Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts.
Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts.
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DOI：
10.18632/oncotarget.2711
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发表时间：
2015-01-20
期刊：
影响因子：
--
通讯作者：
Clayton A
中科院分区：
文献类型：
--
作者：
Chowdhury R;Webber JP;Gurney M;Mason MD;Tabi Z;Clayton A
基质成纤维细胞对实体癌的反应发生改变，表现出肌成纤维细胞的特征，具有促进疾病的影响。浸润性间充质干细胞（MSC）可能有助于这些变化，但癌细胞分泌的影响MSC分化的因素尚不清楚。我们研究了由前列腺癌细胞分泌的纳米大小的囊泡（外泌体）在骨髓间充质干细胞（BM-MSC）分化中的作用，以及这种变化的后续功能后果。纯化的外泌体破坏了经典的脂肪生成分化，向α -平滑肌肌动蛋白（αSMA）阳性的肌成纤维细胞倾斜分化。单个外泌体处理产生的肌成纤维细胞分泌高水平的VEGF-A、HGF和基质调节因子（MMP-1、- 3和- 13）。在3D共培养模型中评估分化的MSC具有促血管生成功能，增强肿瘤增殖和侵袭性。分化依赖于外泌体- tgf - β，但可溶性tgf - β在匹配剂量下不能产生相同的表型。癌细胞分泌组中存在的外泌体是驱动这种表型的主要因素。前列腺癌外泌体主导MSC分化程序，产生具有与疾病促进一致的功能特性的肌成纤维细胞。
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.
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