Extracellular vesicles (EVs), including exosomes and microvesicles, are evolutionarily conserved phospholidpid membrane-bound entities secreted from most eukaryotic cell types. They carry bioactive cargos such as protein and nucleic acids derived from their cells of origin. Over the past 10 years, they have been attracting increased attention in many fields of life science, representing a new route for intercellular communication. In this review article, we will discuss the current knowledge of both normal and virally modified EVs in the regulation of Epstein-Barr virus (EBV)'s life cycle and its associated pathogenesis.

Department of Medicine Peptide Research Laboratories Tulane University Health Sciences Center New Orleans LA 70112 USA

Graduate School of Medicine Hokkaido University Sapporo Hokkaido 060 8638 Japan

Tulane University Health Sciences Center and Tulane Cancer Center New Orleans LA 70112 USA

Zobrazit více v PubMed

Colombo M., Raposo G., Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 2014;30:255–289. doi: 10.1146/annurev-cellbio-101512-122326. PubMed DOI

Lin Z., Swan K., Zhang X., Cao S., Brett Z., Drury S., Strong M.J., Fewell C., Puetter A., Wang X., et al. Secreted Oral Epithelial Cell Membrane Vesicles Induce Epstein-Barr Virus Reactivation in Latently Infected B Cells. J. Virol. 2016;90:3469–3479. doi: 10.1128/JVI.02830-15. PubMed DOI PMC

Walker J.D., Maier C.L., Pober J.S. Cytomegalovirus-infected human endothelial cells can stimulate allogeneic CD4+ memory T cells by releasing antigenic exosomes. J. Immunol. 2009;182:1548–1559. doi: 10.4049/jimmunol.182.3.1548. PubMed DOI PMC

Escola J.-M., Kleijmeer M.J., Stoorvogel W., Griffith J.M., Yoshie O., Geuze H.J. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J. Biol. Chem. 1998;273:20121–20127. doi: 10.1074/jbc.273.32.20121. PubMed DOI

Blanchard N., Lankar D., Faure F., Regnault A., Dumont C., Raposo G., Hivroz C. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J. Immunol. 2002;168:3235–3241. doi: 10.4049/jimmunol.168.7.3235. PubMed DOI

Théry C., Regnault A., Garin J., Wolfers J., Zitvogel L., Ricciardi-Castagnoli P., Raposo G., Amigorena S. Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J. Cell. Biol. 1999;147:599–610. doi: 10.1083/jcb.147.3.599. PubMed DOI PMC

Comelli L., Rocchiccioli S., Smirni S., Salvetti A., Signore G., Citti L., Trivella M.G., Cecchettini A. Characterization of secreted vesicles from vascular smooth muscle cells. Mol. Biosyst. 2014;10:1146–1152. doi: 10.1039/c3mb70544g. PubMed DOI

Faure J., Lachenal G., Court M., Hirrlinger J., Chatellard-Causse C., Blot B., Grange J., Schoehn G., Goldberg Y., Boyer V., et al. Exosomes are released by cultured cortical neurones. Mol. Cell Neurosci. 2006;31:642–648. doi: 10.1016/j.mcn.2005.12.003. PubMed DOI

Wang G., Dinkins M., He Q., Zhu G., Poirier C., Campbell A., Mayer-Proschel M., Bieberich E. Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): Potential mechanism of apoptosis induction in Alzheimer disease (AD) J. Biol. Chem. 2012;287:21384–21395. doi: 10.1074/jbc.M112.340513. PubMed DOI PMC

Kramer-Albers E.M., Bretz N., Tenzer S., Winterstein C., Möbius W., Berger H., Nave K.-A., Schild H., Trotter J. Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: Trophic support for axons? Proteomics Clin. Appl. 2007;1:1446–1461. doi: 10.1002/prca.200700522. PubMed DOI

Johnstone R.M., Bianchini A., Teng K. Reticulocyte maturation and exosome release: Transferrin receptor containing exosomes shows multiple plasma membrane functions. Blood. 1989;74:1844–1851. PubMed

Minciacchi V.R., Freeman M.R., Di Vizio D. Extracellular vesicles in cancer: Exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev. Biol. 2015;40:41–51. doi: 10.1016/j.semcdb.2015.02.010. PubMed DOI PMC

Gill S., Catchpole R., Forterre P. Extracellular membrane vesicles (EVs) in the three domains of life and beyond. FEMS Microbiol. Rev. 2018 doi: 10.1093/femsre/fuy042. PubMed DOI PMC

