Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis

Abstract

Haploinsufficiency of Dll4, a vascular-specific Notch ligand, has shown that it is essential for embryonic vascular development and arteriogenesis. Mechanistically, it is unclear how the Dll4-mediated Notch pathway contributes to complex vascular processes that demand meticulous coordination of multiple signalling pathways. Here we show that Dll4-mediated Notch signalling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing Dll4 with a Dll4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking Dll4 inhibited tumour growth in several tumour models. Remarkably, antibodies against Dll4 and antibodies against vascular endothelial growth factor (VEGF) had paradoxically distinct effects on tumour vasculature. Our data also indicate that Dll4-mediated Notch signalling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signalling globally, neutralizing Dll4 had no discernable impact on intestinal goblet cell differentiation, supporting the idea that Dll4-mediated Notch signalling is largely restricted to the vascular compartment. Therefore, targeting Dll4 might represent a broadly efficacious and well-tolerated approach for the treatment of solid tumours.

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

“…We have previously shown that Notch activation in melanoma has a critical role in driving tumor progression (Balint et al, 2005;Liu et al, 2006), and defined an oncogenic role for Notch signaling in melanocytic transformation (Pinnix et al, 2009). 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).…”

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

“…[69][70][71], inhibiting a signaling pathway predominantly activated in the CSCs (e.g., Notch, Wnt etc.) [72,73], immunomodulation (e.g., CD326, ALDH1 inhibitor) [73,74], sensitizing CSCs to systemic chemotherapy/radiation (e.g., IL4, hyaluronate receptor) [56,75] or inhibiting CSC angiogenesis (e.g., VEGF-R, DLL4) [76][77][78]. An important contribution of CSC research to anti-cancer targeted treatment is that it unveils specific biomarkers which can be targeted in vivo by antibody therapy leading to disrupted tumor growth [60,67,79,80].…”

Neuronal stem cells in the central nervous system and in human diseases

“…The delta-like ligand (Dll) 4, expressed in endothelial cells, is critical for vascular development (Benedito and Duarte, 2005). Using the neutralizing antibodies of Dll4 in glioma leads to an increase of the dysfunctional vascular system (NogueraTroise et al, 2006;Ridgway et al, 2006), resulting in poor tumor perfusion, poor oxygenation, and reduced tumor growth. Due to the essential role of Notch signaling in glioma progression, gamma-secretase inhibitors (GSI), which block Notch activation by transcriptional regulation, can be considered as good candidates for glioma therapeutic drugs (Miele et al, 2006;Gordon et al, 2008;Kovall, 2008).…”