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

Tsunaki Hongu, Yuji Funakoshi, Shigetomo Fukuhara, Teruhiko Suzuki, Susumu Sakimoto, Nobuyuki Takakura, Masatsugu Ema, Satoru Takahashi, Susumu Itoh, Mitsuyasu Kato, Hiroshi Hasegawa, Naoki Mochizuki and Yasunori Kanaho ()
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Tsunaki Hongu: Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba
Yuji Funakoshi: Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba
Shigetomo Fukuhara: National Cerebral and Cardiovascular Center Research Institute
Teruhiko Suzuki: Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba
Susumu Sakimoto: Research Institute for Microbial Diseases, Osaka University
Nobuyuki Takakura: Research Institute for Microbial Diseases, Osaka University
Masatsugu Ema: Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba
Satoru Takahashi: Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba
Susumu Itoh: Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba
Mitsuyasu Kato: Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba
Hiroshi Hasegawa: Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba
Naoki Mochizuki: National Cerebral and Cardiovascular Center Research Institute
Yasunori Kanaho: Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8925

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