Lung tumor exosomes induce a pro-inflammatory phenotype in mesenchymal stem cells via NFκB-TLR signaling pathway

被引:160
作者
Li, Xiaoxia [1 ,2 ,3 ]
Wang, Shihua [1 ,2 ,3 ]
Zhu, Rongjia [1 ,2 ,3 ]
Li, Hongling [1 ,2 ,3 ]
Han, Qin [1 ,2 ,3 ]
Zhao, Robert Chunhua [1 ,2 ,3 ,4 ]
机构
[1] Chinese Acad Med Sci, Inst Basic Med Sci, Key Lab Beijing, Ctr Excellence Tissue Engn, Beijing 100730, Peoples R China
[2] Chinese Acad Med Sci, Sch Basic Med, Beijing 100730, Peoples R China
[3] Peking Union Med Coll, Beijing 100021, Peoples R China
[4] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Ctr Translat Med, Beijing 100730, Peoples R China
基金
中国国家自然科学基金;
关键词
Exosomes; MSCs; Tumor-supportive; Inflammation; NF-kappa B; TLR2; HSP70; STROMAL CELLS; PROGENITOR CELLS; IN-VITRO; MICROENVIRONMENT; MACROPHAGES; REGULATORS; HSP70;
D O I
10.1186/s13045-016-0269-y
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: In tumor microenvironment, a continuous cross-talk between cancer cells and other cellular components is required to sustain tumor progression. Accumulating evidence suggests that exosomes, a novel way of cell communication, play an important role in such cross-talk. Exosomes could facilitate the direct intercellular transfer of proteins, lipids, and miRNA/mRNA/DNAs between cells. Since mesenchymal stem cells (MSCs) can be attracted to tumor sites and become an important component of the tumor microenvironment, there is an urgent need to reveal the effect of tumor exosomes on MSCs and to further explore the underlying molecular mechanisms. Methods: Exosomes were harvested from lung cancer cell line A549 and added to MSCs. Secretion of inflammation-associated cytokines in exosome-treated MSCs were analyzed by RT-PCR and ELISA. The growth-promoting effect of exosome-treated MSCs on lung tumor cells was evaluated by in vivo mouse xenograft model. Signaling pathway involved in exosomes-treated MSCs was detected by PCR array of human toll-like receptor signaling pathway, RT-PCR, and Western blot. Results: Data showed that lung tumor cell A549-derived exosomes could induce a pro-inflammatory phenotype in MSCs named P-MSCs, which have significantly elevated secretion of IL-6, IL-8, and MCP-1. P-MSCs possess a greatly enhanced ability in promoting lung tumor growth in mouse xenograft model. Analysis of the signaling pathways in P-MSCs revealed a fast triggering of NF-kappa B. Genetic ablation of Toll-like receptor 2 (TLR2) by siRNA and TLR2-neutralizing antibody could block NF-kappa B activation by exosomes. We further found that Hsp70 present on the surface of lung tumor exosomes contributed to the induction of P-MSCs by A549 exosomes. Conclusions: Our studies suggest a novel mechanism by which lung tumor cell-derived exosomes induce pro-inflammatory activity of MSCs which in turn get tumor supportive characteristics.
引用
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页数:12
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