Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-12

AUTHORS

Irene Noguera-Troise, Christopher Daly, Nicholas J. Papadopoulos, Sandra Coetzee, Pat Boland, Nicholas W. Gale, Hsin Chieh Lin, George D. Yancopoulos, Gavin Thurston

ABSTRACT

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 non-productive—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. More... »

PAGES

1032-1037

Journal

TITLE

Nature

ISSUE

7122

VOLUME

444

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature05355

    DOI

    http://dx.doi.org/10.1038/nature05355

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1037678066

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/17183313


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    27 schema:description 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 non-productive—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.
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