Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Bile acids promote adenocarcinoma in a novel transgenic mouse model of BarrettM-bM-^@M-^Ys esophagus

ABSTRACT: Esophageal adenocarcinoma (EAC) has the fastest increase of any cancer in the US and Europe, and arises in the setting of BarrettM-bM-^@M-^Ys esophagus (BE), defined by replacement of normal squamous epithelium with columnar intestinal-like epithelium. BE is thought to result from chronic esophageal inflammation but has been elusive to model in animals. Herein, we have generated the first transgenic mouse model of BarrettM-bM-^@M-^Ys esophagus through overexpression of interleukin-1M-CM-^_ (IL-1M-NM-2). IL-1M-NM-2 overexpression in the mouse esophageal mucosa induces chronic inflammation that progresses to intestinal metaplasia, with characteristic expression of TFF2, Bmp4 and Cdx2. With aging, IL-1b transgenic mice progress to esophageal adenocarcinoma (EAC) but the process is markedly accelerated by exposure to bile acids and/or nitrosamines, resembling the human counterpart. Moreover, progenitor cells present in the gastric cardia, but absent from the esophagus in humans and mice, are increased in BE, suggesting the cell of origin in the gastric cardia Comparison of BE and EAC tissue from the mouse with normal squamous epithelium from the mouse.

ORGANISM(S): Mus musculus

SUBMITTER: Michael Quante

PROVIDER: E-GEOD-24931 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia.

Quante Michael M Bhagat Govind G Abrams Julian A JA Marache Frederic F Good Pamela P Lee Michele D MD Lee Yoomi Y Friedman Richard R Asfaha Samuel S Dubeykovskaya Zinaida Z Mahmood Umar U Figueiredo Jose-Luiz JL Kitajewski Jan J Shawber Carrie C Lightdale Charles J CJ Rustgi Anil K AK Wang Timothy C TC

Cancer cell 20120101 1

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 ...[more]

PMID: 22264787

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Project description:Esophageal adenocarcinoma (EAC) has become a major concern in Western countries due to rapid rises in incidence coupled with very poor survival rates. One of the key risk factors for the development of this cancer is the presence of Barrett’s esophagus (BE), which is believed to form in response to repeated gastro-esophageal reflux. In this study we performed comparative, genome-wide expression profiling (using Illumina whole-genome Beadarray) on total RNA extracted from esophageal biopsy tissues from individuals with EAC, BE (in the absence of EAC) and those with normal squamous epithelium. We combined these data with publically accessible raw data from three similar studies to investigate key gene and ontology differences between these three tissue states. The results support the deduction that BE is a tissue with enhanced glycoprotein synthesis machinery (DPP4, ATP2A3, AGR2) designed to provide strong mucosal defenses aimed at resisting gastro-esophageal reflux. EAC exhibits the enhanced extracellular matrix remodeling (collagens, IGFBP7, PLAU) effects expected in an aggressive form of cancer, as well as evidence of reduced expression of genes associated with mucosal (MUC6, CA2, TFF1) and xenobiotic (AKR1C2, AKR1B10) defenses. When our results are compared to previous whole-genome expression profiling studies keratin, mucin, annexin and trefoil factor gene families are the most frequently represented gene families. Eleven genes identified here are also represented in at least 3 other profiling studies. We used these genes to discriminate squamous, BE and EAC within the two largest cohorts using a support vector machine leave one out cross validation analysis. While this method was satisfactory for discriminating squamous and BE, it demonstrates the need for more detailed investigations into profiling changes within BE leading to the progression towards EAC. A comparison of three esophageal biopsy groups from separate individuals: normal squamous (n=9), Barrett's esophagus without dysplasia (n=22) & adenocarcinoma (n=23). Adenocarcinoma samples overlap with members of DNA copy number analysis GEO series GSE10506 such that, in each case genomic DNA and total RNA were extracted from the same biopsy. The matching copy number data GEO samples IDs are noted in characteristics: Matching CN Sample ID

Dataset Information

Bile acids promote adenocarcinoma in a novel transgenic mouse model of BarrettM-bM-^@M-^Ys esophagus

Publications

Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia.

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