Li M., Zeringer E., Barta T., Schageman J., Cheng A., Vlassov A.V. Analysis of the RNA content of the exosomes derived from blood serum and urine and its potential as biomarkers. Philos Trans. R. Soc. Lond. B Biol. Sci. 2014;369 doi: 10.1098/rstb.2013.0502. PubMed DOI PMC

Lasser C., Alikhani V.S., Ekström K., Eldh M., Paredes P.T., Bossios A., Sjöstrand M., Gabrielsson S., Lötvall J., Valadi H. Human saliva, plasma and breast milk exosomes contain RNA: Uptake by macrophages. J. Transl. Med. 2011;9:9. doi: 10.1186/1479-5876-9-9. PubMed DOI PMC

Madison M.N., Roller R.J., Okeoma C.M. Human semen contains exosomes with potent anti-HIV-1 activity. Retrovirology. 2014;11:102. doi: 10.1186/s12977-014-0102-z. PubMed DOI PMC

Dear J.W., Street J.M., Bailey M.A. Urinary exosomes: A reservoir for biomarker discovery and potential mediators of intrarenal signalling. Proteomics. 2013;13:1572–1580. doi: 10.1002/pmic.201200285. PubMed DOI

Dixon C.L., Sheller-Miller S., Saade G.R., Fortunato S.J., Lai A., Palma C., Guanzon D., Salomon C., Menon R. Amniotic Fluid Exosome Proteomic Profile Exhibits Unique Pathways of Term and Preterm Labor. Endocrinology. 2018;159:2229–2240. doi: 10.1210/en.2018-00073. PubMed DOI PMC

Street J.M., Barran P.E., Mackay C.L., Weidt S., Balmforth C., Walsh T.S., Chalmers R.T.A., Webb D.J., Dear J.W. Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J. Transl. Med. 2012;10:5. doi: 10.1186/1479-5876-10-5. PubMed DOI PMC

Yuan Z., Bedi B., Sadikot R.T. Bronchoalveolar Lavage Exosomes in Lipopolysaccharide-induced Septic Lung Injury. J. Vis. Exp. 2018;135:e57737. doi: 10.3791/57737. PubMed DOI PMC

Peng P., Yan Y., Keng S. Exosomes in the ascites of ovarian cancer patients: Origin and effects on anti-tumor immunity. Oncol. Rep. 2011;25:749–762. PubMed

Cocucci E., Racchetti G., Meldolesi J. Shedding microvesicles: Artefacts no more. Trends Cell Biol. 2009;19:43–51. doi: 10.1016/j.tcb.2008.11.003. PubMed DOI

Yang T., Martin P., Fogarty B., Brown A., Schurman K., Phipps R., Yin V.P., Lockman P., Bai S. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm Res. 2015;32:2003–2014. doi: 10.1007/s11095-014-1593-y. PubMed DOI PMC

Guo W., Gao Y., Li N., Shao F., Wang C., Wang P., Yang Z., Li R., He J. Exosomes: New players in cancer (Review) Oncol. Rep. 2017;38:665–675. doi: 10.3892/or.2017.5714. PubMed DOI PMC

Young L.S., Yap L.F., Murray P.G. Epstein-Barr virus: More than 50 years old and still providing surprises. Nat. Rev. Cancer. 2016;16:789–802. doi: 10.1038/nrc.2016.92. PubMed DOI

Lin Z., Flemington E.K. Regulation of EBV latency by viral lytic proteins. In: Robertson E., editor. Epstein-Barr virus: Latency and transformation. Caister Academic Press; Wymondham, Norfolk, UK: 2010. pp. 167–192.

Takada K. Cross-linking of cell surface immunoglobulins induces Epstein-Barr virus in Burkitt lymphoma lines. Int. J. Cancer. 1984;33:27–32. doi: 10.1002/ijc.2910330106. PubMed DOI

Takada K., Ono Y. Synchronous and sequential activation of latently infected Epstein-Barr virus genomes. J. Virol. 1989;63:445–449. PubMed PMC

Chasserot-Golaz S., Schuster C., Dietrich J.B., Beck G., Lawrence D.A. Antagonistic action of RU38486 on the activity of transforming growth factor-beta in fibroblasts and lymphoma cells. J. Steroid Biochem. 1988;30:381–385. doi: 10.1016/0022-4731(88)90127-6. PubMed DOI

