Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells

Sci. Signal., 1 July 2014
Vol. 7, Issue 332, p. ra63
DOI: 10.1126/scisignal.2005231

Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells

  1. Makiko Ono1,
  2. Nobuyoshi Kosaka1,
  3. Naoomi Tominaga1,
  4. Yusuke Yoshioka1,
  5. Fumitaka Takeshita1,
  6. Ryou-u Takahashi1,
  7. Masayuki Yoshida2,
  8. Hitoshi Tsuda3,
  9. Kenji Tamura4, and
  10. Takahiro Ochiya1,*
  1. 1Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
  2. 2Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan.
  3. 3Department of Pathology, National Defense Medical College, Saitama 359-0042, Japan.
  4. 4Breast and Medical Oncology Division, National Cancer Center Hospital, Tokyo 104-0045, Japan.
  1. *Corresponding author. E-mail: tochiya{at}ncc.go.jp

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.

Citation:

M. Ono, N. Kosaka, N. Tominaga, Y. Yoshioka, F. Takeshita, R.-u. Takahashi, M. Yoshida, H. Tsuda, K. Tamura, and T. Ochiya, Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci. Signal. 7, ra63 (2014).

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