Epstein–Barr Virus-Induced VEGF and GM-CSF Drive Nasopharyngeal Carcinoma Metastasis via Recruitment and Activation of Macrophages

鼻咽癌 转移 癌症研究 肿瘤进展 炎症 生物 医学 细胞因子 免疫学 病毒 癌症 内科学 遗传学 放射治疗
作者
Di Huang,Shuangshuang Song,Zi Zhao Wu,Wei Wu,Xiu Ying Cui,Jia Ning Chen,Mu‐Sheng Zeng,Shi Cheng Su
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:77 (13): 3591-3604 被引量:60
标识
DOI:10.1158/0008-5472.can-16-2706
摘要

Abstract Chronic inflammation induced by persistent microbial infection plays an essential role in tumor progression. Although it is well documented that Epstein–Barr virus (EBV) infection is closely associated with nasopharyngeal carcinoma (NPC), how EBV-induced inflammation promotes NPC progression remains largely unknown. Here, we report that tumor infiltration of tumor-associated macrophages (TAM) and expression of CCL18, the cytokine preferentially secreted by TAM, closely correlate with serum EBV infection titers and tumor progression in two cohorts of NPC patients. In vitro, compared with EBV− NPC cell lines, EBV+ NPC cell lines exhibited superior capacity to attract monocytes and skew them to differentiate to a TAM-like phenotype. Cytokine profiling analysis revealed that NPC cells with active EBV replications recruited monocytes by VEGF and induced TAM by GM-CSF in an NF-κB–dependent manner. Reciprocally, TAM induced epithelial–mesenchymal transition and furthered NF-κB activation of tumor cells by CCL18. In humanized mice, NPC cells with active EBV replications exhibited increased metastasis, and neutralization of CCL18, GM-CSF, and VEGF significantly reduced metastasis. Collectively, our work defines a feed-forward loop between tumor cells and macrophages in NPC, which shows how metastatic potential can evolve concurrently with virus-induced chronic inflammation. Cancer Res; 77(13); 3591–604. ©2017 AACR.
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