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

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.

Pubmed ID: 22264787

Authors

  • Quante M
  • Bhagat G
  • Abrams JA
  • Marache F
  • Good P
  • Lee MD
  • Lee Y
  • Friedman R
  • Asfaha S
  • Dubeykovskaya Z
  • Mahmood U
  • Figueiredo JL
  • Kitajewski J
  • Shawber C
  • Lightdale CJ
  • Rustgi AK
  • Wang TC

Journal

Cancer cell

Publication Data

January 17, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: 1U54CA126513,
  • Agency: NCI NIH HHS, Id: 5U01 CA143056
  • Agency: NCI NIH HHS, Id: K07 CA132892
  • Agency: NCI NIH HHS, Id: K07 CA132892
  • Agency: NCI NIH HHS, Id: P01-CA098101
  • Agency: NIDDK NIH HHS, Id: P30-DK050306
  • Agency: NCI NIH HHS, Id: R01 CA136673
  • Agency: NCI NIH HHS, Id: R01CA120979
  • Agency: NIDDK NIH HHS, Id: R01DK060758
  • Agency: NHLBI NIH HHS, Id: T35 HL007616
  • Agency: NCI NIH HHS, Id: U54 CA126513
  • Agency: NCI NIH HHS, Id: U54 CA126513-05
  • Agency: NCI NIH HHS, Id: U54 CA163004
  • Agency: NCI NIH HHS, Id: U54 CA163004-02

Mesh Terms

  • Adenocarcinoma
  • Animals
  • Barrett Esophagus
  • Bile Acids and Salts
  • Bone Morphogenetic Protein 4
  • Cardia
  • Esophageal Neoplasms
  • Esophagitis
  • Homeodomain Proteins
  • Interleukin-1beta
  • Interleukin-6
  • Metaplasia
  • Mice
  • Mice, Transgenic
  • Mucins
  • Muscle Proteins
  • Peptides
  • Receptor, Notch1
  • Signal Transduction
  • Stem Cells
  • Transcription Factors
  • Up-Regulation