title: Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer.
abstract: 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.
authors.affiliation: a Jiangsu Key Laboratory of Medical Science and Laboratory Medicine; School of Medicine ; Jiangsu University ; Zhenjiang , Jiangsu , PR China.
authors.forename: Runbi
authors.initials: R
authors.lastname: Ji
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Jianguo
authors.initials: J
authors.lastname: Xue
authors.forename: Xiao
authors.initials: X
authors.lastname: Yuan
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Yan
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Hui
authors.initials: H
authors.lastname: Qian
authors.forename: Wenrong
authors.initials: W
authors.lastname: Xu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004789:Enzyme Activation; D055354:Exosomes / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D013274:Stomach Neoplasms / Q000188:drug therapy*; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D026901:Membrane Transport Proteins; D034741:RNA, Small Interfering; C106868:CASK kinases; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D051528:Guanylate Kinases; D005472:Fluorouracil
keywords: drug resistance; exosomes; gastric cancer; mesenchymal stem cells