title: Dysfunctional transforming growth factor-β signaling with constitutively active Notch signaling in Barrett's esophageal adenocarcinoma.
abstract: BACKGROUND
  Esophageal adenocarcinoma is often considered to arise from a clonal stem-like population of cells, which is potentially responsible for its poor prognosis. Transforming growth factor β (TGF-β) and Notch signaling pathways play important roles in regulating self-renewal of stem cells and cell-fate determination. Both pathways are frequently implicated in gastrointestinal carcinogenesis. However, their contributions to esophageal adenocarcinoma remain unclear.
  
  
  METHODS
  We evaluated TGF-β and Notch signaling components in normal esophagus, Barrett's esophagus, and adenocarcinoma tissues and cell lines via immunohistochemical analysis and immunoblotting; Hes-1 transcription was assayed using a Hes-1 luciferase reporter.
  
  
  RESULTS
  We observed loss of Smad4 (P<.05) and β2 spectrin (β2SP) (P<.01) in 5/10 Barrett's esophagus and 17/22 adenocarcinoma tissue sections. Concomitantly, dramatically raised levels of Notch signaling components Hes1 and Jagged1 occurred in adenocarcinoma tissues and cell lines compared with normal tissues. In normal esophagus, Oct3/4-positive cells are located in the basal layer (2-3 per cluster), representing a pool of progenitor cells. We observed an expansion of this pool of Oct3/4 positive cells in esophageal adenocarcinoma (15 per cluster). Furthermore, a panel of SOXs proteins documented for stem cell markers exhibit increased expression in tumor cells, indicating expansion of putative cancer stem cells. Finally, we observed growth inhibition in BE3 cells with a γ-secretase inhibitor, but not in SKGT-4 cells. Unlike SKGT-4 cells, BE3 cells have activated Notch signaling with disruption of TGF-β signaling.
  
  
  CONCLUSIONS
  Our findings demonstrated a potential therapeutic value for targeted therapy in esophageal adenocarcinoma in the setting of loss of β2SP/TGF-β with concomitant constitutively active Notch signaling.
authors.affiliation: School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mendelson
authors.forename: Shumei
authors.initials: S
authors.lastname: Song
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Dipen M
authors.initials: DM
authors.lastname: Maru
authors.forename: Bibhuti
authors.initials: B
authors.lastname: Mishra
authors.forename: Marta
authors.initials: M
authors.lastname: Davila
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Hofstetter
authors.forename: Lopa
authors.initials: L
authors.lastname: Mishra
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D001471:Barrett Esophagus / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050677:Core Binding Factor Alpha 3 Subunit; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000378:metabolism*; D004947:Esophagus / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D050677:Core Binding Factor Alpha 3 Subunit; D051358:Cyclin-Dependent Kinase 4; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D050814:Octamer Transcription Factor-3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; D016212:Transforming Growth Factor beta; C000606273:JAG1 protein, human; C494173:POU5F1 protein, human; C493729:Runx3 protein, human; C078493:HES1 protein, human