Hadinoto V., Shapiro M., Sun C.C., Thorley-Lawson D.A. The dynamics of EBV shedding implicate a central role for epithelial cells in amplifying viral output. PLoS Pathog. 2009;5:e1000496. doi: 10.1371/journal.ppat.1000496. PubMed DOI PMC

Hutt-Fletcher L.M. Epstein-Barr virus replicating in epithelial cells. Proc. Natl. Acad. Sci. USA. 2014;111:16242–16243. doi: 10.1073/pnas.1418974111. PubMed DOI PMC

Hutt-Fletcher L.M. The Long and Complicated Relationship between Epstein-Barr Virus and Epithelial Cells. J. Virol. 2017;91 doi: 10.1128/JVI.01677-16. PubMed DOI PMC

Lin Z., Wang X., Fewell C., Cameron J., Yin Q., Flemington E.K. Differential expression of the miR-200 family microRNAs in epithelial and B cells and regulation of Epstein-Barr virus reactivation by the miR-200 family member miR-429. J. Virol. 2010;84:7892–7897. doi: 10.1128/JVI.00379-10. PubMed DOI PMC

Ellis-Connell A.L., Iempridee T., Xu I., Mertz J.E. Cellular microRNAs 200b and 429 regulate the Epstein-Barr virus switch between latency and lytic replication. J. Virol. 2010;84:10329–10343. doi: 10.1128/JVI.00923-10. PubMed DOI PMC

Yu X., Wang Z., Mertz J.E. ZEB1 regulates the latent-lytic switch in infection by Epstein-Barr virus. PLoS Pathog. 2007;3:e194. doi: 10.1371/journal.ppat.0030194. PubMed DOI PMC

Kraus R.J., Perrigoue J.G., Mertz J.E. ZEB negatively regulates the lytic-switch BZLF1 gene promoter of Epstein-Barr virus. J. Virol. 2003;77:199–207. doi: 10.1128/JVI.77.1.199-207.2003. PubMed DOI PMC

Zhang J., Li S., Li L., Li M., Guo C., Yao J., Mi S. Exosome and exosomal microRNA: Trafficking, sorting, and function. Genomics Proteomics Bioinformatics. 2015;13:17–24. doi: 10.1016/j.gpb.2015.02.001. PubMed DOI PMC

Nanbo A., Kawanishi E., Yoshida R., Yoshiyama H. Exosomes derived from Epstein-Barr virus-infected cells are internalized via caveola-dependent endocytosis and promote phenotypic modulation in target cells. J. Virol. 2013;87:10334–10347. doi: 10.1128/JVI.01310-13. PubMed DOI PMC

Nanbo A., Kachi K., Yoshiyama H., Ohba Y. Epstein-Barr virus exploits host endocytic machinery for cell-to-cell viral transmission rather than a virological synapse. J. Gen. Virol. 2016;97:2989–3006. doi: 10.1099/jgv.0.000605. PubMed DOI

Nanbo A., Ohashi M., Yoshiyama H., Ohba Y. The Role of Transforming Growth Factor beta in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission. Front Microbiol. 2018;9:984. doi: 10.3389/fmicb.2018.00984. PubMed DOI PMC

Lin Z., Flemington E.K. miRNAs in the pathogenesis of oncogenic human viruses. Cancer Lett. 2011;305:186–199. doi: 10.1016/j.canlet.2010.08.018. PubMed DOI PMC

Wang M., Yu F., Wu W., Wang Y., Ding H., Qian L. Epstein-Barr virus-encoded microRNAs as regulators in host immune responses. Int. J. Biol. Sci. 2018;14:565–576. doi: 10.7150/ijbs.24562. PubMed DOI PMC

Albanese M., Tagawa T., Bouvet M., Maliqi L., Lutter D., Hoser J., Hastreiter M., Hayes M., Sugden B., Martin L., et al. Epstein-Barr virus microRNAs reduce immune surveillance by virus-specific CD8+ T cells. Proc. Natl. Acad. Sci. USA. 2016;113:E6467–E6475. doi: 10.1073/pnas.1605884113. PubMed DOI PMC

Tagawa T., Albanese M., Bouvet M., Moosmann A., Mautner J., Heissmeyer V., Zielinski C., Lutter D., Hoser J., Hastreiter M., et al. Epstein-Barr viral miRNAs inhibit antiviral CD4+ T cell responses targeting IL-12 and peptide processing. J. Exp. Med. 2016;213:2065–2080. doi: 10.1084/jem.20160248. PubMed DOI PMC

