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Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis

Oncogene volume 36, pages 639–651 (2017)Cite this article

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Abstract

Acquired resistance to chemotherapy remains a major stumbling block in cancer treatment. Chronic inflammation has a crucial role in induction of chemoresistance and results, in part, from the induction and expansion of inflammatory cells that include myeloid-derived suppressor cells (MDSCs) and IL-13+ Th2 cells. The mechanisms that lead to induction of activated MDSCs and IL-13+ Th2 cells have not yet been identified. Here we demonstrated that doxorubicin (DOX) treatment of 4T1 breast tumor-bearing mice led to the induction of IL-13R+miR-126a+ MDSCs (DOX-MDSC). DOX-MDSC promote breast tumor lung metastasis through MDSC miR-126a+ exosomal-mediated induction of IL-13+ Th2 cells and tumor angiogenesis. The induction of DOX-MDSC is regulated in a paracrine manner. DOX treatment not only increases interleukin (IL)-33 released from breast tumor cells, which is crucial for the induction of IL-13+ Th2 cells, but it also participates in the induction of IL-13 receptors and miR-126a expressed on/in the MDSCs. IL-13 released from IL-13+Th2 cells then promotes the production of DOX-MDSC and MDSC miR-126a+ exosomes via MDSC IL-13R. MDSC miR-126a+ exosomes further induce IL13+ Th2 cells in a positive feed-back loop manner. We also showed that MDSC miR-126a rescues DOX-induced MDSC death in a S100A8/A9-dependent manner and promotes tumor angiogenesis. Our findings provide insight into the MDSC exosomal-mediated chemoresistance mechanism, which will be useful for the design of inhibitors targeting the blocking of induction of miR-126a+ MDSCs.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NIH) (R01AT008617, UH3TR000875) and the Louisville Veterans Administration Medical Center (VAMC) Merit Review Grants (to H-G Zhang). H-G Zhang is supported by a Research Career Scientist (RCS) Award, funded by the US Department of Veterans Affairs. We thank Dr Jerald Ainsworth for editorial assistance.

Author contributions

All the authors designed the experiments, analyzed and interpreted the results and wrote the paper. ZD, JM and XZ performed the experiments.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

    Z Deng, Y Rong, Y Teng, X Zhuang, A Samykutty, J Mu, L Zhang, P Cao, J Yan, D Miller & H-G Zhang

  2. Robley Rex VA Medical Center, Louisville, KY, USA

    H-G Zhang

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Deng, Z., Rong, Y., Teng, Y. et al. Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis. Oncogene 36, 639–651 (2017). https://doi.org/10.1038/onc.2016.229

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