Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes

Oncogene. 2015 Jan 15;34(3):290-302. doi: 10.1038/onc.2013.560. Epub 2014 Jan 20.


Activation of myofibroblast rich stroma is a rate-limiting step essential for cancer progression. The responsible factors are not fully understood, but TGFβ1 is probably critical. A proportion of TGFβ1 is associated with extracellular nano-vesicles termed exosomes, secreted by carcinoma cells, and the relative importance of soluble and vesicular TGFβ in stromal activation is presented. Prostate cancer exosomes triggered TGFβ1-dependent fibroblast differentiation, to a distinctive myofibroblast phenotype resembling stromal cells isolated from cancerous prostate tissue; supporting angiogenesis in vitro and accelerating tumour growth in vivo. Myofibroblasts generated using soluble TGFβ1 were not pro-angiogenic or tumour-promoting. Cleaving heparan sulphate side chains from the exosome surface had no impact on TGFβ levels yet attenuated SMAD-dependent signalling and myofibroblastic differentiation. Eliminating exosomes from the cancer cell secretome, targeting Rab27a, abolished differentiation and lead to failure in stroma-assisted tumour growth in vivo. Exosomal TGFβ1 is therefore required for the formation of tumour-promoting stroma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Line, Tumor
  • Cells, Cultured
  • Exosomes / metabolism*
  • Gene Knockdown Techniques
  • Heparitin Sulfate / metabolism
  • Heparitin Sulfate / pharmacology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Immunoblotting
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mice, Nude
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism*
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta1 / pharmacology
  • Transplantation, Heterologous
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism
  • rab27 GTP-Binding Proteins


  • Intercellular Signaling Peptides and Proteins
  • Transforming Growth Factor beta1
  • rab27 GTP-Binding Proteins
  • Heparitin Sulfate
  • RAB27A protein, human
  • rab GTP-Binding Proteins