C94
Delta-like 4 Notch ligand promotes tumour progression and mediates tumour resistance to anti-VEGF therapy in vivo
Ji-Liang Li, Richard Sainson, Chern Oon, Russell Leek, Helen Turley, Laura Harrington, Helen Sheldon, Adrian Harris
University of Oxford, Oxford, UK
VEGF plays a key role in tumour angiogenesis. However, clinical trials targeting the VEGF pathway alone are often ineffective, suggesting that other factors/pathways are also important in tumour angiogenesis. We and others have previously shown that Notch ligand Delta-like 4 (DLL4) is upregulated in tumour vasculature and interacts functionally with the VEGF pathway. We demonstrated further that DLL4, when expressed in tumour cells, functions as a negative regulator of tumour angiogenesis but acts as a positive driver for tumour progression by activating Notch signaling in host endothelial cells and improving tumour vascular function. More importantly, DLL4 mediated tumour resistance to anti-VEGF therapy (bevacizumab) in vivo. Disruption of DLL4-Notch signaling not only abolished tumour resistance to anti-VEGF therapy but also enhanced the therapeutic efficiency of bevacizumab. The mechanisms for the resistance may partially due to reduced VEGFR2 expression in tumour large vessels and increased VEGFR1 expression in the tumour microenvironment thereby decreasing the tumour response to anti-VEGF therapy. Our results indicate that combined blockade of DLL4/Notch signalling and VEGF pathways may improve anti-tumour efficacy of anti-angiogenic therapy in the clinic.
