Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.
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 nonproductive--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.
Noguera-Troise
Irene
I
Regeneron Research Laboratories, 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Daly
Christopher
C
Papadopoulos
Nicholas J
NJ
Coetzee
Sandra
S
Boland
Pat
P
Gale
Nicholas W
NW
Lin
Hsin Chieh
HC
Yancopoulos
George D
GD
Thurston
Gavin
G