Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts
// Ridwana Chowdhury 1, * , Jason P. Webber 1, 2, * , Mark Gurney 1 , Malcolm D. Mason 1 , Zsuzsanna Tabi 1 , Aled Clayton 1, 2 1 Institute of Cancer and Genetics, School of Medicine, Cardiff University, Velindre Cancer Centre, Whitchurch, Cardiff, United Kingdom, CF14 2TL 2 Cardiff Institute for Tissue Engineering and Repair, Cardiff University * These authors have contributed equally to this work Correspondence to: Aled Clayton, e-mail: claytona@cardiff.ac.uk Keywords: exosomes, cancer stroma, mesenchymal stem cells, prostate cancer Received: November 10, 2014 Accepted: November 11, 2014 Published: January 22, 2015 ABSTRACT Stromal fibroblasts become altered in response to solid cancers, to exhibit myofibroblastic characteristics, with disease promoting influence. Infiltrating mesenchymal stem cells (MSC) may contribute towards these changes, but the factors secreted by cancer cells that impact MSC differentiation are poorly understood. We investigated the role of nano-metre sized vesicles (exosomes), secreted by prostate cancer cells, on the differentiation of bone-marrow MSC (BM-MSC), and the subsequent functional consequences of such changes. Purified exosomes impaired classical adipogenic differentiation, skewing differentiation towards alpha-smooth muscle actin (αSMA) positive myofibroblastic cells. A single exosomes treatment generated myofibroblasts secreting high levels of VEGF-A, HGF and matrix regulating factors (MMP-1, −3 and −13). Differentiated MSC had pro-angiogenic functions and enhanced tumour proliferation and invasivity assessed in a 3D co-culture model. Differentiation was dependent on exosomal-TGFβ, but soluble TGFβ at matched dose could not generate the same phenotype. Exosomes present in the cancer cell secretome were the principal factors driving this phenotype. Prostate cancer exosomes dominantly dictate a programme of MSC differentiation generating myofibroblasts with functional properties consistent with disease promotion.