Dll4-Notch signaling as a therapeutic target in tumor angiogenesis

Abstract

Tumor angiogenesis is an important target for cancer therapy, with most current therapies designed to block the VEGF signaling pathway. However, clinical resistance to anti-VEGF therapy highlights the need for targeting additional tumor angiogenesis signaling pathways. The endothelial Notch ligand Dll4 (delta-like 4) has recently emerged as a critical regulator of tumor angiogenesis and thus as a promising new therapeutic anti-angiogenesis target. Blockade of Dll4-Notch signaling in tumors results in excessive, non-productive angiogenesis with resultant inhibitory effects on tumor growth, even in some tumors that are resistant to anti-VEGF therapies. As Dll4 inhibitors are entering clinical cancer trials, this review aims to provide current perspectives on the function of the Dll4-Notch signaling axis during tumor angiogenesis and as a target for anti-angiogenic cancer therapy.

Figure 1

Effects of Dll4-Notch inhibition on tumor angiogenesis. Blockade of Dll4-Notch signaling in endothelial cells leads to tumor vessel abnormalization characterized by increased tumor vessel sprouting and decreased vascular perfusion. It is currently not clear whether hypersprouting leads to decreased tumor perfusion (left hand axis) or decreased perfusion leads to hypersprouting (right hand axis), or whether both occur in parallel. The overall effect of Dll4-Notch blockade is decreased tumor perfusion and reduced tumor growth.

Figure 2

Interaction of the Delta-Notch axis with other signaling pathways in endothelial cells. Solid lines denote protein-protein interactions, while dashed lines indicate transcriptional regulation. Binding of VEGF to VEGF receptors (VEGFR2) results in the transcriptional up-regulation of Dll4. Dll4-mediated activation of the Notch receptor on an adjacent endothelial cell leads to the transcriptional repression of VEGFR expression. EphrinB2 is a Dll4-Notch target gene, but also acts upstream of Dll4-Notch signaling as a regulator of VEGFR endocytosis and signaling. Other putative signaling pathways downstream of Dll4-Notch include apelin, ESM-1, Ang2 and Wnt, while FGF, Wnt and Ang1 are potential upstream activators of Dll4 expression.