Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype.
Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype.
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DOI：
10.1158/1078-0432.ccr-11-0414
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发表时间：
2011-07-15
期刊：
影响因子：
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通讯作者：
Heimberger AB
中科院分区：
文献类型：
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作者：
Dziurzynski K;Wei J;Qiao W;Hatiboglu MA;Kong LY;Wu A;Wang Y;Cahill D;Levine N;Prabhu S;Rao G;Sawaya R;Heimberger AB
巨细胞病毒在高级别胶质瘤中普遍存在，但其在胶质瘤发生中的作用尚未完全阐明。通过流式细胞术分析多形性胶质母细胞瘤（GBM）肿瘤，以确定各种胶质瘤相关免疫群体内的CMV抗原表达。通过ELISA测定gCSC CMV IL-10产生。用重组CMV IL-10刺激人单核细胞，并通过流式细胞术测定p-STAT 3、VEGF、TGF-β、病毒IE 1和pp 65的表达水平。通过功能测定确定CMV IL-10处理的单核细胞对gCSC生物学的影响。CMV表现出对GBM内的巨噬细胞（MΦ）/小胶质细胞和⑶ 133 + gCSC的嗜性。gCSC产生CMV IL-10，其诱导人单核细胞（CNS MΦs/小胶质细胞的前体）呈现M2免疫抑制表型（如通过下调主要组织相容性复合物和共刺激分子所表现的），同时上调免疫抑制性B7-H1。CMV IL-10还诱导病毒IE 1的表达，病毒IE 1是单核细胞中病毒复制和转录的调节剂。最后，CMV IL-10处理的单核细胞产生血管生成VEGF、免疫抑制性TGF-β和增强的gCSC迁移。CMV通过诱导肿瘤支持性单核细胞触发胶质瘤发生的前馈机制。
CMV has been ubiquitously detected within high-grade gliomas, but its role in gliomagenesis has not been fully elicited. Glioblastoma multiforme (GBM) tumors were analyzed by flow cytometry to determine CMV antigen expression within various glioma-associated immune populations. The gCSC CMV IL-10 production was determined by ELISA. Human monocytes were stimulated with recombinant CMV IL-10 and levels of expression of p-STAT3, VEGF, TGF-β, viral IE1 and pp65 were determined by flow cytometry. The influence of CMV IL-10 treated monocytes on gCSC biology was ascertained by functional assays. CMV demonstrated a tropism for macrophages (MΦs)/microglia and CD133+ gCSCs within GBMs. The gCSCs produce CMV IL-10, which induces human monocytes (the precursor to the CNS MΦs/microglia) to assume an M2 immunosuppressive phenotype (as manifested by down modulation of the major histocompatibility complex and costimulatory molecules) while up regulating immune inhibitory B7-H1. CMV IL-10 also induces expression of viral IE1, a modulator of viral replication and transcription in the monocytes. Finally, the CMV IL-10-treated monocytes produced angiogeneic VEGF, immunosuppressive TGF-β, and enhanced migration of gCSCs. CMV triggers a feed-forward mechanism of gliomagenesis by inducing tumor-supportive monocytes.