Pegtel D.M., van de Garde M.D., Middeldorp J.M. Viral miRNAs exploiting the endosomal-exosomal pathway for intercellular cross-talk and immune evasion. Biochim. Biophys. Acta. 2011;1809:715–721. doi: 10.1016/j.bbagrm.2011.08.002. PubMed DOI

Gallo A., Vella S., Miele M., Timoneri F., Bella M.D., Bosi S., Sciveres M., Conaldi P.G. Global profiling of viral and cellular non-coding RNAs in Epstein-Barr virus-induced lymphoblastoid cell lines and released exosome cargos. Cancer Lett. 2017;388:334–343. doi: 10.1016/j.canlet.2016.12.003. PubMed DOI

Haneklaus M., Gerlic M., Kurowska-Stolarska M., Rainey A.A., Pich D., McInnes I.B., Hammerschmidt W., O’Neill L.A.J., Masters S.L. Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1beta production. J. Immunol. 2012;189:3795–3799. doi: 10.4049/jimmunol.1200312. PubMed DOI

Nanbo A., Katano H., Kataoka M., Hoshina S., Sekizuka T., Kuroda M., Ohba Y. Infection of Epstein(-)Barr Virus in Type III Latency Modulates Biogenesis of Exosomes and the Expression Profile of Exosomal miRNAs in the Burkitt Lymphoma Mutu Cell Lines. Cancers. 2018;10 doi: 10.3390/cancers10070237. PubMed DOI PMC

Higuchi H., Yamakawa N., Imadome K.-I., Yahata T., Kotaki R., Ogata J., Kakizaki M., Fujita K., Lu J., Yokoyama K., et al. Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma. Blood. 2018;131:2552–2567. doi: 10.1182/blood-2017-07-794529. PubMed DOI

Meckes D.G., Shair K.H.Y., Marquitz A.R., Kung C.P., Edwards R.H., Raab-Traub N. Human tumor virus utilizes exosomes for intercellular communication. Proc. Natl. Acad. Sci. USA. 2010;107:20370–20375. doi: 10.1073/pnas.1014194107. PubMed DOI PMC

Ramayanti O., Verkuijlen S.A.W.M., Novianti P., Scheepbouwer C., Misovic B., Koppers-Lalic D., Weering J.V., Beckers L., Adham M., Martorelli D., et al. Vesicle-bound EBV-BART13-3p miRNA in circulation distinguishes nasopharyngeal from other head and neck cancer and asymptomatic EBV-infections. Int. J. Cancer. 2018 doi: 10.1002/ijc.31967. PubMed DOI PMC

Elgui de Oliveira D., Muller-Coan B.G., Pagano J.S. Viral Carcinogenesis Beyond Malignant Transformation: EBV in the Progression of Human Cancers. Trends Microbiol. 2016;24:649–664. doi: 10.1016/j.tim.2016.03.008. PubMed DOI PMC

Wang L.W., Jiang S., Gewurz B.E. Epstein-Barr Virus LMP1-Mediated Oncogenicity. J. Virol. 2017;91 doi: 10.1128/JVI.01718-16. PubMed DOI PMC

Kieser A., Sterz K.R. The Latent Membrane Protein 1 (LMP1), in Epstein Barr Virus Volume 2. In: Münz C., editor. Current Topics in Microbiology and Immunology. Springer; Cham, Switzerland: 2015. pp. 119–149. PubMed

Dukers D.F., Meij P., Vervoort M.B.H.J., Vos W., Scheper R.J., Meijer C.J.L.M., Bloemena E., Middeldorp J.M. Direct immunosuppressive effects of EBV-encoded latent membrane protein 1. J. Immunol. 2000;165:663–670. doi: 10.4049/jimmunol.165.2.663. PubMed DOI

Vazirabadi G., Geiger T.R., Coffin W.F., 3rd, Martin J.M. Epstein-Barr virus latent membrane protein-1 (LMP-1) and lytic LMP-1 localization in plasma membrane-derived extracellular vesicles and intracellular virions. J. Gen. Virol. 2003;84:1997–2008. doi: 10.1099/vir.0.19156-0. PubMed DOI

Houali K., Wang X., Shimizu Y., Djennaoui D., Nicholls J., Fiorini S., Bouguermouh A., Ooka T. A new diagnostic marker for secreted Epstein-Barr virus encoded LMP1 and BARF1 oncoproteins in the serum and saliva of patients with nasopharyngeal carcinoma. Clin. Cancer Res. 2007;13:4993–5000. doi: 10.1158/1078-0432.CCR-06-2945. PubMed DOI

