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Exosomes derived from gastric cancer cells activate NF-κB pathway in macrophages to promote cancer progression

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Tumor Biology

Abstract

Exosomes are nano-sized membrane vesicles secreted by both normal and cancer cells. Emerging evidence indicates that cancer cells derived exosomes contribute to cancer progression through the modulation of tumor microenvironment. However, the effects of exosomes derived from gastric cancer cells on macrophages are not well understood. In this study, we investigated the biological role of gastric cancer cells derived exosomes in the activation of macrophages. We demonstrated that gastric cancer cells derived exosomes activated macrophages to express increased levels of proinflammatory factors, which in turn promoted tumor cell proliferation and migration. In addition, gastric cancer cells derived exosomes remarkably upregulated the phosphorylation of NF-κB in macrophages. Inhibiting the activation of NF-κB reversed the upregulation of proinflammatory factors in macrophages and blocked their promoting effects on gastric cancer cells. Moreover, we found that gastric cancer cells derived exosomes could also activate macrophages from human peripheral blood monocytes through the activation of NF-κB. In conclusion, our results suggest that gastric cancer cells derived exosomes stimulate the activation of NF-κB pathway in macrophages to promote cancer progression, which provides a potential therapeutic approach for gastric cancer by interfering with the interaction between exosomes and macrophages in tumor microenvironment.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81572075, 81201660), the Natural Science Foundation of the Jiangsu Province (BK20141303), Jiangsu Province for Outstanding Sci-tech Innovation Team in Colleges and Universities (SJK2013-10), Jiangsu Province’s Outstanding Medical Academic Leader and Sci-tech Innovation Team Program (LJ201117), Jiangsu Province’s Major Project in Research and Development (BE2015667), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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    Authors and Affiliations

    1. Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, China

      Lijun Wu, Xu Zhang, Bin Zhang, Hui Shi, Xiao Yuan, Yaoxiang Sun, Zhaoji Pan, Hui Qian & Wenrong Xu

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    1. Lijun Wu
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    2. Xu Zhang
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    3. Bin Zhang
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    Correspondence to Hui Qian or Wenrong Xu.

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    The medical ethics committee of Jiangsu University approved this study.

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    Lijun Wu and Xu Zhang contributed equally to this work.

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    Fig. S1

    Cell number counting of SGC-7901(a) and MGC-803(b) cells that were treated with the supernatant from cancer exosomes-activated macrophages for 5 days. ***P < 0.001; **P < 0.01; ns, no significance. (GIF 21 kb)

    High Resolution Image (TIF 1267 kb)

    Fig. S2

    Flow cytometry analyses of the apoptosis of SGC-7901(a) and MGC-803(b) cells after treatment with the supernatant from cancer exosomes-activated THP-1 cells for 24 h. (GIF 2393 kb)

    High Resolution Image (TIF 1412 kb)

    Fig. S3

    Western blot analyses of p-P65 and p65 protein levels in THP-1 cells at different time point after the treatment with GES-1 cells derived exosomes. (GIF 486 kb)

    High Resolution Image (TIF 461 kb)

    Fig. S4

    Quantitative RT-PCR for IL-1β and IL-8 mRNA expression in primary macrophages pre-treated with 10 μM Bay 11–7082 for 2 h followed by stimulation with MGC-803 cells derived exosomes for 12 h. ***P < 0.001; **P < 0.01. (GIF 594 kb)

    High Resolution Image (TIF 700 kb)

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    Wu, L., Zhang, X., Zhang, B. et al. Exosomes derived from gastric cancer cells activate NF-κB pathway in macrophages to promote cancer progression. Tumor Biol. 37, 12169–12180 (2016). https://doi.org/10.1007/s13277-016-5071-5

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    • DOI: https://doi.org/10.1007/s13277-016-5071-5

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