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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

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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 12

Poorly metastatic 4TO7 orthotopic tumors acquire metastatic capability from distal metastatic tumors expressing miR-200s.

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Poorly metastatic 4TO7 orthotopic tumors acquire metastatic capability f...
(A) BALB/c SCID mice were injected with 4TO7-Fluc-mCherry cells in the right fourth mammary fat pads and an equal number of GFP+ 4TO7V, 4TO7OE, or 4T1E cells in the left fourth mammary fat pads. Luminescent images were taken every 5 days, and the mice were sacrificed on day 20. (B) Representative luminescent images. The type of GFP+ cells implanted in the right mammary fad pads is indicated at left. (C) log2 luminescent photon flux of metastases in the anterior halves of the mice measured after implantation. Number of mice with metastasis versus the total is indicated. (D) Volume of the mCherry tumors in the right mammary fat pad and GFP+ tumors in the left mammary fat pad measured by calipers in mice that received different types of GFP+ cells, as indicated. Asterisks indicate differences at day 20. (E) Representative lung luminescent images (left) and the average lung luminescent photon flux (right). (F) Representative lung mCherry images (left) and the average mCherry photon flux (right). (G) Representative lung GFP images (left) and the average GFP photon flux (right). *P < 0.05; **P < 0.01, Mann-Whitney U test.

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