Blocking of DLL4/Notch signaling deregulates tumor angiogenesis

1621 Haploinsufficiency of Dll4, a vascular specific Notch ligand, underscores its essential role in embryonic vascular development and arteriogenesis. Mechanistically, it remains to be defined how the Dll4-mediated Notch pathway contributes to the complex vascular processes. We took advantage of a Dll4-selective antibody and found that neutralizing Dll4 rendered endothelial cells hyperproliferative, and caused defective cell fate specification /differentiation both in vitro and in vivo. Preferential expression of Dll4 in tumor vasculature as opposed to normal tissue vessels suggests its possible role in tumor angiogenesis, yet it is still speculative whether Dll4 is directly involved in tumor angiogenesis. In our study, blocking of Dll4 showed significant anti-tumor efficacy in tumor models. Remarkably, anti-Dll4 and anti-VEGF exhibited paradoxically distinct effects on tumor vasculature. Our data also supports the notion that Dll4-mediated Notch signaling is largely restricted to the vascular compartment. Therefore, targeting Dll4 may represent a broadly efficacious and well-tolerated approach for the treatment of solid tumors.