The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth.
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?
Thurston
Gavin
G
Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA. Gavin.Thurston@regeneron.com
Noguera-Troise
Irene
I
Yancopoulos
George D
GD
D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A