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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.

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


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.

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