Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier.
Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier.
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脑转移性癌细胞释放了能够破坏血脑屏障的含MicroRNA-181C的细胞外囊泡。
DOI：
10.1038/ncomms7716
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发表时间：
2015-04-01
影响因子：
16.6
通讯作者：
Ochiya, Takahiro
中科院分区：
文献类型：
--
作者：
Tominaga, Naoomi;Kosaka, Nobuyoshi;Ono, Makiko;Katsuda, Takeshi;Yoshioka, Yusuke;Tamura, Kenji;Lotvall, Jan;Nakagama, Hitoshi;Ochiya, Takahiro
脑转移是乳腺癌患者死亡的重要原因。脑转移过程中的一个关键事件是癌细胞通过血脑屏障（BBB）的迁移。然而，通过这一天然屏障背后的分子机制仍不清楚。在这里，我们表明，癌症来源的细胞外囊泡（EV），介导的细胞间通讯通过蛋白质和microRNA（miRNA）的交付，触发BBB的崩溃。重要的是，miR-181 c通过其靶基因PDPK 1的下调，通过肌动蛋白的异常定位促进BBB的破坏。miR-181 c降解PDPK 1导致磷酸化cofilin下调，并由此激活cofilin诱导的肌动蛋白动力学调节。此外，我们证明了全身注射脑转移癌细胞衍生的EV促进了乳腺癌细胞系的脑转移，并优先在体内并入脑中。综上所述，这些结果表明了由EV介导的脑转移的新机制，其触发了BBB的破坏。 转移到脑期间的一个关键事件是癌细胞通过血脑屏障（BBB）的迁移。在这里，作者表明，癌细胞衍生的细胞外囊泡通过促进血脑屏障破坏来促进转移。
Brain metastasis is an important cause of mortality in breast cancer patients. A key event during brain metastasis is the migration of cancer cells through blood–brain barrier (BBB). However, the molecular mechanism behind the passage through this natural barrier remains unclear. Here we show that cancer-derived extracellular vesicles (EVs), mediators of cell–cell communication via delivery of proteins and microRNAs (miRNAs), trigger the breakdown of BBB. Importantly, miR-181c promotes the destruction of BBB through the abnormal localization of actin via the downregulation of its target gene, PDPK1. PDPK1 degradation by miR-181c leads to the downregulation of phosphorylated cofilin and the resultant activated cofilin-induced modulation of actin dynamics. Furthermore, we demonstrate that systemic injection of brain metastatic cancer cell-derived EVs promoted brain metastasis of breast cancer cell lines and are preferentially incorporated into the brain in vivo. Taken together, these results indicate a novel mechanism of brain metastasis mediated by EVs that triggers the destruction of BBB. A key event during metastasis to the brain is the migration of cancer cells through the blood–brain barrier (BBB). Here the authors show that cancer-cell-derived extracellular vesicles promote metastasis by promoting BBB breaching.
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