CX3CL1 Induces Vertebral Microvascular Barrier Dysfunction via the Src/P115-RhoGEF/ROCK Signaling Pathway
CX3CL1 Induces Vertebral Microvascular Barrier Dysfunction via the Src/P115-RhoGEF/ROCK Signaling Pathway
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CX3CL1 通过 Src/P115-RhoGEF/ROCK 信号通路诱导椎体微血管屏障功能障碍
DOI：
10.3389/fncel.2020.00096
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发表时间：
2020-04
影响因子：
5.3
通讯作者：
Jian Dong
中科院分区：
文献类型：
--
作者：
Lei Yi;Yun Liang;Quanming Zhao;Houlei Wang;Jian Dong
癌细胞的跨内皮迁移是肿瘤转移的关键步骤。远隔器官微血管屏障的破坏在肿瘤细胞的透射电子显微镜中起着重要作用。脊柱是多发性癌细胞转移的首选部位。我们先前的研究发现，椎体松质骨中富含CX3CL1，CX3CL1可以吸引表达Fractalkine受体的肿瘤细胞进入脊柱。在本研究中，我们确定了CX3CL1是否参与了椎体微血管屏障的破坏，并在椎体微血管系统中阻止了循环中的肿瘤细胞后促进了肿瘤细胞的透射电子显微镜。我们检测了CX3CL1在椎体微血管内皮细胞屏障功能中的作用，并探讨了CX3CL1导致椎体微血管内皮细胞屏障破坏的分子机制。我们的结果表明，CX3CL1导致VECs中F-肌动蛋白的形成和ZO-1的破坏，并导致椎体微血管屏障的破坏。重要的是，我们发现，在CX3CL1诱导的血管内皮细胞应激纤维形成、ZO-1破坏以及椎体微血管屏障高通透性的形成过程中，Src/P115-Rhogef/ROCK信号通路的激活起着重要作用。抑制VMECs中的Src/P115-Rhogef/ROCK信号有效地阻断了CX3CL1诱导的椎体血管内皮细胞功能障碍和随后的肿瘤细胞透射电子显微镜。本研究和我们以前的研究结果表明，除了趋化作用外，CX3CL1还在调节椎体微血管屏障功能和肿瘤细胞透射电子显微镜中发挥关键作用。CX3CL1通过激活Src/P115-Rhogef/ROCK信号通路，诱导血管内皮细胞应激纤维形成、ZO-1断裂，进而导致血管内皮细胞通透性增高。抑制VMECs中的Src/P115-Rhogef/ROCK信号通路有效地阻断了椎体松质骨中的肿瘤细胞TEM，可能是未来治疗脊柱转移瘤的一种潜在策略。
Trans-endothelial migration (TEM) of cancer cells is a critical step in metastasis. Micro-vascular barrier disruptions of distant organs play important roles in tumor cells TEM. The spine is a preferred site for multiple cancer cell metastases. Our previous study found that vertebral spongy bone was rich in CX3CL1 and that CX3CL1 can attract fractalkine receptor-expressing tumor cells to the spine. In the present study, we determined whether CX3CL1 was involved in vertebral micro-vascular barrier disruption and promoted tumor cell TEM after circulating tumor cells were arrested in the vertebral micro-vasculature. We examined the role of CX3CL1 in the barrier function of vertebral micro-vascular endothelial cells (VMECs) and explored the molecular mechanisms of CX3CL1-induced VMEC barrier disruption. Our results demonstrated that CX3CL1 led to F-actin formation and ZO-1 disruption in VMECs and induced the vertebral micro-vascular barrier disruption. Importantly, we found that the activation of the Src/P115-RhoGEF/ROCK signaling pathway plays an important role in CX3CL1-induced VMEC stress fiber formation, ZO-1 disruption and then vertebral micro-vascular barrier hyper-permeability. Inhibiting Src/P115-RhoGEF/ROCK signaling in VMECs effectively blocked CX3CL1-induced vertebral vascular endothelial dysfunction and subsequent tumor cell TEM. The results of this study and our previous study indicate that in addition to its chemotaxis, CX3CL1 plays a critical role in regulating vertebral micro-vascular barrier function and tumor cell TEM. CX3CL1 induced VMECs stress fiber formation, ZO-1 disruption and then vascular endothelial hyperpermeability via activation of the Src/P115-RhoGEF/ROCK signaling pathway. The inhibition of the Src/P115-RhoGEF/ROCK signaling pathway in VMECs effectively blocked tumor cells TEMs in vertebral spongy bone and maybe a potential therapeutic strategy for spine metastases in the future.
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影响因子：
3.7
作者：
S. Pedersen;E. Hoffmann
通讯作者：
S. Pedersen;E. Hoffmann
影响因子：
5.3
作者：
Yi Lei;Chang Mengling;Zhao Quanming;Zhou Zengding;Huang Xiaoqin;Guo Feng;Huan Jingning
通讯作者：
Huan Jingning
影响因子：
4
作者：
Feifei Ren;Qitai Zhao;Lan Huang;Yujia Zheng;Lifeng Li;Qianyi He;Chaoqi Zhang;Feng Li;N. R. Maimela;Zhi Sun;Qing‐quan Jia;Y. Ping;Zhen Zhang;Xinfeng Chen;Ying Yue;Shasha Liu;Ling Cao;Yi Zhang
通讯作者：
Feifei Ren;Qitai Zhao;Lan Huang;Yujia Zheng;Lifeng Li;Qianyi He;Chaoqi Zhang;Feng Li;N. R. Maimela;Zhi Sun;Qing‐quan Jia;Y. Ping;Zhen Zhang;Xinfeng Chen;Ying Yue;Shasha Liu;Ling Cao;Yi Zhang
影响因子：
2.1
作者：
Lum, H;Malik, AB
通讯作者：
Malik, AB
影响因子：
4.6
作者：
Wu TH;Kuo YY;Lee HH;Kuo JC;Ou MH;Chang ZF
通讯作者：
Chang ZF