Blockade of Dll4 Inhibits Tumour Growth by Promoting Non-Productive Angiogenesis

  1. Derek J. Chadwick Organizer and
  2. Jamie Goode
  1. Irene Noguera-Troise,
  2. Christopher Daly,
  3. Nicholas J. Papadopoulos,
  4. Sandra Coetzee,
  5. Pat Boland,
  6. Nicholas W. Gale,
  7. Hsin Chieh Lin,
  8. George D. Yancopoulos and
  9. Gavin Thurston

Published Online: 11 SEP 2007

DOI: 10.1002/9780470319413.ch9

Vascular Development: Novartis Foundation Symposium 283

Vascular Development: Novartis Foundation Symposium 283

How to Cite

Noguera-Troise, I., Daly, C., Papadopoulos, N. J., Coetzee, S., Boland, P., Gale, N. W., Lin, H. C., Yancopoulos, G. D. and Thurston, G. (2007) Blockade of Dll4 Inhibits Tumour Growth by Promoting Non-Productive Angiogenesis, in Vascular Development: Novartis Foundation Symposium 283 (eds D. J. Chadwick and J. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/9780470319413.ch9

Author Information

  1. Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA

  1. This paper was presented at the symposium by George D. Yancopoulos, to whom correspondence should be addressed.

  1. This paper is reproduced in modified form from Noguera-Troise et al (2006). Reprinted with permission from Macmillan Publishers Ltd: Nature 444:1032–1037, copyright 2006.

Publication History

  1. Published Online: 11 SEP 2007
  2. Published Print: 20 JUL 2007

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470034286

Online ISBN: 9780470319413

SEARCH

Keywords:

  • tumour angiogenesis Dll4 function;
  • Dll4 blockade and tumour growth inhibition;
  • vascular endothelial growth factor (VEGF) pathway blockade;
  • Dll4/Notch pathway in tumour angiogenesis;
  • tumour-derived VEGF and Dll4 expression

Summary

Tumour growth requires accompanying expansion of the host vasculature, with tumour progression often correlated with vascular density. Vascular endothelial growth factor (VEGF) is the best-characterized inducer of tumour angiogenesis. We report that VEGF dynamically regulates tumour endothelial expression of Delta-like ligand 4 (Dll4), which was previously shown to be absolutely required for normal embryonic vascular development. To define Dll4 function in tumour angiogenesis, we manipulated this pathway in murine tumour models using several approaches. Here we show that blockade resulted in markedly increased tumour vascularity, associated with enhanced angiogenic sprouting and branching. Paradoxically, this increased vascularity was nonproductive—as shown by poor perfusion and increased hypoxia, and most importantly, by decreased tumour growth—even for tumours resistant to anti-VEGF therapy. Thus, VEGF-induced Dll4 acts as a negative regulator of tumour angiogenesis; its blockade results in a striking uncoupling of tumour growth from vessel density, presenting a novel therapeutic approach even for tumours resistant to anti-VEGF therapies.