Endothelial Dll4-Notch signaling in tumor microenvironment: is there any hidden therapeutic opportunity?

Tumor microenvironmental cross-talk between endothelial and cancer cells plays an essential role in growth, progression and therapeutic outcome of cancer. In response to tumor cell-derived vascular endothelial growth factor (VEGF), the endothelial delta-like ligand 4 (Dll4) regulates angiogenesis and tumor growth via Notch signaling. However, in view of intriguing effects of emerging Dll4-Notch signaling in various tumor types, the missing links need to be elucidated for development of this signaling as a possible therapeutic target for cancer therapy.