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.
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Acknowledgements
This work was supported by a Cancer Research Wales programme grant awarded to AC, ZT, WGJ and MDM. Confocal microscopy studies were supported by a CR-UK studentship awarded to JPW and ATJ. In vivo studies were supported by a CR-UK development grant to AC and JPW. Drs Jane Lane and Tracey Martin are acknowledged for their help with the in vivo work. Dr H Sheldon and Professor A Harris, Oxford University, UK assisted with establishing in vitro angiogenesis assays.
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Webber, J., Spary, L., Sanders, A. et al. Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene 34, 290–302 (2015). https://doi.org/10.1038/onc.2013.560
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DOI: https://doi.org/10.1038/onc.2013.560
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