title: Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells.
abstract: Breast cancer patients often develop metastatic disease years after resection of the primary tumor. The patients are asymptomatic because the disseminated cells appear to become dormant and are undetectable. Because the proliferation of these cells is slowed, dormant cells are often unresponsive to traditional chemotherapies that exploit the rapid cell cycling of most cancer cells. We generated a bone marrow-metastatic human breast cancer cell line (BM2) by tracking and isolating fluorescent-labeled MDA-MB-231 cells that disseminated to the bone marrow in mice. Coculturing BM2 cells with bone marrow mesenchymal stem cells (BM-MSCs) isolated from human donors revealed that BM-MSCs suppressed the proliferation of BM2 cells, decreased the abundance of stem cell-like surface markers, inhibited their invasion through Matrigel Transwells, and decreased their sensitivity to docetaxel, a common chemotherapy agent. Acquisition of these dormant phenotypes in BM2 cells was also observed by culturing the cells in BM-MSC-conditioned medium or with exosomes isolated from BM-MSC cultures, which were taken up by BM2 cells. Among various microRNAs (miRNAs) increased in BM-MSC-derived exosomes compared with those from adult fibroblasts, overexpression of miR-23b in BM2 cells induced dormant phenotypes through the suppression of a target gene, MARCKS, which encodes a protein that promotes cell cycling and motility. Metastatic breast cancer cells in patient bone marrow had increased miR-23b and decreased MARCKS expression. Together, these findings suggest that exosomal transfer of miRNAs from the bone marrow may promote breast cancer cell dormancy in a metastatic niche.
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Ono
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kosaka
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Naoomi
authors.initials: N
authors.lastname: Tominaga
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Takeshita
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Ryou-u
authors.initials: RU
authors.lastname: Takahashi
authors.affiliation: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Pathology, National Defense Medical College, Saitama 359-0042, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsuda
authors.affiliation: Breast and Medical Oncology Division, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan. tochiya@ncc.go.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
mesh_terms: D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D055354:Exosomes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008565:Membrane Proteins / Q000096:biosynthesis; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009362:Neoplasm Metastasis; D012334:RNA, Neoplasm / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; C552430:MIRN23a microRNA, human; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D012334:RNA, Neoplasm; D000076250:Myristoylated Alanine-Rich C Kinase Substrate