Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes

Webber, J. P. ORCID: https://orcid.org/0000-0003-4772-3014, Spary, L. K., Sanders, A. J. ORCID: https://orcid.org/0000-0002-7997-5286, Chowdhury, R., Jiang, W. G. ORCID: https://orcid.org/0000-0002-3283-1111, Steadman, R. ORCID: https://orcid.org/0000-0002-1303-2496, Wymant, J., Jones, A. T. ORCID: https://orcid.org/0000-0003-2781-8905, Kynaston, H. ORCID: https://orcid.org/0000-0003-1902-9930, Mason, M. D. ORCID: https://orcid.org/0000-0003-1505-2869, Tabi, Z. and Clayton, A. ORCID: https://orcid.org/0000-0002-3087-9226 2015. Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene 34 (3) , pp. 290-302. 10.1038/onc.2013.560

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	exosomes; prostate; stroma; fibroblast; TGFβ
Additional Information:	Published online before print 20 Jan 2014.
Publisher:	Springer Nature
ISSN:	0950-9232
Funders:	Cancer Research UK
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	22 November 2013
Last Modified:	08 Oct 2024 01:52
URI:	https://orca.cardiff.ac.uk/id/eprint/57143

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