Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier

被引：643

作者：

Tominaga, Naoomi ^{[1
,2
,3
]}

Kosaka, Nobuyoshi ^{[1
,4
,5
]}

Ono, Makiko ^{[1
]}

Katsuda, Takeshi ^{[1
]}

Yoshioka, Yusuke ^{[1
]}

Tamura, Kenji ^{[6
]}

Lotvall, Jan ^{[7
,8
]}

Nakagama, Hitoshi ^{[2
,9
]}

Ochiya, Takahiro ^{[1
]}

机构：

[1] Natl Canc Ctr, Res Inst, Div Mol & Cellular Med, Chuo Ku, Tokyo 1040045, Japan

[2] Univ Tokyo, Grad Sch Med, Bunkyo Ku, Tokyo 1130033, Japan

[3] Japan Soc Promot Sci, Chiyoda Ku, Tokyo 1020083, Japan

[4] Univ Oxford, Dept Zool, Oxford OX1 3PS, England

[5] Japan Soc Promot Sci, Res Abroad, Chiyoda Ku, Tokyo 1020083, Japan

[6] Natl Canc Ctr, Res Inst, Div Breast & Med Oncol, Chuo Ku, Tokyo 1040045, Japan

[7] Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med, SE-40530 Gothenburg, Sweden

[8] Univ Gothenburg, Sahlgrenska Acad, Dept Resp Med & Allergol, SE-40530 Gothenburg, Sweden

[9] Natl Canc Ctr, Res Inst, Div Canc Dev Syst, Chuo Ku, Tokyo 1040045, Japan

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

日本学术振兴会;

关键词：

ENDOTHELIAL GROWTH-FACTOR; BREAST-CANCER; IN-VITRO; MICRORNAS; EXPRESSION; RECEPTOR;

D O I：

10.1038/ncomms7716

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：12

共 32 条

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