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Nat Commun. 2015 Aug 4;6:7925. doi: 10.1038/ncomms8925.

Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling.

Author information

1
Department of Physiological Chemistry, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
2
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
3
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
4
Department of Anatomy and Embryology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
5
Department of Experimental Pathology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.

Abstract

Anti-angiogenic drugs targeting vascular endothelial cell growth factor receptor have provided modest clinical benefit, in part, owing to the actions of additional angiogenic factors that stimulate tumour neoangiogenesis in parallel. To overcome this redundancy, approaches targeting these other signalling pathways are required. Here we show, using endothelial cell-targeted mice, that the small GTPase Arf6 is required for hepatocyte growth factor (HGF)-induced tumour neoangiogenesis and growth. Arf6 deletion from endothelial cells abolishes HGF-stimulated β1 integrin recycling. Pharmacological inhibition of the Arf6 guanine nucleotide exchange factor (GEF) Grp1 efficiently suppresses tumour vascularization and growth. Grp1 as well as other Arf6 GEFs, such as GEP100, EFA6B and EFA6D, regulates HGF-stimulated β1 integrin recycling. These findings provide insight into the mechanism of HGF-induced tumour angiogenesis and offer the possibility that targeting the HGF-activated Arf6 signalling pathway may synergize with existing anti-angiogenic drugs to improve clinical outcomes.

PMID:
26239146
DOI:
10.1038/ncomms8925
[Indexed for MEDLINE]

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