Vasculogenic mimicry formation in EBV-associated epithelial malignancies.
Vasculogenic mimicry formation in EBV-associated epithelial malignancies.
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EBV 相关上皮恶性肿瘤中血管生成拟态的形成
DOI：
10.1038/s41467-018-07308-5
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发表时间：
2018-11-27
影响因子：
16.6
通讯作者：
Feng L
中科院分区：
文献类型：
--
作者：
Xiang T;Lin YX;Ma W;Zhang HJ;Chen KM;He GP;Zhang X;Xu M;Feng QS;Chen MY;Zeng MS;Zeng YX;Feng L
EB病毒（EBV）相关的上皮癌，包括鼻咽癌（NPC）和大约10%的胃癌，称为EBVaGC，占所有EBV相关恶性肿瘤的80%。然而，EBV在上皮癌中的确切作用仍然难以捉摸。在这里，我们报告，EBV的功能，血管生成拟态（VM）。感染EBV的上皮癌细胞形成与肿瘤生长相关的肿瘤血管网络，其不同于内皮源性血管生成血管，并且是VEGF非依赖性的。从机制上讲，部分由LMP 2A介导的PI 3 K/AKT/mTOR/HIF-1α信号级联反应的激活负责EBV诱导的VM形成。NPC和EBVaGC的异种移植物和临床样品在组织学上均表现出VM，其与AKT和HIF-1α活化相关。此外，尽管抗VEGF单药治疗显示出有限的效果，但通过与VEGF和HIF-1α靶向药物的联合治疗可实现有效的协同抗肿瘤活性。我们的研究结果表明，EBV在上皮细胞中产生可塑性以表达内皮表型，并提供了一种新的EBV靶向抗肿瘤策略。
Epstein-Barr virus (EBV)-associated epithelial cancers, including nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancers, termed EBVaGC, represent 80% of all EBV-related malignancies. However, the exact role of EBV in epithelial cancers remains elusive. Here, we report that EBV functions in vasculogenic mimicry (VM). Epithelial cancer cells infected with EBV develop tumor vascular networks that correlate with tumor growth, which is different from endothelial-derived angiogenic vessels and is VEGF-independent. Mechanistically, activation of the PI3K/AKT/mTOR/HIF-1α signaling cascade, which is partly mediated by LMP2A, is responsible for EBV-induced VM formation. Both xenografts and clinical samples of NPC and EBVaGC exhibit VM histologically, which are correlated with AKT and HIF-1α activation. Furthermore, although anti-VEGF monotherapy shows limited effects, potent synergistic antitumor activities are achieved by combination therapy with VEGF and HIF-1α-targeted agents. Our findings suggest that EBV creates plasticity in epithelial cells to express endothelial phenotype and provides a novel EBV-targeted antitumor strategy.
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影响因子：
50.3
作者：
Jain RK
通讯作者：
Jain RK
影响因子：
6.7
作者：
Kong QL;Hu LJ;Cao JY;Huang YJ;Xu LH;Liang Y;Xiong D;Guan S;Guo BH;Mai HQ;Chen QY;Zhang X;Li MZ;Shao JY;Qian CN;Xia YF;Song LB;Zeng YX;Zeng MS
通讯作者：
Zeng MS
影响因子：
11.2
作者：
Kondo, Satoru;Seo, So Young;Pagano, Joseph S.
通讯作者：
Pagano, Joseph S.
影响因子：
50.3
作者：
Mabjeesh, NJ;Escuin, D;Giannakakou, P
通讯作者：
Giannakakou, P
影响因子：
2.1
作者：
Benders, Alexander A.;Tang, Weihua;Gulley, Margaret L.
通讯作者：
Gulley, Margaret L.