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 8

miR-200 overexpression in mammary fat-pad tumors promotes lung colonization by circulating 4TO7 cells.

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miR-200 overexpression in mammary fat-pad tumors promotes lung colonizat...
(A) Schema of in vivo metastasis assay. 4TO7V or 4TO7OE cells were injected into the mammary fat pad of BALB/c mice, and 10 days later, when the tumor diameter approached 9 mm, 4TO7 cells were injected into the tail vein. Macroscopic lung colonies were counted 8 days later. (B) Representative photographs of the lungs. (C) Colony number per lung. Seven mice in each control group did not receive tail-vein injection; 8 mice bearing 4TO7V tumors and 11 mice bearing 4TO7OE tumors were injected with 4TO7 cells by tail vein. *P < 0.05, Student’s t test. (D) Mammary tumor volume as measured by calipers.