Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-12

AUTHORS

John Ridgway, Gu Zhang, Yan Wu, Scott Stawicki, Wei-Ching Liang, Yvan Chanthery, Joe Kowalski, Ryan J. Watts, Christopher Callahan, Ian Kasman, Mallika Singh, May Chien, Christine Tan, Jo-Anne S. Hongo, Fred de Sauvage, Greg Plowman, Minhong Yan

ABSTRACT

Haploinsufficiency of Dll4, a vascular-specific Notch ligand, has shown that it is essential for embryonic vascular development and arteriogenesis. Mechanistically, it is unclear how the Dll4-mediated Notch pathway contributes to complex vascular processes that demand meticulous coordination of multiple signalling pathways. Here we show that Dll4-mediated Notch signalling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing Dll4 with a Dll4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking Dll4 inhibited tumour growth in several tumour models. Remarkably, antibodies against Dll4 and antibodies against vascular endothelial growth factor (VEGF) had paradoxically distinct effects on tumour vasculature. Our data also indicate that Dll4-mediated Notch signalling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signalling globally, neutralizing Dll4 had no discernable impact on intestinal goblet cell differentiation, supporting the idea that Dll4-mediated Notch signalling is largely restricted to the vascular compartment. Therefore, targeting Dll4 might represent a broadly efficacious and well-tolerated approach for the treatment of solid tumours. More... »

PAGES

1083

Journal

TITLE

Nature

ISSUE

7122

VOLUME

444

Author Affiliations

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature05313

    DOI

    http://dx.doi.org/10.1038/nature05313

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/17183323


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