Ceccarelli S., Visco V., Raffa S., Wakisaka N., Pagano J.S., Torrisi M.R. Epstein-Barr virus latent membrane protein 1 promotes concentration in multivesicular bodies of fibroblast growth factor 2 and its release through exosomes. Int. J. Cancer. 2007;121:1494–1506. doi: 10.1002/ijc.22844. PubMed DOI

Aga M., Bentz G.L., Raffa S., Torrisi M.R., Kondo S., Wakisaka N., Yoshizaki T., Pagano J.S., Shackelford J. Exosomal HIF1alpha supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene. 2014;33:4613–4622. doi: 10.1038/onc.2014.66. PubMed DOI PMC

Kobayashi E., Aga M., Kondo S., Whitehurst C., Yoshizaki T., Pagano J.S., Shackelford J. C-Terminal Farnesylation of UCH-L1 Plays a Role in Transport. of Epstein-Barr Virus Primary Oncoprotein LMP1 to Exosomes. mSphere. 2018;3 doi: 10.1128/mSphere.00030-18. PubMed DOI PMC

Hurwitz S.N., Nkosi D., Conlon M.M., York S.B., Liu X., Tremblay D.C., Meckes D.G. CD63 Regulates Epstein-Barr Virus LMP1 Exosomal Packaging, Enhancement of Vesicle Production, and Noncanonical NF-kappaB Signaling. J. Virol. 2017;91 doi: 10.1128/JVI.02251-16. PubMed DOI PMC

Hurwitz S.N., Cheerathodi M.R., Nkosi D., York S.B., Meckes D.G. Tetraspanin CD63 Bridges Autophagic and Endosomal Processes To Regulate Exosomal Secretion and Intracellular Signaling of Epstein-Barr Virus LMP1. J. Virol. 2018;92 doi: 10.1128/JVI.01969-17. PubMed DOI PMC

Ikeda M., Longnecker R. Cholesterol is critical for Epstein-Barr virus latent membrane protein 2A trafficking and protein stability. Virology. 2007;360:461–468. doi: 10.1016/j.virol.2006.10.046. PubMed DOI PMC

Arrand J.R., Rymo L. Characterization of the major Epstein-Barr virus-specific RNA in Burkitt lymphoma-derived cells. J. Virol. 1982;41:376–389. PubMed PMC

Clarke P.A., Schwemmle M., Schickinger J., Hilse K., Clemens M.J. Binding of Epstein-Barr virus small RNA EBER-1 to the double-stranded RNA-activated protein kinase DAI. Nucleic Acids Res. 1991;19:243–248. doi: 10.1093/nar/19.2.243. PubMed DOI PMC

Lerner M.R., Andrews N.C., Miller G., Steitz J.A. Two small RNAs encoded by Epstein-Barr virus and complexed with protein are precipitated by antibodies from patients with systemic lupus erythematosus. Proc. Natl. Acad. Sci. USA. 1981;78:805–809. doi: 10.1073/pnas.78.2.805. PubMed DOI PMC

Samanta M., Iwakiri D., Kanda T., Imaizumi T., Takada K. EB virus-encoded RNAs are recognized by RIG-I and activate signaling to induce type I IFN. EMBO J. 2006;25:4207–4214. doi: 10.1038/sj.emboj.7601314. PubMed DOI PMC

Nanbo A., Inoue K., Adachi-Takasawa K., Takada K. Epstein-Barr virus RNA confers resistance to interferon-alpha-induced apoptosis in Burkitt’s lymphoma. EMBO J. 2002;21:954–965. doi: 10.1093/emboj/21.5.954. PubMed DOI PMC

Gregorovic G., Bosshard R., Karstegl C.E., White R.E., Pattle S., Chiang A.K.S., Dittrich-Breiholz O., Kracht M., Russ R., Farrell P.J. Cellular gene expression that correlates with EBER expression in Epstein-Barr Virus-infected lymphoblastoid cell lines. J. Virol. 2011;85:3535–3545. doi: 10.1128/JVI.02086-10. PubMed DOI PMC

Ahmed W., Philip P.S., Tariq S., Khan G. Epstein-Barr virus-encoded small RNAs (EBERs) are present in fractions related to exosomes released by EBV-transformed cells. PLoS ONE. 2014;9:e99163. doi: 10.1371/journal.pone.0099163. PubMed DOI PMC

