Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration.
Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration.
复制标题
肿瘤源性外泌体诱导中性粒细胞N2极化促进胃癌细胞迁移
DOI：
10.1186/s12943-018-0898-6
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发表时间：
2018-10-06
期刊：
影响因子：
37.3
通讯作者：
Xu W
中科院分区：
文献类型：
--
作者：
Zhang X;Shi H;Yuan X;Jiang P;Qian H;Xu W
研究背景外泌体是一种细胞外囊泡，在健康和疾病中介导细胞通讯。中性粒细胞可被肿瘤极化为促肿瘤表型。肿瘤来源的exosomes在中性粒细胞regulation的功能仍然不清楚。MethodsWe研究胃癌细胞来源的exosomes（GC-Ex）对中性粒细胞的促肿瘤激活的影响，并阐明了潜在的mechanism. ResultsGC-Ex延长中性粒细胞的生存和诱导中性粒细胞中的炎症因子的表达。GC-Ex激活的中性粒细胞反过来促进胃癌细胞迁移。GC-Ex通过转运高迁移率族蛋白1（HMGB 1），与TLR 4相互作用激活NF-κB通路，导致中性粒细胞自噬反应增强。阻断HMGB 1/TLR 4相互作用、NF-κB通路和自噬可逆转GC-Ex诱导的中性粒细胞活化。在胃癌细胞中沉默HMGB 1证实了HMGB 1是GC-Ex介导的中性粒细胞活化的关键因子。HMGB 1在胃癌组织中表达上调。HMGB 1表达增高与胃癌患者预后不良相关。结论胃癌细胞来源的exosomes通过HMGB 1/TLR 4/NF-κB信号通路诱导中性粒细胞的自噬和促肿瘤活化，为研究肿瘤中中性粒细胞的调控机制提供了新的视角，并揭示了exosomes在重塑肿瘤微环境中的多方面作用。
BackgroundExosomes are extracellular vesicles that mediate cellular communication in health and diseases. Neutrophils could be polarized to a pro-tumor phenotype by tumor. The function of tumor-derived exosomes in neutrophil regulation remains unclear.MethodsWe investigated the effects of gastric cancer cell-derived exosomes (GC-Ex) on the pro-tumor activation of neutrophils and elucidated the underlying mechanisms.ResultsGC-Ex prolonged neutrophil survival and induced expression of inflammatory factors in neutrophils. GC-Ex-activated neutrophils, in turn, promoted gastric cancer cell migration. GC-Ex transported high mobility group box-1 (HMGB1) that activated NF-κB pathway through interaction with TLR4, resulting in an increased autophagic response in neutrophils. Blocking HMGB1/TLR4 interaction, NF-κB pathway, and autophagy reversed GC-Ex-induced neutrophil activation. Silencing HMGB1 in gastric cancer cells confirmed HMGB1 as a key factor for GC-Ex-mediated neutrophil activation. Furthermore, HMGB1 expression was upregulated in gastric cancer tissues. Increased HMGB1 expression was associated with poor prognosis in patients with gastric cancer. Finally, gastric cancer tissue-derived exosomes acted similarly as exosomes derived from gastric cancer cell lines in neutrophil activation.ConclusionWe demonstrate that gastric cancer cell-derived exosomes induce autophagy and pro-tumor activation of neutrophils via HMGB1/TLR4/NF-κB signaling, which provides new insights into mechanisms for neutrophil regulation in cancer and sheds lights on the multifaceted role of exosomes in reshaping tumor microenvironment.
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影响因子：
11.2
作者：
Ashiru O;Boutet P;Fernández-Messina L;Agüera-González S;Skepper JN;Valés-Gómez M;Reyburn HT
通讯作者：
Reyburn HT
影响因子：
10.6
作者：
Kang, Rui;Chen, Ruochan;Zhang, Qiuhong;Hou, Wen;Wu, Sha;Cao, Lizhi;Huang, Jin;Yu, Yan;Fan, Xue-gong;Yan, Zhengwen;Sun, Xiaofang;Wang, Haichao;Wang, Qingde;Tsung, Allan;Billiar, Timothy R.;Zeh, Herbert J., III;Lotze, Michael T.;Tang, Daolin
通讯作者：
Tang, Daolin
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
自噬的增加维持中性粒细胞在人肝细胞癌中的存活和促肿瘤作用
影响因子：
25.7
作者：
Li, Xue-Feng;Chen, Dong-Ping;Zheng, Limin
通讯作者：
Zheng, Limin
影响因子：
20.3
作者：
Leveque-El Mouttie, Lucie;Vu, Therese;Lane, Steven W.
通讯作者：
Lane, Steven W.