Increasing expression of hypoxia-inducible proteins in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence

Br J Cancer. 2007 May 7;96(9):1377-83. doi: 10.1038/sj.bjc.6603744. Epub 2007 Apr 17.


Hypoxia-associated markers are involved in the progression of several malignancies, but are relatively unstudied in Barrett's carcinogenesis. Our aim was to assess the immunohistochemical expression of hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, erythropoietin (Epo), Epo receptor (Epo-R), Glut-1 and vascular endothelial growth factor (VEGF) along with Ki67/MIB-1 in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. Endoscopic biopsies of normal squamous epithelium (NSE) (n=20), columnar-lined oesophagus (CLO) (n=15), CLO with intestinal metaplasia (n=20), dysplasia (n=17) and Barrett's type adenocarcinoma (n=20) were obtained. Immunohistochemistry was performed on the paraffin-embedded tissue. A score was calculated for each marker (range 0-300) by multiplying intensity (none 0, weak 1, moderate 2, strong 3) by percentage of expression (range 0-100). Significant increases in the expression of HIF-2alpha (P=0.014), VEGF (P<0.0001), Epo-R (P<0.0001) and Ki67 (P<0.0001) were found as tissue progressed from NSE to adenocarcinoma. HIF-2alpha was expressed late in the sequence and was only seen in dysplasia and adenocarcinoma. High HIF-2alpha expression was seen in 12 out of 20 Barrett's type adenocarcinoma. The late expression of HIF-2alpha in the Barrett's carcinogenesis sequence and its high expression in adenocarcinoma suggest that it is worth further investigation as a marker of disease progression and therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology*
  • Barrett Esophagus / genetics
  • Barrett Esophagus / pathology*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Biopsy
  • Disease Progression
  • Epithelial Cells / cytology
  • Epithelial Cells / pathology
  • Esophageal Diseases / pathology
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / pathology*
  • Esophagus / cytology
  • Esophagus / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunohistochemistry
  • Ki-67 Antigen / metabolism
  • Metaplasia
  • Receptors, Erythropoietin / metabolism
  • Reference Values
  • Vascular Endothelial Growth Factor A / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ki-67 Antigen
  • Receptors, Erythropoietin
  • Vascular Endothelial Growth Factor A
  • endothelial PAS domain-containing protein 1