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Role of ephrinB2 in nonproductive angiogenesis induced by Delta-like 4 blockade

Shinsuke Yamanda1, Satoru Ebihara, Masanori Asada

  • 1Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Japan.

Blood
|February 17, 2009
PubMed

Insights

Blocking Delta-like 4 (DLL4) triggers nonproductive angiogenesis by suppressing ephrinB2. This mechanism reveals a crucial role for ephrinB2 in DLL4-mediated anti-tumor effects and vascular development.

Area of Science:

  • Oncology
  • Vascular Biology
  • Molecular Signaling

Background:

  • Delta-like 4 (DLL4) is a Notch ligand vital for vascular development.
  • DLL4 blockade inhibits tumor growth via nonproductive angiogenesis, but mechanisms are unclear.

Purpose of the Study:

  • Investigate the VEGF-DLL4-ephrinB2 cascade in DLL4 blockade-induced nonproductive angiogenesis.
  • Elucidate the role of ephrinB2 in the anti-angiogenic effects of DLL4 blockade.

Main Methods:

  • Utilized newly developed neutralizing antibodies against mouse and human DLL4.
  • Assessed tumor growth, vascular density, and tissue perfusion in vivo.
  • Examined human umbilical vein endothelial cell (HUVEC) proliferation, cord length, and branch points in vitro.
  • Investigated ephrinB2 expression and function using RNA interference.

Main Results:

  • DLL4 blockade suppressed tumor growth and induced nonproductive angiogenesis.
  • DLL4 blockade reduced ephrinB2 expression in tumors.
  • DLL4 blockade promoted HUVEC proliferation, additively with VEGF.
  • Knockdown of ephrinB2 mimicked DLL4 blockade effects on HUVEC tubular formation.

Conclusions:

  • EphrinB2 plays a critical role in nonproductive angiogenesis induced by DLL4 blockade.
  • The VEGF-DLL4-ephrinB2 pathway is implicated in the anti-tumor effects of DLL4 blockade.

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