Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis

Haploinsufficiency of DII4, a vascular-specific Notch ligand, has shown that it is essential for embryonic vascular development and arteriogenesis(1-3). Mechanistically, it is unclear how the DII4-mediated Notch pathway contributes to complex vascular processes that demand meticulous coordination of multiple signalling pathways. Here we show that DII4-mediated Notch signalling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing DII4 with a DII4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking DII4 inhibited tumour growth in several tumour models. Remarkably, antibodies against DII4 and antibodies against vascular endothelial growth factor (VEGF) had paradoxically distinct effects on tumour vasculature. Our data also indicate that DII4-mediated Notch signalling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signalling globally, neutralizing DII4 had no discernable impact on intestinal goblet cell differentiation(4,5), supporting the idea that DII4-mediated Notch signalling is largely restricted to the vascular compartment. Therefore, targeting DII4 might represent a broadly efficacious and well-tolerated approach for the treatment of solid tumours.