Effects of overexpression of ephrin-B2 on tumour growth in human colorectal cancer

Br J Cancer. 2004 Apr 19;90(8):1620-6. doi: 10.1038/sj.bjc.6601723.


Eph receptor tyrosine kinases (RTKs) and their membrane-bound ligands, the ephrins, are essential for embryonic vascular development. Recently, it has been demonstrated that overexpression of specific Ephs and ephrins is associated with a poor prognosis in human tumours. Our group has shown that EphB and the ephrin-B subfamilies are coexpressed in human colorectal cancer, and ephrin-B2 is expressed at higher levels in human colorectal cancer than in adjacent normal mucosa. As the Eph/ephrin system is involved in embryologic vasculogenesis and ephrin-B2 is expressed ubiquitously in all colon cancers studied in our laboratory, we hypothesised that overexpression of ephrin-B2 in colon cancer cells may induce tumour angiogenesis and increase tumour growth. To investigate this hypothesis, we stably transfected KM12L4 human colon cancer cells with ephrin-B2 to study its effect on tumour growth in vivo. We found that overexpression of ephrin-B2 markedly decreased tumour growth in a mouse xenograft model. Immunohistochemical staining showed that ephrin-B2 transfectants produced higher tumour microvessel density and lower tumour cell proliferation than did parental or vector-transfected control cells. Using (51)Cr-labelled red blood cells (RBCs) to determine the functional blood volume in tumours, we demonstrated that tumours from ephrin-B2-transfected cells had significantly decreased blood volume compared with tumours from parental or vector-transfected control cells. Evaluation of in vitro parameters of cell cycle mediators demonstrated no alteration in the cell cycle. Although ephrin-B2 transfection increased tumour vessel density, the decrease in blood perfusion suggests that these vessels may be 'dysfunctional'. We conclude that overexpression of ephrin-B2 suppresses tumour cell growth and vascular function in this in vivo colon cancer model.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Northern
  • Cell Cycle
  • Cell Division
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / pathology*
  • Ephrin-B2 / analysis
  • Ephrin-B2 / biosynthesis*
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry
  • Ligands
  • Mice
  • Mice, Nude
  • Neoplasms, Experimental
  • Neovascularization, Pathologic*
  • Protein-Tyrosine Kinases / pharmacology
  • Transfection
  • Tumor Cells, Cultured


  • Ephrin-B2
  • Ligands
  • Protein-Tyrosine Kinases