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

Naoomi Tominaga, Nobuyoshi Kosaka, Makiko Ono, Takeshi Katsuda, Yusuke Yoshioka, Kenji Tamura,

 Jan Lötvall, Hitoshi Nakagama and Takahiro Ochiya

Nat Commun. 2015 Apr 1;6:6716

Speaker: Chun-I Li (李俊毅)                                               Time: 14:00~15:00, May, 04, 2016

Commentator: Dr. Pai-Sheng Chen (陳百昇 老師)             Place: Room 601

Abstract:

Brain metastasis from breast cancer is oftern assoicated with poor prognosis and high mortality. One key feature of brain metastasis is the migration of cancer cells through blood–brain barrier (BBB)(1). However, how the destruction of BBB occurs during metastasis is not fully understood. Extracellular vesicles (EVs), mediating cell–cell communication via the delivery of the cargos, including protein, mRNA and microRNA (2), are known to regulate multiple aspects of malignancy in cancer cells (3). In this study, the authors investigated the role of EVs in the destruction of BBB during metastasis using established brain metastasis breast cancer cell lines through in vivo selection and an in vitro model. They demonstrated that inhibition of EVs secretion could suppress invasiveness through BBB, and brain metastatic cancer cell-derived EVs trigger BBB destruction to promote the extravasation of cancer cells through BBB. Tight junction proteins and N-cadherin, a transmembrane protein mediating cell–cell adhesion, regulate cell polarity through their intimate association with the actin cytoskeletal network. Tight junction proteins, Claudin-5, Occludin and ZO-1, are known to regulate the permeability of BBB in endothelial cells. N-cadherin is mostly expressed on the apical and basal membranes of the cell. The authors further found that cancer-derived EVs led to BBB breakdown by changing the localization of the tight junction proteins, N-cadherin and actin filaments, without affecting their expression levels. The authors also found that miR-181c was significantly upregulated in brain metastasis derived EVs as compared with the parental cells. Moreover, miR-181c-induced the abnormal localization of actin results in the destruction of BBB via the downregulation of its target gene, PDPK1. Decreased PDPK1 by miR-181c leads to downregulation of phosphorylated cofilin and cofilin-induced modulation of actin dynamics. The authors further 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 EVs-mediated mechanism of brain metastasis that triggers the destruction of BBB.

References:

1.         Arshad, F., Wang, L., Sy, C., Avraham, S., and Avraham, H.K. (2010). Blood-brain barrier integrity and breast cancer metastasis to the brain. Patholog Res Int 2011, 920509.

2.         Valadi, H., Ekstrom, K., Bossios, A., Sjostrand, M., Lee, J.J., and Lotvall, J.O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9, 654-659.

3.         Yang, C., and Robbins, P.D. (2011). The roles of tumor-derived exosomes in cancer pathogenesis. Clin Dev Immunol 2011, 842849.