Ephrin-B3 supports glioblastoma growth by inhibiting apoptosis induced by the dependence receptor EphA4

Oncotarget. 2017 Apr 4;8(14):23750-23759. doi: 10.18632/oncotarget.16077.


EphA4, an Ephrins tyrosine kinase receptor, behaves as a dependence receptor (DR) by triggering cell apoptosis in the absence of its ligand Ephrin-B3. DRs act as conditional tumor suppressors, engaging cell death based on ligand availability; this mechanism is bypassed by overexpression of DRs ligands in some aggressive cancers. The pair EphA4/Ephrin-B3 favors survival of neuronal progenitors of the brain subventricular zone, an area where glioblastoma multiform (GBM) are thought to originate. Here, we report that Ephrin-B3 is highly expressed in human biopsies and that it inhibits EphA4 pro-apoptotic activity in tumor cells. Angiogenesis is directly correlated with GBM aggressiveness and we demonstrate that Ephrin-B3 also supports the survival of endothelial cells in vitro and in vivo. Lastly, silencing of Ephrin-B3 decreases tumor vascularization and growth in a xenograft mice model. Interference with EphA4/Ephrin-B3 interaction could then be envisaged as a relevant strategy to slow GBM growth by enhancing EphA4-induced cell death.

Keywords: Ephrin-B3/EphA4; angiogenesis; apoptosis; dependence receptors; glioblastoma.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Chick Embryo
  • Ephrin-B3 / metabolism*
  • Female
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology*
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Mice
  • Mice, Nude
  • Receptor, EphA4 / metabolism*
  • Zebrafish


  • Ephrin-B3
  • Receptor, EphA4