miR-200–containing extracellular vesicles promote breast cancer cell metastasis
Minh T.N. Le, … , Leonora Balaj, Judy Lieberman
Minh T.N. Le, … , Leonora Balaj, Judy Lieberman
Published November 17, 2014
Citation Information: J Clin Invest. 2014;124(12):5109-5128. https://doi.org/10.1172/JCI75695.
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Research Article

miR-200–containing extracellular vesicles promote breast cancer cell metastasis

Abstract

Metastasis is associated with poor prognosis in breast cancer patients. Not all cancer cells within a tumor are capable of metastasizing. The microRNA-200 (miR-200) family, which regulates the mesenchymal-to-epithelial transition, is enriched in the serum of patients with metastatic cancers. Ectopic expression of miR-200 can confer metastatic ability to poorly metastatic tumor cells in some settings. Here, we investigated whether metastatic capability could be transferred between metastatic and nonmetastatic cancer cells via extracellular vesicles. miR-200 was secreted in extracellular vesicles from metastatic murine and human breast cancer cell lines, and miR-200 levels were increased in sera of mice bearing metastatic tumors. In culture, murine and human metastatic breast cancer cell extracellular vesicles transferred miR-200 microRNAs to nonmetastatic cells, altering gene expression and promoting mesenchymal-to-epithelial transition. In murine cancer and human xenograft models, miR-200–expressing tumors and extracellular vesicles from these tumors promoted metastasis of otherwise weakly metastatic cells either nearby or at distant sites and conferred to these cells the ability to colonize distant tissues in a miR-200–dependent manner. Together, our results demonstrate that metastatic capability can be transferred by the uptake of extracellular vesicles.

Authors

Minh T.N. Le, Peter Hamar, Changying Guo, Emre Basar, Ricardo Perdigão-Henriques, Leonora Balaj, Judy Lieberman

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Figure 6

Inhibition of miR-200s in recipient cells reduces the prometastatic effect of EVs derived from metastatic cells.

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Inhibition of miR-200s in recipient cells reduces the prometastatic effe...
(A) 4TO7 cells were transfected with control anti-miR (AM) or a combination of anti–miR-200c and anti–miR-141 (200c/141 anti-miR) and then incubated with 4TO7V or 4TO7OE EVs. Treated 4TO7 cells were injected into the tail vein of BALB/c mice, and the lungs were analyzed 8 days later. (B) Levels of miR-200 miRNAs and their targets in 4TO7 cells transfected with anti-miRs and treated with EVs (3 experiments). (C) Representative photographs of the lungs treated as in A. (D) Number of tumor colonies in the lungs (n = 9 mice). *P < 0.05; **P < 0.01, Student’s t test.