Dll4-Notch signaling as a therapeutic target in tumor angiogenesis

The concept that solid tumors require the growth of new blood vessels (angiogenesis) for oxygen and nutrient supply, first proposed by Folkman 40 years ago [1], is now solidly accepted and has spurred substantial efforts to develop anticancer therapeutics that interfere with tumor angiogenesis. Many of the angiogenic signaling pathways necessary for embryonic development are reactivated during tumor angiogenesis, and as such represent targets for anti-angiogenic cancer therapy. VEGF (vascular endothelial growth factor) is a primary endothelial cell growth factor, and blockade of the VEGF signaling pathway is now a clinically approved and widely used therapy for cancer. However, inherent or acquired resistance to anti-VEGF therapy is frequently observed in tumors, thus illustrating the need for targeting additional angiogenesis pathways to fully exploit the promise of anti-angiogenic cancer therapy. Notch signaling has recently emerged as a critical regulator of developmental and tumor angiogenesis. Notch signaling in both endothelial and smooth muscle cells appears to provide critical regulatory information to these cells downstream of the initiating signal induced by VEGF. In particular, the Notch ligand Dll4 (delta-like 4) has been identified as a promising new target in tumor angiogenesis in preclinical studies. Pharmacological Dll4 inhibitors have been developed and are entering clinical trials for solid tumors. This review aims to provide current perspectives on the function of Dll4-Notch signaling axis during tumor angiogenesis and on mechanisms and applications of targeting this pathway for cancer therapy.The Notch pathway is an evolutionary conserved signaling system that regulates cell fate specification, tissue patterning and morphogenesis by modulating cell differentiation, proliferation, apoptosis and survival [2-4]. In mammals, the core components of the pathway include five canonical DSL (Delta, Serrate, Lag2) ligands (called Dll1, 3, 4, and Jagged1 an