The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth

Abstract

Anti-angiogenesis therapies have emerged as important treatment options for several types of tumours. To date, these therapies have focused on blocking the vascular endothelial growth factor (VEGF) pathway. A recent series of papers have shown that one ligand for the Notch receptors, Delta-like ligand 4 (DLL4), is normally induced by VEGF and is a negative-feedback regulator that restrains vascular sprouting and branching. Consistent with this role, the deletion or inhibition of DLL4 results in excessive, non-productive angiogenesis. This unrestrained angiogenesis unexpectedly and paradoxically decreases tumour growth, even in tumours resistant to anti-VEGF therapies. Can too much angiogenesis be bad for tumours but good for patients?

Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1

“…Additionally, Notch and Notch ligands, for example, Delta-like 4 (Dll4), are robustly expressed in tumor endothelial cells in comparison with that in neighboring, normal tissue vessels (Mailhos et al, 2001), and vascular endothelial growth factor, which can be predominately produced by tumor cells, can induce endothelial cells to express Notch1 and Dll4 (Liu et al, 2003;Noguera-Troise et al, 2006;Ridgway et al, 2006). In fact, blockade of Dll4-Notch signaling is an emerging therapeutic approach to inhibit tumor angiogenesis (Thurston et al, 2007;Dufraine et al, 2008;Yin et al, 2010). It appears that both the status of Notch signaling and outcomes of Notch pathway activation in terms of cellular behavior are opposite in melanoma and Fbs.…”

JAG2 Induction in Hypoxic Tumor Cells Alters Notch Signaling and Enhances Endothelial Cell Tube Formation

“…The mechanism behind the extension/formation of the new vasculature has been a recent subject of intense interest and has led to development of VEGF inhibitors for antiangiogenic tumor therapies. Recent studies have also unveiled the pivotal importance of Notch signaling in the process of angiogenesis, with specific focus on 2 Notch ligands DLL4 and JAG1 (5,(38)(39)(40)(41)(42). It is suggested that branching of new vasculature is a result of modulation of Notch signaling within the endothelial cells.…”

“…This process is a result of endothelial cell proliferation, migration, and differentiation along the VEGF gradient produced by the tumor (1). In addition to VEGF regulation of vascular development, branching and expansion of the vasculature are under the control of cell-cell activation of Notch signaling (5). Notch signaling is activated by membrane-bound ligand presentation to a Notch receptor on adjacent cells.…”

Inhibition of Notch and HIF enhances the antitumor effect of radiation in Notch expressing lung cancer

“…HIF-1α activates genes related to angiogenic factors, glycolytic enzymes and glucose transporters [32][33][34]. It has been reported that VEGF, which is a target gene for HIF signaling increases expression of DLL4, which is a ligand of Notch pathway, and, in turn, up-regulates Notch expression, leading to productive Notch signaling [35][36][37]. Moreover, Snail and Slug, which induced epithelial mesenchymal transition (EMT), were reported to be involved by the interaction of Notch and HIF under hypoxia (29.…”