Exosomes Derived From Mesenchymal Stem Cells Suppress Angiogenesis by Down-Regulating VEGF Expression in Breast Cancer Cells

PLoS One. 2013 Dec 31;8(12):e84256. doi: 10.1371/journal.pone.0084256. eCollection 2013.

Abstract

Exosomes are small membrane vesicles released by a variety of cell types. Exosomes contain genetic materials, such as mRNAs and microRNAs (miRNAs), implying that they may play a pivotal role in cell-to-cell communication. Mesenchymal stem cells (MSCs), which potentially differentiate into multiple cell types, can migrate to the tumor sites and have been reported to exert complex effects on tumor progression. To elucidate the role of MSCs within the tumor microenvironment, previous studies have suggested various mechanisms such as immune modulation and secreted factors of MSCs. However, the paracrine effects of MSC-derived exosomes on the tumor microenvironment remain to be explored. The hypothesis of this study was that MSC-derived exosomes might reprogram tumor behavior by transferring their molecular contents. To test this hypothesis, exosomes from MSCs were isolated and characterized. MSC-derived exosomes exhibited different protein and RNA profiles compared with their donor cells and these vesicles could be internalized by breast cancer cells. The results demonstrated that MSC-derived exosomes significantly down-regulated the expression of vascular endothelial growth factor (VEGF) in tumor cells, which lead to inhibition of angiogenesis in vitro and in vivo. Additionally, miR-16, a miRNA known to target VEGF, was enriched in MSC-derived exosomes and it was partially responsible for the anti-angiogenic effect of MSC-derived exosomes. The collective results suggest that MSC-derived exosomes may serve as a significant mediator of cell-to-cell communication within the tumor microenvironment and suppress angiogenesis by transferring anti-angiogenic molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / physiopathology*
  • Cell Line, Tumor
  • DNA Primers / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Exosomes / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / physiology*
  • Immunohistochemistry
  • Mesenchymal Stem Cells / cytology*
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / metabolism
  • Neovascularization, Pathologic / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Tumor Microenvironment / physiology*
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • DNA Primers
  • MicroRNAs
  • Mirn16 microRNA, mouse
  • Vascular Endothelial Growth Factor A

Grant support

This work was supported by the Global Core Research Center (GCRC) grant (No. 2012-0001190) from the National Research Foundation (NRF), Ministry of Education, Science and Technology (MEST), Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.