Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells
Autor: | Yanhui Ma, Xiangliang Yuan, Lei Chen, Peiming Zheng, Lisong Shen, Guohua Xie, Yi Liu, Qin Luo |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine Cancer Research Apoptosis Tumor-associated macrophage Biology Exosomes Exosome lcsh:RC254-282 Mice 03 medical and health sciences Stomach Neoplasms Cell Line Tumor medicine Animals Humans PTEN PI3K/AKT/mTOR pathway Cisplatin resistance Cisplatin Macrophages Research Tumor-associated macrophages lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Microvesicles Mice Inbred C57BL MicroRNAs 030104 developmental biology Oncology Drug Resistance Neoplasm Cancer cell Immunology Cancer research biology.protein miR-21 Gastric cancer medicine.drug |
Zdroj: | Journal of Experimental & Clinical Cancer Research, Vol 36, Iss 1, Pp 1-13 (2017) Journal of Experimental & Clinical Cancer Research : CR |
ISSN: | 1756-9966 |
Popis: | Background Cisplatin-based chemotherapy is frequently used to treat advanced gastric cancer (GC). However, the resistance often occurs with the mechanisms being not well understood. Recently, emerging evidence indicates that tumor-associated macrophages (TAMs) play an important role in chemoresistance of cancer. As the important mediators in intercellular communications, exosomes secreted by host cells mediate the exchange of genetic materials and proteins to be involved in tumor aggressiveness. The aim of the study was to investigate whether exosomes derived from TAMs mediate cisplatin resistance in gastric cancer. Methods M2 polarized macrophages were obtained from mouse bone marrow or human PBMCs stimulated with IL-4 and IL-13. Exosomes isolated from M2 macrophages culture medium were characterized, and miRNA expression profiles of M2 derived exosomes (M2-exos) were analyzed using miRNA microarray. In vitro cell coculture was further conducted to investigate M2-exos mediated crosstalk between TAMs and tumor cells. Moreover, the in vivo experiments were performed using a subcutaneous transplantation tumor model in athymic nude mice. Results In this study, we showed that M2 polarized macrophages promoted cisplatin (DDP) resistance in gastric cancer cells and exosomes derived from M2 macrophages (M2-exos) are involved in mediating the resistance to DDP. Using miRNA profiles assay, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and cell lysate isolated from M2 polarized macrophage. Functional studies revealed that exosomal miR-21 can be directly transferred from macrophages to the gastric cancer cells, where it suppresses cell apoptosis and enhances activation of PI3K/AKT signaling pathway by down-regulation of PTEN. Conclusions Our findings suggest that exosomal transfer of tumor-associated macrophages derived miR-21 confer DDP resistance in gastric cancer, and targeting exosome communication may be a promising new therapeutic strategy for gastric cancer patients. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0528-y) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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