title: Activation of the BMP4 pathway and early expression of CDX2 characterize non-specialized columnar metaplasia in a human model of Barrett's esophagus.
abstract: BACKGROUND
  A human model of gastroesophageal reflux disease was used to examine the contribution of a non-specialized columnar type of metaplasia (NSCM) and key molecular events (BMP4 and CDX2) in the development of Barrett's esophagus.
  
  
  METHODS
  Biopsies of the remnant esophagus from 18 patients undergoing esophagectomy with gastric preservation were taken at 6-36-month intervals postoperatively and examined for activation of the BMP pathway (BMP4/P-Smad 1/5/8) and CDX2 and CDX1 expression by imunohistochemistry, quantitative real-time PCR, Western blot, and in situ hybridization.
  
  
  RESULTS
  A short segment (mean 15.6 mm) of NSCM was detected in 10 (56%) patients, with an increasing prevalence from 17% at 6 months to 62% at 36 months. Nuclear expression of P-Smad 1/5/8 in the squamous epithelium close to the anastomosis with strong expression in all epithelial cells of NSCM areas was found. Forty-eight (63%) biopsies with NSCM showed scattered nuclear expression of CDX2. Two cases showed isolated glands at 18, 24, and 36 months that fully expressed CDX2 and co-expressed CDX1. BMP4 mRNA and CDX2 mRNA levels were significantly greater in NSCM than in squamous epithelium.
  
  
  CONCLUSIONS
  BMP4 activation in NSCM and early expression of CDX2 are involved in the columnar epithelial differentiation of Barrett's esophagus.
authors.affiliation: Section of Gastrointestinal Surgery, Parc de Salut Mar and Institut de Recerca Hospital del Mar (IMIM-Hospital del Mar), Universitat Autònoma de Barcelona, Passeig Maritim 25-29, 08003, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castillo
authors.forename: Sonia
authors.initials: S
authors.lastname: Puig
authors.forename: Mar
authors.initials: M
authors.lastname: Iglesias
authors.forename: Agustín
authors.initials: A
authors.lastname: Seoane
authors.forename: Carme
authors.initials: C
authors.lastname: de Bolós
authors.forename: Vicente
authors.initials: V
authors.lastname: Munitiz
authors.forename: Pascual
authors.initials: P
authors.lastname: Parrilla
authors.forename: Laura
authors.initials: L
authors.lastname: Comerma
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.forename: Kausilia K
authors.initials: KK
authors.lastname: Krishnadath
authors.forename: Luís
authors.initials: L
authors.lastname: Grande
authors.forename: Manuel
authors.initials: M
authors.lastname: Pera
mesh_terms: D000368:Aged; D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D000071616:CDX2 Transcription Factor; D016629:Esophagectomy; D005260:Female; D005500:Follow-Up Studies; D005764:Gastroesophageal Reflux / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008679:Metaplasia / Q000378:metabolism; D008875:Middle Aged; D055262:Mucin-2 / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism
chemical_list: C525809:BMP4 protein, human; D015415:Biomarkers; D055415:Bone Morphogenetic Protein 4; C491273:CDX1 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; C524625:MUC2 protein, human; D055262:Mucin-2; D051896:Smad Proteins, Receptor-Regulated
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