Bile Acid and Inflammation Activate Gastric Cardia Stem Cells in a Mouse Model of Barrett-Like Metaplasia

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
Cancer cell (Impact Factor: 23.52). 01/2012; 21(1):36-51. DOI: 10.1016/j.ccr.2011.12.004
Source: PubMed


Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5(+) gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1β-IL-6 signaling cascade and Dll1-dependent Notch signaling.

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    • "Bmp4, Kit19, and Tff2, which are known to be involved in cellular differentiation and proliferation , were also associated with BA treatment and/or BA reflux (Figure 5). These increased gene levels were also confirmed in previous studies [14] [15]. "
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    ABSTRACT: Barrett's esophagus (BE) is associated with the development of esophageal adenocarcinoma (EAC). Bile acids (BAs) refluxing into the esophagus contribute to esophageal injury, which results in BE and subsequent EAC. We developed two animal models to test the role of BAs in the pathogenesis of BE. We surgically generated BA reflux, with or without gastric acid, in rats. In a second experiment, we fed animals separately with BAs and gastric acid. Pathologic changes were examined and the expression of Muc2 and Cdx2 in BE tissue was tested by immunostaining. Inflammatory factors in the plasma, as well as differentiation genes in BE were examined through highly sensitive ELISA and semi-quantitative RT-PCR techniques. We found that BAs are sufficient for the induction of esophagitis and Barrett's-like metaplasia in the esophagus. Overexpression of inflammatory cells, IL-6, and TNF-α was observed both in animals fed with BAs and surgically generated BA reflux. Furthermore, elevated levels of Cdx2, Muc2, Bmp4, Kit19, and Tff2 (differentiation genes in BE) were found in BA-treated rats. In conclusion, BAs, but not gastric acid, are a major causative factor for BE. We confirmed that BAs contribute to the development of BE by inducing the inflammatory response in the esophagus. Inhibiting BAs may be a promising therapy for BE.
    International journal of clinical and experimental pathology 05/2015; 8(2):1384-92. · 1.89 Impact Factor
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    • "Whether Barrett’s mucosa is caused by a translocation or migration of gastric cells, by bone marrow stem cells, or by true metaplasia of esophageal cells is controversial. However, proinflammatory cytokines such as IL-6, IL-8, and IL-1β appear to be involved in the development of Barrett’s mucosa.70–73 Consistently, inhibition of COX-2 inhibits proliferation of Barrett’s mucosal cells.74 "
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    ABSTRACT: Chronic inflammation has been identified as an important risk factor for the development of malignancy, and knowledge about its molecular and cellular mechanisms is increasing. Several chronic inflammatory diseases of the gastrointestinal tract are important as risk factors for malignancy and have been studied in detail. In this review, we summarize important molecular mechanisms in chronic inflammation and highlight established and potential links between chronic inflammation and gastrointestinal cancer. In addition, we present the role of chronic inflammation in numerous tumors within the gastrointestinal tract as well as the relevant pathways or epidemiologic observations linking the pathogenesis of these tumors to inflammation.
    Clinical and Experimental Gastroenterology 08/2014; 7(1):261-72. DOI:10.2147/CEG.S43457
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    • "Microenvironmental factors, especially inflammation, have been also shown to contribute to Barret esophagus (BE) and esophageal adenocarcinoma (EAC). In BE the stratified epithelium of the esophagus is replaced by metaplastic intestinal-like epithelium , that may originate from Lgr5 + cardia cells which in response to NF-jB-dependent cytokines, such as IL-6 and IL-1b, migrate up to the esophagus and serve as cell of origin for BE and EAC [5]. "
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    ABSTRACT: Tumor cell plasticity is an event that has been observed in several malignancies. In fact, most of the solid tumors are characterized by cellular heterogeneity and undergo constant changes as the tumor develops. The increased plasticity displayed by these cells allows them to acquire additional properties, enabling epithelial-mesenchymal transitions, dedifferentiation and the acquisition of stem cell-like properties. Here we discuss the particular importance of an inflammatory microenvironment for the bidirectional control of cellular plasticity and the potential for therapeutic intervention.
    FEBS letters 06/2014; DOI:10.1016/j.febslet.2014.06.019 · 3.17 Impact Factor
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