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

By N. Tominaga, N. Kosaka, M. Ono, T. Katsuda, Y. Yoshioka, K. Tamura, Jan Lötvall, H. Nakagama, T. Ochiya. Nature Communications, 2015

657 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/78e9ee19f7fe9e1075e06de442cf911adc805ad0

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In Cancer Research

1. Lin Zhang
2. Dihua Yu

In Molecular Biology

1. Ka-Lok Ng
2. Lin Zhang
3. Chi-Ying F. Huang
4. Dihua Yu
5. Chien-Hung Huang
6. Chia-Wei Hsu
7. Peter Mu-Hsin Chang

Citations in the corpus

• Exosome-Based Cell-Cell Communication in the Tumor Microenvironment (2018, background): “Another example involves brain tumor-derived exosomes containing miR-181c, which modulates ECs actin dynamics and promote breakdown of the blood-brain barrier by 3-Phosphoinostide-dependent Protein Kinase-1 degradation (Tominaga et al., 2015).”
• Exosomes in cancer development, metastasis, and immunity (2019, background): “These EVs from brain metastatic cancer cells transferred miR-181c into endothelial cells of the BBB, resulting in destruction of cell-cell contacts and therefore breakdown of the BBB to allow brain metastasis [95].”
• Drug repositioning for non-small cell lung cancer by using machine learning algorithms and topological graph theory (2016, background): “Tominaga et al. [47] demonstrated that cancer-derived extracellular vesicles (EVs), which are mediators of cell – cell communication, trigger the breakdown of the blood – brain barrier, which controls the migration of cancer cells.”