Aromseree S., Middeldorp J.M., Pientong C., Eijndhoven M.V., Ramayanti O., Lougheed S.M., Pegtel D.M., Steenbergen R.D.M., Ekalaksananan T. High Levels of EBV-Encoded RNA 1 (EBER1) Trigger Interferon and Inflammation-Related Genes in Keratinocytes Expressing HPV16 E6/E7. PLoS ONE. 2017;12:e0169290. doi: 10.1371/journal.pone.0169290. PubMed DOI PMC

Vallhov H., Gutzeit C., Johansson S.M., Nagy N., Paul M., Li Q., Friend S., George T.C., Klein E., Scheynius A., et al. Exosomes containing glycoprotein 350 released by EBV-transformed B cells selectively target B cells through CD21 and block EBV infection in vitro. J. Immunol. 2011;186:73–82. doi: 10.4049/jimmunol.1001145. PubMed DOI

Canitano A., Venturi G., Borghi M., Ammendolia M.G., Fais S. Exosomes released in vitro from Epstein-Barr virus (EBV)-infected cells contain EBV-encoded latent phase mRNAs. Cancer Lett. 2013;337:193–199. doi: 10.1016/j.canlet.2013.05.012. PubMed DOI

Meckes D.G., Gunawardena H.P., Dekroon R.M., Heaton P.R., Edwards R.H., Ozgur S., Griffith J.D., Damania B., Raab-Traub N. Modulation of B-cell exosome proteins by gamma herpesvirus infection. Proc. Natl. Acad. Sci. USA. 2013;110:E2925–E2933. doi: 10.1073/pnas.1303906110. PubMed DOI PMC

Lai C.P., Mardini O., Ericsson M., Prabhakar S., Maguire C.A., Chen J.W., Tannous B.A., Breakefield X.O. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano. 2014;8:483–494. doi: 10.1021/nn404945r. PubMed DOI PMC

Lai C.P., Tannous B.A., Breakefield X.O. Noninvasive in vivo monitoring of extracellular vesicles. Methods Mol. Biol. 2014;1098:249–258. PubMed PMC

Lai C.P., Kim E.Y., Badr C.E., Weissleder R., Mempel T.R., Tannous B.A., Breakefield X.O. Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters. Nat. Commun. 2015;6:7029. doi: 10.1038/ncomms8029. PubMed DOI PMC

Witwer K.W., Buzás E.I., Bemis L.T., Bora A., Lässer C., Lötvall J., Nolte-‘t Hoen E.N., Piper M.G., Sivaraman S., Skog J., et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell Vesicles. 2013;2 doi: 10.3402/jev.v2i0.20360. PubMed DOI PMC

Palma J., Yaddanapudi S.C., Pigati L., Havens M.A., Jeong S., Weiner G.A., Weimer K.M.E., Stern B., Hastings M.L., Duelli D.M. MicroRNAs are exported from malignant cells in customized particles. Nucleic Acids Res. 2012;40:9125–9138. doi: 10.1093/nar/gks656. PubMed DOI PMC

Vickers K.C., Palmisano B.T., Shoucri B.M., Shamburek R.D., Remaley A.T. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 2011;13:423–433. doi: 10.1038/ncb2210. PubMed DOI PMC

Chen X., Liang H., Zhang J., Zen K., Zhang C.-Y. Secreted microRNAs: A new form of intercellular communication. Trends Cell Biol. 2012;22:125–132. doi: 10.1016/j.tcb.2011.12.001. PubMed DOI

Lotvall J., Hill A.F., Hochberg F., Buzás E.I., Vizio D.D., Gardiner C., Gho Y.S., Kurochkin I.V., Mathivanan S., Quesenberry P., et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: A position statement from the International Society for Extracellular Vesicles. J. Extracell Vesicles. 2014;3:26913. doi: 10.3402/jev.v3.26913. PubMed DOI PMC

Kowal J., Arras G., Colombo M., Jouve M., Morath J.P., Primdal-Bengtson B., Dingli F., Loew D., Tkach M., Théry C. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc. Natl. Acad. Sci. USA. 2016;113:E968–E977. doi: 10.1073/pnas.1521230113. PubMed DOI PMC

MicroRNA and Other Non-Coding RNAs in Epstein-Barr Virus-Associated Cancers