Oncotarget

Research Papers:

Role of Delta-like 4 in Jagged1-induced tumour angiogenesis and tumour growth

Chern Ein Oon, Esther Bridges, Helen Sheldon, Richard C.A. Sainson, Adrian Jubb, Helen Turley, Russell Leek, Francesca Buffa, Adrian L. Harris and Ji-Liang Li _

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Oncotarget. 2017; 8:40115-40131. https://doi.org/10.18632/oncotarget.16969

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Abstract

Chern Ein Oon1,2, Esther Bridges1, Helen Sheldon1, Richard C.A. Sainson1, Adrian Jubb1, Helen Turley1, Russell Leek1, Francesca Buffa1, Adrian L. Harris1,* and Ji-Liang Li1,3,*

1 Molecular Oncology Laboratories, Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

2 Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang, Malaysia

3 Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK

* These authors are joint senior authors

Correspondence to:

Ji-Liang Li, email:

Keywords: Notch signalling, DLL4, JAG1, angiogenesis, bevacizumab

Received: January 23, 2017 Accepted: March 11, 2017 Published: April 08, 2017

Abstract

Delta-like 4 (DLL4) and Jagged1 (JAG1) are two key Notch ligands implicated in tumour angiogenesis. They were shown to have opposite effects on mouse retinal and adult regenerative angiogenesis. In tumours, both ligands are upregulated but their relative effects and interactions in tumour biology, particularly in tumour response to therapeutic intervention are unclear. Here we demonstrate that DLL4 and JAG1 displayed equal potency in stimulating Notch target genes in HMEC-1 endothelial cells but had opposing effects on sprouting angiogenesis in vitro. Mouse DLL4 or JAG1 expressed in glioblastoma cells decreased tumour cell proliferation in vitro but promoted tumour growth in vivo. mDLL4-expressing tumours showed fewer but larger vessels whereas mJAG1-tumours produced more vessels. In both tumour types pericyte coverage was decreased but the vessels were more perfused. Both ligands increased tumour resistance towards anti-VEGF therapy but the resistance was higher in mDLL4-tumours versus mJAG1-tumours. However, their sensitivity to the therapy was restored by blocking Notch signalling with dibenzazepine. Importantly, anti-DLL4 antibody blocked the effect of JAG1 on tumour growth and increased vessel branching in vivo. The mechanism behind the differential responsiveness was due to a positive feedback loop for DLL4-Notch signalling, rendering DLL4 more dominant in activating Notch signalling in the tumour microenvironment. We concluded that DLL4 and JAG1 promote tumour growth by modulating tumour angiogenesis via different mechanisms. JAG1 is not antagonistic but utilises DLL4 in tumour angiogenesis. The results suggest that anti-JAG1 therapy should be explored in conjunction with anti-DLL4 treatment in developing anti-Notch therapies in clinics.


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