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.
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Nat Commun. 2015 Aug 4;6:7925. doi: 10.1038/ncomms8925.
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.
针对血管内皮细胞生长因子受体的抗血管生成药物提供了适度的临床益处，但部分原因是其他血管生成因子的作用，这些因子平行刺激肿瘤新生血管生成。为了克服这种冗余，需要针对这些其他信号通路的方法。在这里，我们使用内皮细胞靶向小鼠表明，小 GTPase Arf6 是肝细胞生长因子 (HGF) 诱导的肿瘤新生血管生成和生长所必需的。内皮细胞中 Arf6 的缺失会消除 HGF 刺激的β1 整合素回收。Arf6 的鸟嘌呤核苷酸交换因子 (GEF) Grp1 的药理学抑制可有效抑制肿瘤血管生成和生长。Grp1 以及其他 Arf6 GEF，如 GEP100、EFA6B 和 EFA6D，调节 HGF 刺激的β1 整合素回收。这些发现为 HGF 诱导的肿瘤血管生成的机制提供了深入了解，并提供了靶向 HGF 激活的 Arf6 信号通路可能与现有的抗血管生成药物协同作用以改善临床结果的可能性。
