malignant condition.

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Section: Introductionmentioning

confidence: 99%

Conversion of metaplastic Barrett’s epithelium into post-mitotic goblet cells by γ-secretase inhibition

Menke¹,

Lau

et al. 2010

Disease Models &Amp; Mechanisms

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show abstract

“…La patogénesis de esta enfermedad se relaciona estrechamente con un reflujo gastroesofágico crónico y persistente [9][10][11] , compuesto principalmente por un reflujo mixto, tanto de contenido gástrico e intestinal, demostrado tanto experimentalmente [12][13][14] , como en numerosos estudios clínicos [1][2][3][4][5][6][7][8]15 . Su importancia clínica se relaciona al hecho que hay un significativo aumento del riesgo a desarrollar un adenocarcinoma, el que es 30 a 120 veces mayor comparado con la población general [5][6][7] , con una incidencia de cáncer de 0,5 a 1% por 100 pacientes-año.…”

Section: Resultados De La Esofaguectomía En 53 Pacientes Con Adenocarunclassified

Resultados de la esofaguectomía en 53 pacientes con adenocarcinoma del esófago y Barrett extenso

et al. 2013

Rev Chil Cir

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Results of esophagectomy among patients with esophageal cancer and Barrett esophagusBackground: The incidence of esophageal carcinoma has increased notoriously worldwide. Aim: To assess clinical features, immediate surgical results and long term survival of patients with esophageal carcinoma and Barrett esophagus. Material and Methods: Retrospective review of medical records of all patients operated for esophageal carcinoma, between 1996 y 2011. Results: The records of 53 patients aged 58 ± 9 years (45 males) were analyzed. The number of operated patients increased from 7 in the period 1968-1983 to 31 in the period 2004-2011. Peritoneal metastases were found in two patients, precluding a resection. Video assisted trans-hiatal approach was the most commonly used technique followed by minimally invasive thoracoscopic and laparoscopic surgery. Transit reconstruction was performed ascending the stomach to the neck in 90% of patients. The average length of Barrett esophagus was 7.4 cm and the mean number of excised lymph nodes was 19. Ten patients had an incipient cancer and their five years survival was 80%. The survival of those with tumors involving the muscular layer and those with transmural cancer was 25 and 5%, respectively. Conclusions: There is an increase in the incidence of esophageal cancer in the last 10 years. The survival after surgery is highly dependent on the invasiveness of the tumor.

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“…Until recently, the best animal model used to study BE has been a rat surgical model, in which an esophagojejunostomy is used to induce gastroduodenal reflux. 10 However, this is a model that has been difficult to reproduce in mice. We recently generated a novel transgenic mouse model for BE and EAC that has provided fundamental insights into the early pathogenesis of BE, and offers a molecular basis for an emerging paradigm shift regarding the cell of origin of BE and EAC.…”

Section: Modeling Barrett Esophagus In the Mousementioning

confidence: 99%

Barrett esophagus

et al. 2012

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T he incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the western world and accounts for 2% of all cancer-related deaths. The precursor lesion for EAC is Barrett esophagus (BE), which is strongly associated with gastresophageal reflux disease. A major limitation to the study of EAC has been the absence of tractable and genetically modifiable preclinical models of BE. A mouse model of BE and EAC that resembles human disease could provide novel insights into the origins and molecular pathogenesis of BE. In addition, validated animal models could help stratify BE patients given the limited predictive power of current standard endoscopic measures and clinical assessment. Here, we review the findings from recently developed mouse models of BE and EAC and their impact on clinical decision making, surveillance programs and therapeutic options. The data, taken together, suggest potential origins of BE from the gastric cardia, a role of bile acid and hypergatrinemia for carcinogenesis, a growing importance for columnar-like epithelium and a critical role for Notch signaling.

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Duodenoesophageal reflux induces esophageal adenocarcinoma without exogenous carcinogen

Cited by 129 publications

References 20 publications

Conversion of metaplastic Barrett’s epithelium into post-mitotic goblet cells by γ-secretase inhibition

Conversion of metaplastic Barrett’s epithelium into post-mitotic goblet cells by γ-secretase inhibition

Resultados de la esofaguectomía en 53 pacientes con adenocarcinoma del esófago y Barrett extenso

Barrett esophagus

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