Deng Z, Rong Y, Teng Y, Zhuang X, Samykutty A, Mu J, Zhang L, Cao P, Yan J, Miller D, Zhang H-G
James Graham Brown Cancer Center, Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
Robley Rex VA Medical Center, Louisville, KY, USA.
Oncogene. 2017 Feb 2;36(5):639-651. doi: 10.1038/onc.2016.229. Epub 2016 Jun 27.
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-13RmiR-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-13Th2 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.
化疗获得性耐药仍然是癌症治疗中的一个主要障碍。慢性炎症在化疗耐药的诱导中起关键作用，部分原因是包括髓系来源的抑制细胞（MDSCs）和IL-13 Th2细胞在内的炎症细胞的诱导和扩增。导致活化的MDSCs和IL-13 Th2细胞诱导的机制尚未明确。在这里，我们证明多柔比星（DOX）治疗携带4T1乳腺肿瘤的小鼠会导致IL-13RmiR-126a MDSCs（DOX-MDSC）的诱导。DOX-MDSC通过MDSC miR-126a外泌体介导的IL-13 Th2细胞诱导和肿瘤血管生成促进乳腺肿瘤肺转移。DOX-MDSC的诱导以旁分泌方式调节。DOX治疗不仅增加了乳腺肿瘤细胞释放的白细胞介素（IL）-33，这对IL-13 Th2细胞的诱导至关重要，而且还参与了MDSCs上/内表达的IL-13受体和miR-126a的诱导。然后，从IL-13 Th2细胞释放的IL-13通过MDSC IL-13R促进DOX-MDSC和MDSC miR-126a外泌体的产生。MDSC miR-126a外泌体以正反馈回路方式进一步诱导IL13 Th2细胞。我们还表明，MDSC miR-126a以S100A8/A9依赖的方式挽救DOX诱导的MDSC死亡并促进肿瘤血管生成。我们的研究结果为MDSC外泌体介导的化疗耐药机制提供了见解，这将有助于设计靶向阻断miR-126a MDSCs诱导的抑制剂。
