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

Tsunaki Hongu,Naoki Mochizuki,Yasunori Kanaho,Yuji Funakoshi,Susumu Sakimoto,Masatsugu Ema,Nobuyuki Takakura,Satoru Takahashi,Susumu Itoh,Hiroshi Hasegawa,Teruhiko Suzuki,Shigetomo Fukuhara,Mitsuyasu Kato

doi:10.1038/ncomms8925

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.

Highlights

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
It has been reported in a preclinical model that hepatocyte growth factor (HGF)/cMet signalling can act as an alternative angiogenic pathway in sunitinib-resistant tumours[16]
Since Tie[2] is expressed in haematopoietic as well as endothelial cells[28] and Tie2-expressing bone marrow-derived monocytes have been reported to promote tumour angiogenesis in mouse tumour models[29,30], we examined the possibility that ablation of Arf[6] in haematopoietic cells contributed to or created the tumour angiogenesis phenotype by performing bone marrow transplantations

Summary

Introduction

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. Grp[1] as well as other Arf[6] GEFs, such as GEP100, EFA6B and EFA6D, regulates HGF-stimulated b1 integrin recycling These findings provide insight into the mechanism of HGF-induced tumour angiogenesis and offer the possibility that targeting the HGF-activated Arf[6] signalling pathway may synergize with existing anti-angiogenic drugs to improve clinical outcomes. The in vivo functions of Arf[6] in endothelial cells, in particular in relationship to HGF-regulated tumour angiogenesis and growth, have not been explored

Methods

Results

Conclusion