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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?

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Figure 1: The Delta/Jagged–Notch signalling pathway.
Figure 2: Comparison of VEGF versus DLL4–Notch inhibition in tumour angiogenesis.

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Acknowledgements

The authors gratefully acknowledge the valuable scientific contributions of many Regeneron colleagues, including I. Lobov, S. Wiegand, N. Gale, N. Papadopoulos, C. Daly, J. Rudge, E. Smith, S. Davis and H. C. Lin.

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Correspondence to Gavin Thurston.

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The authors are employees of Regeneron Pharmaceuticals.

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Thurston, G., Noguera-Troise, I. & Yancopoulos, G. The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer 7, 327–331 (2007). https://doi.org/10.1038/nrc2130

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