EphB Receptor Activity Suppresses Colorectal Cancer Progression

Nature. 2005 Jun 23;435(7045):1126-30. doi: 10.1038/nature03626.

Abstract

Most sporadic colorectal cancers are initiated by activating Wnt pathway mutations, characterized by the stabilization of beta-catenin and constitutive transcription by the beta-catenin/T cell factor-4 (Tcf-4) complex. EphB guidance receptors are Tcf4 target genes that control intestinal epithelial architecture through repulsive interactions with Ephrin-B ligands. Here we show that, although Wnt signalling remains constitutively active, most human colorectal cancers lose expression of EphB at the adenoma-carcinoma transition. Loss of EphB expression strongly correlates with degree of malignancy. Furthermore, reduction of EphB activity accelerates tumorigenesis in the colon and rectum of Apc(Min/+) mice, and results in the formation of aggressive adenocarcinomas. Our data demonstrate that loss of EphB expression represents a critical step in colorectal cancer progression.

MeSH terms

  • Adenoma / metabolism
  • Adenoma / pathology
  • Animals
  • Cell Line, Tumor
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Disease Progression
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Genes, APC
  • Genes, Dominant / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Eph Family / deficiency
  • Receptors, Eph Family / genetics
  • Receptors, Eph Family / metabolism*
  • Signal Transduction
  • Wnt Proteins

Substances

  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Wnt Proteins
  • Receptors, Eph Family