Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.
Haploinsufficiency of Dll4, a vascular-specific Notch ligand, has shown that it is essential for embryonic vascular development and arteriogenesis. Mechanistically, it is unclear how the Dll4-mediated Notch pathway contributes to complex vascular processes that demand meticulous coordination of multiple signalling pathways. Here we show that Dll4-mediated Notch signalling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing Dll4 with a Dll4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking Dll4 inhibited tumour growth in several tumour models. Remarkably, antibodies against Dll4 and antibodies against vascular endothelial growth factor (VEGF) had paradoxically distinct effects on tumour vasculature. Our data also indicate that Dll4-mediated Notch signalling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signalling globally, neutralizing Dll4 had no discernable impact on intestinal goblet cell differentiation, supporting the idea that Dll4-mediated Notch signalling is largely restricted to the vascular compartment. Therefore, targeting Dll4 might represent a broadly efficacious and well-tolerated approach for the treatment of solid tumours.
Ridgway
John
J
Tumor Biology & Angiogenesis, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Zhang
Gu
G
Wu
Yan
Y
Stawicki
Scott
S
Liang
Wei-Ching
WC
Chanthery
Yvan
Y
Kowalski
Joe
J
Watts
Ryan J
RJ
Callahan
Christopher
C
Kasman
Ian
I
Singh
Mallika
M
Chien
May
M
Tan
Christine
C
Hongo
Jo-Anne S
JA
de Sauvage
Fred
F
Plowman
Greg
G
Yan
Minhong
M
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000166:cytology; D006706:Homeostasis; D006801:Humans; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology*; D009389:Neovascularization, Pathologic; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C064045:delta protein