Tumour cell-derived exosomes endow mesenchymal stromal cells with tumour-promotion capabilities

Oncogene. 2016 Nov 17;35(46):6038-6042. doi: 10.1038/onc.2016.131. Epub 2016 May 2.

Abstract

Mesenchymal stromal cells (MSCs) are a major component of the tumour microenvironment. A plethora of elegant studies focusing on tumour-derived MSCs have shown that they, unlike normal MSCs in other tissue, exhibit a strong ability to promote tumour progression. However, the mechanisms underlying the conversion of normal MSCs into tumour-associated MSCs are unknown. We report here a critical role of tumour cell-derived exosomes in endowing bone marrow-derived MSCs (BM-MSCs) with a tumour-favourable phenotype. Tumour cell-derived exosomes affected neither the growth factor production nor the immunosuppressive property of MSCs; rather, they endowed MSCs with a strong ability to promote macrophage infiltration into B16-F0 melanoma or EL-4 lymphoma. Ablation of macrophages by clodronate liposome administration reversed the tumour-promoting effect of MSCs educated by tumour cell-derived exosomes (TE-MSCs) on the tumour growth. By comparing the chemokine profile of BM-MSCs with that of TE-MSCs, we found that TE-MSCs produced a large amount of CCR2 ligands, CCL2 and CCL7, which are responsible for macrophage recruitment. CCR2-specific inhibitor was found to block the tumour-promoting effect of TE-MSCs. Thus, our investigations demonstrated that tumour cell-derived exosomes confer BM-MSCs the ability to enhance tumour growth. Therefore, we uncovered a novel mechanism underlying the conversion of normal MSCs to tumour-associated MSCs.

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / metabolism*
  • Cell-Derived Microparticles
  • Exosomes / metabolism*
  • Exosomes / ultrastructure
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Melanoma, Experimental
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Neoplasms / immunology
  • Neoplasms / metabolism*
  • Receptors, CCR2 / metabolism
  • Tumor Microenvironment

Substances

  • Receptors, CCR2