Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells
Extracellular Vesicles From Osteotropic Breast Cancer Cells Affect Bone Resident Cells
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DOI：
10.1002/jbmr.3891
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发表时间：
2020-02-01
影响因子：
6.2
通讯作者：
Rucci, Nadia
中科院分区：
文献类型：
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作者：
Loftus, Alexander;Cappariello, Alfredo;Rucci, Nadia
细胞外囊泡（EV）正在成为包括癌症在内的一系列病理过程的介质。然而，它们在骨转移中的作用却很少被探索。我们研究了EV介导的骨转移性乳腺癌细胞（MDA-MB-231）对骨驻留细胞和内皮细胞的影响。用MDA-MB-231（MDA）细胞的条件培养基（CM）预处理成骨细胞可促进成骨细胞EV（OB-EV）的促破骨细胞生成和促血管生成作用，以及RANKL阳性OB-EV的增加。此外，当用MDA-EV处理成骨细胞时，我们观察到它们的数量、代谢活性和碱性磷酸酶（Alp）活性降低。MDA-EV还减少了细胞周期蛋白D1和成骨细胞分化基因的转录，同时增强了前破骨细胞生成因子Rankl、Lcn 2、Illb和Il 6的表达。有趣的是，来自用MDA-EV处理的成骨细胞的CM上的细胞因子阵列显示细胞因子CCL 3、CXCL 2、Reg 3G和VEGF增加，而OPG和WISP 1下调。MDA-EV含有参与骨代谢的基因的mRNA，以及细胞因子，包括PDGF-BB、CCL 3、CCL 27、VEGF和血管生成素2。与此特征一致，MDA-EV增加了破骨细胞生成和体内血管生成。最后，在小鼠中腹膜内注射MDA-EV揭示了它们到达骨微环境并被成骨细胞和破骨细胞整合的能力。总之，我们证明了成骨细胞衍生的EV和肿瘤细胞衍生的EV在骨和内皮细胞生理失调中的作用，从而加剧了骨肿瘤诱导的恶性循环。(c)2019年美国骨与矿物质研究学会。
Extracellular vesicles (EVs) are emerging as mediators of a range of pathological processes, including cancer. However, their role in bone metastases has been poorly explored. We investigated EV-mediated effects of osteotropic breast cancer cells (MDA-MB-231) on bone resident cells and endothelial cells. Pretreatment of osteoblasts with conditioned medium (CM) of MDA-MB-231 (MDA) cells promoted pro-osteoclastogenic and pro-angiogenic effects by osteoblast EVs (OB-EVs), as well as an increase of RANKL-positive OB-EVs. Moreover, when treating osteoblasts with MDA-EVs, we observed a reduction of their number, metabolic activity, and alkaline phosphatase (Alp) activity. MDA-EVs also reduced transcription of Cyclin D1 and of the osteoblast-differentiating genes, while enhancing the expression of the pro-osteoclastogenic factors Rankl, Lcn2, Il1b, and Il6. Interestingly, a cytokine array on CM from osteoblasts treated with MDA-EVs showed an increase of the cytokines CCL3, CXCL2, Reg3G, and VEGF, while OPG and WISP1 were downregulated. MDA-EVs contained mRNAs of genes involved in bone metabolism, as well as cytokines, including PDGF-BB, CCL3, CCL27, VEGF, and Angiopoietin 2. In line with this profile, MDA-EVs increased osteoclastogenesis and in vivo angiogenesis. Finally, intraperitoneal injection of MDA-EVs in mice revealed their ability to reach the bone microenvironment and be integrated by osteoblasts and osteoclasts. In conclusion, we showed a role for osteoblast-derived EVs and tumor cell-derived EVs in the deregulation of bone and endothelial cell physiology, thus fueling the vicious cycle induced by bone tumors. (c) 2019 American Society for Bone and Mineral Research.