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

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.

间充质干细胞（Mesenchymal stem cells，MSCs）在化疗耐药过程中发挥重要作用。已有研究证实，外泌体可通过介导细胞间通讯，调控细胞表型与功能。本研究旨在探讨间充质干细胞来源外泌体（MSC-exosomes）是否参与胃癌化疗耐药的调控，并解析其潜在分子机制。研究结果显示，MSC-exosomes可在体内及离体水平显著诱导胃癌细胞对5-氟尿嘧啶产生耐药性。MSC-exosomes可拮抗5-氟尿嘧啶诱导的细胞凋亡，并上调多药耐药相关蛋白的表达，包括MDR、MRP及LRP。机制层面，MSC-exosomes可激活胃癌细胞内的钙/钙调蛋白依赖性蛋白激酶（calcium/calmodulin-dependent protein kinases，CaM-Ks）通路与Raf/MEK/ERK激酶级联反应。阻断CaM-Ks/Raf/MEK/ERK通路，可抑制MSC-exosomes对胃癌化疗耐药的促进作用。综上，MSC-exosomes可通过激活CaM-Ks/Raf/MEK/ERK通路，诱导胃癌细胞产生耐药性。本研究结果表明，MSC-exosomes在胃癌细胞耐药性形成过程中具有显著调控效应。靶向干预MSC-exosomes与胃癌细胞间的相互作用，或可有效提升胃癌化疗的临床疗效。