Gastroenterology
Volume 138, Issue 5 , Pages 1810-1822.e2, May 2010

Aberrant Epithelial–Mesenchymal Hedgehog Signaling Characterizes Barrett's Metaplasia

  • David H. Wang

      Affiliations

    • Graduate Training Program in Cellular and Molecular Medicine, Johns Hopkins University, Baltimore, Maryland
    • Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
    • Department of Oncology, Johns Hopkins University, Baltimore, Maryland
    • Corresponding Author InformationReprint requests Address requests for reprints to: David H. Wang, MD, PhD, VANTHCS/UT Southwestern Medical Center, Research Service (151), 4500 S. Lancaster Road, Dallas, Texas 75216. fax: (214) 462-4953
    • ,
  • Nicholas J. Clemons

      Affiliations

    • Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
    • ,
  • Tomoharu Miyashita

      Affiliations

    • Department of Surgery, Johns Hopkins University, Baltimore, Maryland
    • ,
  • Adam J. Dupuy

      Affiliations

    • Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa
    • ,
  • Wei Zhang

      Affiliations

    • Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
    • Department of Oncology, Johns Hopkins University, Baltimore, Maryland
    • ,
  • Anette Szczepny

      Affiliations

    • Centre for Cancer Research, Monash Institute of Medical Research, Clayton, Victoria, Australia
    • ,
  • Ian M. Corcoran–Schwartz

      Affiliations

    • Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
    • Department of Oncology, Johns Hopkins University, Baltimore, Maryland
    • ,
  • Daniel L. Wilburn

      Affiliations

    • Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
    • Department of Oncology, Johns Hopkins University, Baltimore, Maryland
    • ,
  • Elizabeth A. Montgomery

      Affiliations

    • Department of Pathology, Johns Hopkins University, Baltimore, Maryland
    • ,
  • Jean S. Wang

      Affiliations

    • Department of Medicine, Johns Hopkins University, Baltimore, Maryland
    • ,
  • Nancy A. Jenkins

      Affiliations

    • Institute of Molecular and Cell Biology, Singapore
    • ,
  • Neal A. Copeland

      Affiliations

    • Institute of Molecular and Cell Biology, Singapore
    • ,
  • John W. Harmon

      Affiliations

    • Department of Surgery, Johns Hopkins University, Baltimore, Maryland
    • ,
  • Wayne A. Phillips

      Affiliations

    • Surgical Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
    • ,
  • D. Neil Watkins

      Affiliations

    • Graduate Training Program in Cellular and Molecular Medicine, Johns Hopkins University, Baltimore, Maryland
    • Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
    • Department of Oncology, Johns Hopkins University, Baltimore, Maryland
    • Centre for Cancer Research, Monash Institute of Medical Research, Clayton, Victoria, Australia
    • Corresponding Author InformationD. Neil Watkins, MMBS, PhD, FRACP, Monash Institute of Medical Research, 27-31 Wright Street, Clayton VIC 3168, Australia. fax: +61 3 9594-7252

Received 19 March 2008; accepted 27 January 2010. published online 04 February 2010.

Background & Aims

The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium.

Methods

Immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice.

Results

Marked up-regulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barrett's epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barrett's epithelium. We further show that expression of Deleted in Malignant Brain Tumors 1, the human homologue of the columnar cell factor Hensin, occurs in Barrett's epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9, and columnar cytokeratins.

Conclusions

Epithelial Hedgehog ligand expression may contribute to the initiation of Barrett's esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype.

Keywords: Hedgehog Signaling, Barrett's Esophagus, BMP4, SOX9

Abbreviations used in this paper: BE, Barrett's esophagus, Bmp, bone morphogenetic protein, DMBT, Deleted in Malignant Brain Tumors 1, Hh, Hedgehog, Ihh, Indian hedgehog, Ptch1, Patched1, qRT-PCR, quantitative real-time polymerase chain reaction, Shh, Sonic hedgehog, siRNA, small interfering RNA

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 Conflicts of interest The authors disclose no conflicts.

 Funding This work was supported by an American Society of Clinical Oncology (ASCO) Young Investigator Award (D.H.W.), Ruth L. Kirschstein NRSA F32CA-123945 (D.H.W.), a Victorian Cancer Agency Early Career Seed Grant (N.J.C.), Australian Research Council Discovery Project Grant DP0878303 (N.J.C.), National Institutes of Health grant 1K23DK068149 (J.S.W.), the Sidney Kimmel Cancer Research Foundation (D.N.W.), and the National Health and Medical Research Council (NHMRC) Australia, Fellowship 546107/Project Grant 546098 (D.N.W.). The Jerry D'Amato Charity Foundation and the Roy L. Jeannotte Foundation supported construction of the esophageal tissue microarrays.

PII: S0016-5085(10)00157-5

doi:10.1053/j.gastro.2010.01.048

Gastroenterology
Volume 138, Issue 5 , Pages 1810-1822.e2, May 2010

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