Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis.
Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis.
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DOI：
10.1038/onc.2016.229
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发表时间：
2017-02-02
期刊：
影响因子：
8
通讯作者：
Zhang HG
中科院分区：
文献类型：
--
作者：
Deng Z;Rong Y;Teng Y;Zhuang X;Samykutty A;Mu J;Zhang L;Cao P;Yan J;Miller D;Zhang HG
对化疗的获得性耐药性仍然是癌症治疗的主要绊脚石。慢性炎症在诱导化疗抗性中起关键作用，并且部分地由包括髓源性抑制细胞（MDSC）和IL-13+ Th 2细胞的炎性细胞的诱导和扩增引起。导致诱导活化的MDSC和IL-13+ Th 2细胞的机制尚未确定。在此，我们证明了多柔比星治疗4 T1乳腺肿瘤荷瘤小鼠导致IL-13 R +miR-126 a +MDSC（DOX-MDSC）的诱导。DOX-MDSC通过MDSC miR-126 a+外泌体介导诱导IL-13+ Th 2细胞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治疗不仅增加从乳腺肿瘤细胞释放的IL-33（这对于诱导IL-13+ Th 2细胞至关重要），而且还参与诱导MDSC上/中表达的IL-13受体和miR-126 a。然后，从IL-13+ Th 2细胞释放的IL-13通过MDSC IL-13 R促进DOX-MDSC和MDSC miR-126 a+外泌体的产生。MDSC miR-126 a+外泌体以正反馈环方式进一步诱导IL 13 + Th 2细胞。我们还显示MDSC miR-126 a以S100 A8/A9依赖性方式挽救阿霉素诱导的MDSC死亡并促进肿瘤血管生成。我们的研究结果提供了MDSC外泌体介导的化疗耐药机制的见解，这将有助于设计靶向阻断miR-126 a +MDSC诱导的抑制剂。
Acquired resistance to chemotherapy remains a major stumbling block in cancer treatment. Chronic inflammation plays a crucial role in induction of chemo resistance, and results in part from the induction and expansion of inflammatory cells that include myeloid derived suppressor cells (MDSC) 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 treatment of 4T1 breast tumor bearing mice led to the induction of IL-13R+miR-126a+MDSC (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 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 doxorubicin induced MDSC death in a S100A8/A9 dependent manner and promotes tumor angiogenesis. Our findings provide insight into the MDSC exosomal mediated chemo resistance mechanism, which will be useful for the design of inhibitors targeting the blocking of induction of miR-126a+MDSC.