Editors' ChoiceCancer

Processing On-the-Go in Exosomes

Sci. Signal.  18 Nov 2014:
Vol. 7, Issue 352, pp. ec318
DOI: 10.1126/scisignal.aaa2956

Exosomes are small vesicles that are secreted from cells and can carry various molecules, proteins, and RNAs. Melo et al. found that breast cancer cell exosomes included proteins that process precursor miRNAs. Exosomes from MDA-MB-231 cells (a breast cancer cell line) incubated in cell- and serum-free culture medium showed increased abundance of mature miRNAs and decreased abundance of precursor miRNAs (pre-miRNAs) over time, whereas the content of exosomes from MCF10A cells (a normal mammary epithelial cell line) was unchanged, suggesting active miRNA processing in the cancer cell-derived exosomes. Serum from breast cancer patients had greater abundance of exosomes than did that from healthy donors, and cancer patient exosomes showed a similar switch in the pre-to-mature miRNA ratio over time in culture. Exosomes from MDA-MB-231, but not MCF10A cells, contained proteins involved in miRNA biogenesis (including Dicer, Ago2, TRBP, and RISC-loading complex proteins). Expressing Flag-tagged Dicer or green fluorescent protein (GFP)–tagged Ago2 in both cell types showed that Dicer and Ago2 were recruited into exosomes only in the cancer cells. MCF10A cells took up GFP-tagged exosomes from MDA-MB-231 cells, resulting in global changes in the MCF10A transcriptome, including a decrease in PTEN and HOXD10 expression, which are associated with breast cancer. MCF10A cells cultured with the cancer cell-derived exosomes exhibited increased cell viability, proliferation, and colony formation in culture. When coinjected with exosomes from MDA-MB-231 cells or exosomes from breast cancer patient serum MCF10A cells formed tumors in the mammary fat pads of mice. The serum from mice bearing these tumors or orthotopic grafts of patient breast, ovarian, or endometrial tumors contained exosomes that carried only human (not mouse) Dicer protein. The findings suggest that exosomes transfer the machinery and molecules that may promote miRNA-mediated malignant transformation in target cells.

S. A. Melo, H. Sugimoto, J. T. O’Connell, N. Kato, A. Villanueva, A. Vidal, L. Qiu, E. Vitkin, L. T. Perelman, C. A. Melo, A. Lucci, C. Ivan, G. A. Calin, R. Kalluri, Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26, 707–721 (2014). [Online Journal]