Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis

摘要: VEGF, or vascular endothelial growth factor, is the best-characterized inducer of tumour angiogenesis, and blockade VEGF has become an important tool in cancer therapy. But not effective against all tumours, so search for alternative approaches continues. Two groups this week report that one such could be Dll4, Delta-like ligand 4. This transmembrane molecule part Notch signalling pathway. It was known to essential normal development blood vessels embryo: new work shows it also required angiogenesis. may a viable — potentially well tolerated patients with solid tumours are resistant anti-VEGF One two papers showing inhibition Dll4-mediated inhibits by deregulation Haploinsufficiency vascular-specific ligand, shown embryonic arteriogenesis1,2,3. Mechanistically, unclear how pathway contributes complex processes demand meticulous coordination multiple pathways. Here we show unique role regulating cell proliferation differentiation. Neutralizing Dll4 Dll4-selective antibody rendered cells hyperproliferative, caused defective fate specification differentiation both vitro vivo. In addition, blocking inhibited several models. Remarkably, antibodies factor (VEGF) had paradoxically distinct effects on vasculature. Our data indicate crucial during active vascularization, but less vessel maintenance. Furthermore, unlike globally, neutralizing no discernable impact intestinal goblet differentiation4,5, supporting idea largely restricted compartment. Therefore, targeting might represent broadly efficacious well-tolerated approach treatment tumours.