Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts

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.

miR-450a-5p within rat adipose tissue exosome-like vesicles promotes adipogenic differentiation by targeting WISP2

“…It has been indicated that proteins and miRNAs are involved in exosome-mediated differentiation. For example, TGF-β1 in cancer cell exosomes induce the differentiation of MSCs into cancer-associated myofibroblasts via the TGF-β1/SMAD signaling pathway (Chowdhury et al, 2015). Several studies have shown that exosomal miRNAs participate in multiple differentiation processes, such as osteogenesis, neurogenesis, angiogenesis and myogenesis (Lee et al, 2014;Qi et al, 2016), which indicates that miRNAs could be the main mechanism for exosome-mediated differentiation.…”

A new role for extracellular vesicles: how small vesicles can feed tumors' big appetite

“…Cancer cell EVs can also be internalized by endothelial cells, leading to their activation and angiogenesis in squamous cell carcinoma (32), glioma (33) and chronic myeloid leukemia (34). Angiogenesis, but also cell invasion, are also promoted by mesenchymal stem cells (MSCs) upon by guest, on June 8, 2019 www.jlr.org Downloaded from activation by prostate cancer-derived EVs (35). Tumor-derived EVs also promote tumor progression by exerting immunosuppressive functions (36).…”

Prostate cancer exosomes as modulators of the tumor microenvironment

“…The ability of prostate cancer exosomes to trigger secretion of pro-angiogenic factors extends to bone marrow-derived mesenchymal stem cells (BM-MSCs), which can also gain exosome-induced pro-angiogenic function [42] . Exosome-activated MSCs were shown to secrete elevated levels of HGF, VEGF and MMPs, and support the formation of endothelial vessel-like structures.…”

“…Chowdhury et al [42] demonstrated that prostate cancer exosomes can also drive BM-MSC differentiation, resulting in myofibroblasts with increased VEGFA, HGF and MMP secretion, capable of enhancing cancer cell growth. Exosome differentiated BM-MSCs drove prostate cancer cell invasion in a 3D spheroid model and stimulated endothelial cell migration, proliferation and angiogenic potential.…”