Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts
Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts
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DOI：
10.1182/blood-2014-12-618025
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发表时间：
2015-08-27
期刊：
影响因子：
20.3
通讯作者：
Moussay, Etienne
中科院分区：
文献类型：
--
作者：
Paggetti, Jerome;Haderk, Franziska;Moussay, Etienne
来源于实体瘤细胞的外泌体参与免疫抑制、血管生成和转移，但白血病来源的外泌体的作用研究较少。慢性淋巴细胞白血病（CLL）的发病机制与肿瘤支持微环境和免疫系统功能失调密切相关。在这里，我们探讨了CLL衍生的外泌体在恶性细胞创造这种有利环境的细胞和分子机制中的作用。我们表明，CLL衍生的外泌体被离体和体内的内皮和间充质干细胞积极纳入，并且外泌体蛋白和microRNA的转移在靶细胞中诱导炎症表型，其类似于癌症相关成纤维细胞（CAF）的表型。因此，基质细胞显示出增强的增殖、迁移和炎性细胞因子的分泌，有助于肿瘤支持性微环境。内皮细胞的外泌体摄取增加了离体和体内血管生成，并且CLL衍生的外泌体和CLL细胞的共注射促进了免疫缺陷小鼠中的肿瘤生长。最后，我们在CLL患者的淋巴结中检测到α-平滑肌动蛋白阳性基质细胞。这些发现表明，CLL衍生的外泌体通过调节获得癌症相关成纤维细胞特征的周围基质细胞的几种功能来积极促进疾病进展。
Exosomes derived from solid tumor cells are involved inimmune suppression, angiogenesis, and metastasis, but the role of leukemia-derived exosomes has been less investigated. The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumor-supportive microenvironment and a dysfunctional immune system. Here, we explore the role of CLL-derived exosomes in the cellular and molecular mechanisms by which malignant cells create this favorable surrounding. We show that CLL-derived exosomes are actively incorporated by endothelial and mesenchymal stem cells ex vivo and in vivo and that the transfer of exosomal protein and microRNA induces an inflammatory phenotype in the target cells, which resembles the phenotype of cancer-associated fibroblasts (CAFs). As a result, stromal cells show enhanced proliferation, migration, and secretion of inflammatory cytokines, contributing to a tumor-supportive microenvironment. Exosome uptake by endothelial cells increased angiogenesis ex vivo and in vivo, and coinjection of CLL-derived exosomes and CLL cells promoted tumor growth in immunodeficient mice. Finally, we detected a-smooth actin-positive stromal cells in lymph nodes of CLL patients. These findings demonstrate that CLL-derived exosomes actively promote disease progression by modulating several functions of surrounding stromal cells that acquire features of cancer-associated fibroblasts.