Blockade of Dll4 Inhibits Tumour Growth by Promoting Non-Productive Angiogenesis

Nature. 2006 Dec 21;444(7122):1032-7. doi: 10.1038/nature05355.

Abstract

Tumour growth requires accompanying expansion of the host vasculature, with tumour progression often correlated with vascular density. Vascular endothelial growth factor (VEGF) is the best-characterized inducer of tumour angiogenesis. We report that VEGF dynamically regulates tumour endothelial expression of Delta-like ligand 4 (Dll4), which was previously shown to be absolutely required for normal embryonic vascular development. To define Dll4 function in tumour angiogenesis, we manipulated this pathway in murine tumour models using several approaches. Here we show that blockade resulted in markedly increased tumour vascularity, associated with enhanced angiogenic sprouting and branching. Paradoxically, this increased vascularity was non-productive-as shown by poor perfusion and increased hypoxia, and most importantly, by decreased tumour growth-even for tumours resistant to anti-VEGF therapy. Thus, VEGF-induced Dll4 acts as a negative regulator of tumour angiogenesis; its blockade results in a striking uncoupling of tumour growth from vessel density, presenting a novel therapeutic approach even for tumours resistant to anti-VEGF therapies.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Cell Hypoxia
  • Cell Line, Tumor
  • Gene Expression Regulation
  • Genes, Reporter / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Neoplasms / blood supply*
  • Neoplasms / drug therapy
  • Neoplasms / pathology*
  • Neovascularization, Pathologic* / drug therapy
  • Rats
  • Receptors, Notch / metabolism
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Notch
  • Vascular Endothelial Growth Factor A
  • delta protein