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

Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes.

Author information

1
Section of Oncology, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
2
Section of Surgery, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
3
Section of Nephrology, Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK.
4
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff, UK.

Abstract

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.

PMID:
24441045
DOI:
10.1038/onc.2013.560
[Indexed for MEDLINE]

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