Hongu Tsunaki, Yamauchi Yohei, Funakoshi Yuji, Katagiri Naohiro, Ohbayashi Norihiko, Kanaho Yasunori
a Department of Physiological Chemistry , Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba , Tsukuba , Japan.
Small GTPases. 2016 Apr 2;7(2):47-53. doi: 10.1080/21541248.2016.1154640. Epub 2016 Feb 24.
Although several lines of evidence have shown that the small GTPase ADP-ribosylation factor 6 (Arf6) plays pivotal roles in cancer progression of several types of cancers, little is known about the functions of Arf6 in tumor microenvironment. We demonstrated that Arf6 in vascular endothelial cells (VECs) plays a crucial role in tumor angiogenesis and growth using endothelial cell-specific Arf6 conditional knockout mice into which B16 melanoma and Lewis lung carcinoma cells were implanted. It was also found that Arf6 in VECs positively regulates hepatocyte growth factor (HGF)-induced β1 integrin recycling, which is a critical event for tumor angiogenesis by promoting cell migration. Importantly, pharmacological inhibition of HGF-induced Arf6 activation significantly suppresses tumor angiogenesis and growth in mice, suggesting that Arf6 signaling would be a potential target for anti-angiogenic therapy. In this manuscript, we summarize the multiple roles of Arf6 in cancer progression, particularly in cancer cell invasion/metastasis and our recent findings on tumor angiogenesis, and discuss a possible approach to develop innovative anti-cancer drugs.
尽管有几条证据表明小GTP酶ADP核糖基化因子6（Arf6）在多种癌症的进展中起关键作用，但对于Arf6在肿瘤微环境中的功能却知之甚少。我们利用植入了B16黑色素瘤和Lewis肺癌细胞的内皮细胞特异性Arf6条件性敲除小鼠，证明了血管内皮细胞（VECs）中的Arf6在肿瘤血管生成和生长中起关键作用。还发现VECs中的Arf6正向调节肝细胞生长因子（HGF）诱导的β1整合素循环，这是通过促进细胞迁移实现肿瘤血管生成的关键事件。重要的是，对HGF诱导的Arf6激活的药理学抑制显著抑制了小鼠的肿瘤血管生成和生长，这表明Arf6信号可能是抗血管生成治疗的潜在靶点。在本手稿中，我们总结了Arf6在癌症进展中的多种作用，特别是在癌细胞侵袭/转移方面以及我们最近关于肿瘤血管生成的发现，并讨论了开发创新抗癌药物的可能方法。
