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?