RRC ID 69012
Author Ono M, Kosaka N, Tominaga N, Yoshioka Y, Takeshita F, Takahashi RU, Yoshida M, Tsuda H, Tamura K, Ochiya T.
Title Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells.
Journal Sci Signal
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.
Volume 7(332)
Pages ra63
Published 2014-7-1
DOI 10.1126/scisignal.2005231
PII 7/332/ra63
PMID 24985346
MeSH Adult Animals Bone Marrow Cells / metabolism* Bone Marrow Cells / pathology Breast Neoplasms / metabolism* Breast Neoplasms / pathology Cell Line, Tumor Coculture Techniques Exosomes / metabolism* Exosomes / pathology Female Gene Expression Regulation, Neoplastic Humans Intracellular Signaling Peptides and Proteins / biosynthesis Membrane Proteins / biosynthesis Mesenchymal Stem Cells / metabolism* Mesenchymal Stem Cells / pathology Mice Mice, SCID MicroRNAs / metabolism* Myristoylated Alanine-Rich C Kinase Substrate Neoplasm Metastasis RNA, Neoplasm / metabolism*
IF 6.467
Human and Animal Cells MSC-R14(HMS0008) MSC-R36(HMS0019) MSC-R37(HMS0020)