Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer

被引：231

作者：

Ji, Runbi ^{[1
]}

Zhang, Bin ^{[1
]}

Zhang, Xu ^{[1
]}

Xue, Jianguo ^{[1
]}

Yuan, Xiao ^{[1
]}

Yan, Yongmin ^{[1
]}

Wang, Mei ^{[1
]}

Zhu, Wei ^{[1
]}

Qian, Hui ^{[1
]}

Xu, Wenrong ^{[1
,2
]}

机构：

[1] Jiangsu Univ, Sch Med, Jiangsu Key Lab Med Sci & Lab Med, Zhenjiang, Jiangsu, Peoples R China

[2] Jiangsu Univ, Affiliated Hosp, Zhenjiang, Jiangsu, Peoples R China

来源：

CELL CYCLE | 2015年 / 14卷 / 15期

基金：

中国国家自然科学基金;

关键词：

drug resistance; exosomes; mesenchymal stem cells; gastric cancer; TUMOR MICROENVIRONMENT; STROMAL CELLS; CHEMOTHERAPY; ACTIVATION; VESICLES;

D O I：

10.1080/15384101.2015.1005530

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Mesenchymal stem cells (MSCs) play an important role in chemoresistance. Exosomes have been reported to modify cellular phenotype and function by mediating cell-cell communication. In this study, we aimed to investigate whether exosomes derived from MSCs (MSC-exosomes) are involved in mediating the resistance to chemotherapy in gastric cancer and to explore the underlying molecular mechanism. We found that MSC-exosomes significantly induced the resistance of gastric cancer cells to 5-fluorouracil both in vivo and ex vivo. MSC-exosomes antagonized 5-fluorouracil-induced apoptosis and enhanced the expression of multi-drug resistance associated proteins, including MDR, MRP and LRP. Mechanistically, MSC-exosomes triggered the activation of calcium/calmodulin-dependent protein kinases (CaM-Ks) and Raf/MEK/ERK kinase cascade in gastric cancer cells. Blocking the CaM-Ks/Raf/MEK/ERK pathway inhibited the promoting role of MSC-exosomes in chemoresistance. Collectively, MSC-exosomes could induce drug resistance in gastric cancer cells by activating CaM-Ks/Raf/MEK/ERK pathway. Our findings suggest that MSC-exosomes have profound effects on modifying gastric cancer cells in the development of drug resistance. Targeting the interaction between MSC-exosomes and cancer cells may help improve the efficacy of chemotherapy in gastric cancer.

引用

页码：2473 / 2483

页数：11

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