Vasculogenic mimicry formation in EBV-associated epithelial malignancies

Tong Xiang, Yu-Xin Lin, Wenlong Ma, Hao-Jiong Zhang, Ke-Ming Chen, Gui-Ping He, Xiao Zhang, Miao Xu, Qi-Sheng Feng, Ming-Yuan Chen, Mu-Sheng Zeng, Yi-Xin Zeng () and Lin Feng ()
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Tong Xiang: Sun Yat-sen University Cancer Center
Yu-Xin Lin: Sun Yat-sen University Cancer Center
Wenlong Ma: Chinese Academy of Medical Sciences and Peking Union Medical College
Hao-Jiong Zhang: Sun Yat-sen University Cancer Center
Ke-Ming Chen: Sun Yat-sen University Cancer Center
Gui-Ping He: Sun Yat-sen University Cancer Center
Xiao Zhang: Sun Yat-sen University Cancer Center
Miao Xu: Sun Yat-sen University Cancer Center
Qi-Sheng Feng: Sun Yat-sen University Cancer Center
Ming-Yuan Chen: Sun Yat-sen University Cancer Center
Mu-Sheng Zeng: Sun Yat-sen University Cancer Center
Yi-Xin Zeng: Sun Yat-sen University Cancer Center
Lin Feng: Sun Yat-sen University Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-07308-5

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