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 15

Circulating MB-231 cells acquire colonization capability from primary tumor–expressing miR-200.

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Circulating MB-231 cells acquire colonization capability from primary tu...
(A) Schema for imaging lung colonization. Two weeks after CA1a cells, untreated or transduced with anti–miR-200–TuD vector, were injected into the flanks of nude mice, MB-231–Fluc–mCherry cells were injected into the tail vein. Luminescence was imaged every week until the mice were sacrificed when tumor diameter approached 20 mm (week 3 or 4). (B) Levels of miR-200 miRNAs and (C) their targets in CA1a-control and CA1a-200-TuD cells, as determined by TaqMan or Ssofast qPCR, respectively (3 experiments). (D) Representative luminescent images of the mice at indicated times after i.v. injection. The type of primary flank tumor is indicated at left for each group of mice. (E) log2 luminescent photon flux (photons/s) of the whole body. The number of mice in each group with detectable metastases is indicated. (F) Representative lung luminescent images (left) and the average lung luminescent photon flux at time of sacrifice (right). *P < 0.05; **P < 0.01, Student’s t test.