The role of sema4D in vasculogenic mimicry formation in non-small cell lung cancer and the underlying mechanisms
The role of sema4D in vasculogenic mimicry formation in non-small cell lung cancer and the underlying mechanisms
复制标题
sema4D在非小细胞肺癌血管生成拟态形成中的作用及其机制
DOI：
10.1002/ijc.31958
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发表时间：
2018
影响因子：
6.4
通讯作者：
Gang Wu
中科院分区：
文献类型：
--
作者：
Yun Xia;Xian-Yi Cai;Ji-Quan Fan;Li-Ling Zhang;Jing-Hua Ren;Zhen-Yu Li;Rui-Guang Zhang;Fang Zhu;Gang Wu
血管生成拟态（VM）是恶性肿瘤中一种特殊的血管模式，由高度侵袭性的肿瘤细胞组成。这种肿瘤细胞介导的血液供应模式与癌症患者的不良预后密切相关。轴突导向因子Sema4D与其高亲和力受体plexinB1相互作用可激活小GTPase RhoA及其下游ROCKs；这一过程在内皮细胞的迁移和肿瘤血管生成中具有积极的作用。在此，我们开始揭示该通路在非小细胞肺癌 (NSCLC) VM 形成中的作用。首先，我们证实了NSCLC组织中这种特殊形式的脉管系统，并发现肿瘤组织中VM通道的存在与Sema4D表达相关。此外，我们发现在人 NSCLC 细胞 H1299 和 HCC827 中抑制 Sema4D 可以减少体内和体外 VM 的形成。此外，我们证明通过siRNA表达载体下调plexinB1的表达并使用fasudil抑制RhoA/ROCK信号通路可以减少H1299和HCC827细胞的VM形成。最后，我们发现抑制 Sema4D 会导致应力纤维减少并耗尽 H1299 和 HCC827 细胞的运动性。总的来说，我们的研究表明 Sema4D 通过激活 RhoA/ROCK 通路并调节肿瘤细胞的可塑性和迁移，在 NSCLC VM 形成过程中发挥重要作用。调节 Sema4D/plexinB1 和下游 RhoA/ROCK 通路可能会通过 VM 模式阻止肿瘤血液供应，最终可能阻止 NSCLC 的生长和转移。
Vasculogenic mimicry (VM) is a special vascular pattern in malignant tumors, which is composed of highly aggressive tumor cells. This tumor cell‐mediated blood supply pattern is closely associated with a poor prognosis in cancer patients. The interaction of axon guidance factor Sema4D and its high affinity receptor plexinB1 could activate small GTPase RhoA and its downstream ROCKs; this process has an active role in the migration of endothelial cells and tumor angiogenesis. Here, we have begun to uncover the role of this pathway in VM formation in non‐small cell lung cancer (NSCLC). First, we confirmed this special form of vasculature in NSCLC tissues and found the existence of VM channels in tumor tissues was correlated with Sema4D expression. Further, we found that inhibition of Sema4D in the human NSCLC cells H1299 and HCC827 reduces VM formation bothin vitroandin vivo. Moreover, we demonstrated that downregulating the expression of plexinB1 by siRNA expressing vectors and inhibiting the RhoA/ROCK signaling pathway using fasudil can reduce VM formation of H1299 and HCC827 cells. Finally, we found that suppression of Sema4D leads to less stress fibers and depleted the motility of H1299 and HCC827 cells. Collectively, our study implicates Sema4D plays an important role in the process of VM formation in NSCLC through activating the RhoA/ROCK pathway and regulating tumor cell plasticity and migration. Modulation of the Sema4D/plexinB1 and downstream RhoA/ROCK pathway may prevent the tumor blood supply through the VM pattern, which may eventually halt growth and metastasis of NSCLC.