title: Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis.
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.
authors.affiliation: James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Deng
authors.affiliation: James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Rong
authors.affiliation: James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Teng
authors.affiliation: James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Samykutty
authors.affiliation: James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mu
authors.affiliation: James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Cao
authors.affiliation: James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yan
authors.affiliation: James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Miller
authors.affiliation: James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.|Robley Rex VA Medical Center, Louisville, KY, USA.
authors.forename: H-G
authors.initials: HG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis
chemical_list: D000903:Antibiotics, Antineoplastic; C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D004317:Doxorubicin