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Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes

Webber, Jason P., Spary, Lisa Kate, Sanders, Andrew James, Chowdhury, Ruhena, Jiang, Wen, Steadman, Robert, Wymant, Jennifer, Jones, Arwyn Tomos, Kynaston, Howard, Mason, Malcolm David, Tabi, Zsuzsanna and Clayton, Aled 2015. Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene 34 , 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: Medicine
Pharmacy
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: Nature Publishing
ISSN: 0950-9232
Funders: Cancer Research UK
Date of First Compliant Deposit: 30 March 2016
Last Modified: 16 Mar 2019 22:30
URI: http://orca.cf.ac.uk/id/eprint/57143

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Cited 19 times in Web of Science. View in Web of Science.

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