The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth

Nat Rev Cancer. 2007 May;7(5):327-31. doi: 10.1038/nrc2130.

Abstract

Anti-angiogenesis therapies have emerged as important treatment options for several types of tumours. To date, these therapies have focused on blocking the vascular endothelial growth factor (VEGF) pathway. A recent series of papers have shown that one ligand for the Notch receptors, Delta-like ligand 4 (DLL4), is normally induced by VEGF and is a negative-feedback regulator that restrains vascular sprouting and branching. Consistent with this role, the deletion or inhibition of DLL4 results in excessive, non-productive angiogenesis. This unrestrained angiogenesis unexpectedly and paradoxically decreases tumour growth, even in tumours resistant to anti-VEGF therapies. Can too much angiogenesis be bad for tumours but good for patients?

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Angiogenesis Inhibitors / pharmacology*
  • Calcium-Binding Proteins / metabolism
  • Disease Progression
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Membrane Proteins / metabolism
  • Models, Biological
  • Neoplasms / drug therapy*
  • Neovascularization, Pathologic*
  • Neovascularization, Physiologic
  • Receptors, Notch / metabolism
  • Serrate-Jagged Proteins
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*

Substances

  • Adaptor Proteins, Signal Transducing
  • Angiogenesis Inhibitors
  • Calcium-Binding Proteins
  • DLL4 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A