Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB.
Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB.
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DOI：
10.1038/srep05750
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发表时间：
2014-07-18
影响因子：
4.6
通讯作者：
Wang SE
中科院分区：
文献类型：
--
作者：
Chow A;Zhou W;Liu L;Fong MY;Champer J;Van Haute D;Chin AR;Ren X;Gugiu BG;Meng Z;Huang W;Ngo V;Kortylewski M;Wang SE
越来越多的证据将肿瘤进展与慢性炎症过程和各种免疫细胞的失调活性联系起来。在这项研究中，我们证明了各种类型的巨噬细胞内化微泡，称为外泌体，由乳腺癌和非癌细胞系分泌。尽管两种类型的外泌体都靶向巨噬细胞，但只有癌症来源的外泌体刺激巨噬细胞中的NF-κB活化，导致促炎细胞因子（如IL-6、TNFα、GCSF和CCL 2）分泌。体内小鼠实验证实，静脉注射的外泌体被肺和脑中的巨噬细胞有效地内化，这与炎性细胞因子的上调相关。在携带异种移植的人乳腺癌的小鼠中，肿瘤来源的外泌体被腋窝淋巴结中的巨噬细胞内化，从而触发IL-6的表达。Toll样受体2（TLR 2）或MyD 88（NF-κB通路中的关键信号转导衔接子）的基因切除完全消除了肿瘤源性外泌体的作用。相反，抑制TLR 4或内体TLRs（TLR 3/7/8/9）不能消除外泌体对NF-κB的激活。我们进一步发现，肿瘤分泌的外泌体表面上存在的棕榈酰化蛋白有助于NF-κB活化。因此，我们的研究结果突出了乳腺癌细胞通过癌症进展期间分泌的循环外泌体囊泡诱导远端巨噬细胞的促炎活性的新机制。
Growing evidence links tumor progression with chronic inflammatory processes and dysregulated activity of various immune cells. In this study, we demonstrate that various types of macrophages internalize microvesicles, called exosomes, secreted by breast cancer and non-cancerous cell lines. Although both types of exosomes targeted macrophages, only cancer-derived exosomes stimulated NF-κB activation in macrophages resulting in secretion of pro-inflammatory cytokines such as IL-6, TNFα, GCSF, and CCL2. In vivo mouse experiments confirmed that intravenously injected exosomes are efficiently internalized by macrophages in the lung and brain, which correlated with upregulation of inflammatory cytokines. In mice bearing xenografted human breast cancers, tumor-derived exosomes were internalized by macrophages in axillary lymph nodes thereby triggering expression of IL-6. Genetic ablation of Toll-like receptor 2 (TLR2) or MyD88, a critical signaling adaptor in the NF-κB pathway, completely abolished the effect of tumor-derived exosomes. In contrast, inhibition of TLR4 or endosomal TLRs (TLR3/7/8/9) failed to abrogate NF-κB activation by exosomes. We further found that palmitoylated proteins present on the surface of tumor-secreted exosomes contributed to NF-κB activation. Thus, our results highlight a novel mechanism used by breast cancer cells to induce pro-inflammatory activity of distant macrophages through circulating exosomal vesicles secreted during cancer progression.
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影响因子：
4.1
作者：
Ru, QHC;Zhu, LWA;Shriver, CD
通讯作者：
Shriver, CD
DOI：
10.1073/pnas.1209414109
发表时间：
2012-07-31
影响因子：
11.1
作者：
Fabbri, Muller;Paone, Alessio;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
S1PR1-STAT3信号传导对于未来转移性位点的髓样细胞定植至关重要。
影响因子：
50.3
作者：
Deng J;Liu Y;Lee H;Herrmann A;Zhang W;Zhang C;Shen S;Priceman SJ;Kujawski M;Pal SK;Raubitschek A;Hoon DSB;Forman S;Figlin RA;Liu J;Jove R;Yu H
通讯作者：
Yu H
影响因子：
4.3
作者：
Chefetz, Ilana;Alvero, Ayesha B.;Mor, Gil
通讯作者：
Mor, Gil
DOI：
10.1073/pnas.0804543106
发表时间：
2009-03-10
影响因子：
11.1
作者：
Al-Nedawi, Khalid;Meehan, Brian;Rak, Janusz
通讯作者：
Rak, Janusz