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

• DOI: 10.1038/ncomms7716
• Publication Date: 2015-04-01T12:11:49Z
• Authors: Naoomi Tominaga; Nobuyoshi Kosaka; Makiko Ono; Takeshi Katsuda; Yusuke Yoshioka; Kenji Tamura; Jan Lötvall; Hitoshi Nakagama; Takahiro Ochiya
• Keywords: 0303 health sciences; Brain Neoplasms; Down-Regulation; Breast Neoplasms; Mice, SCID; Article; Actins; 3. Good health; 3-Phosphoinositide-Dependent Protein Kinases; Gene Expression Regulation, Neoplastic; Extracellular Vesicles; Mice; MicroRNAs; Protein Transport; 03 medical and health sciences; Actin Depolymerizing Factors; Blood-Brain Barrier; Cell Line, Tumor; Animals; Humans; Female; Phosphorylation; Neoplasm Transplantation

AbstractBrain 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 brainin vivo. Taken together, these results indicate a novel mechanism of brain metastasis mediated by EVs that triggers the destruction of BBB.