Biogenesis and Functions of Exosomes and Extracellular Vesicles

Part of the Methods in Molecular Biology book series (MIMB, volume 1448)


Research on extracellular vesicles (EVs) is a new and emerging field that is rapidly growing. Many features of these structures still need to be described and discovered. This concerns their biogenesis, their release and cellular entrance mechanisms, as well as their functions, particularly in vivo. Hence our knowledge on EV is constantly evolving and sometimes changing. In our review we summarize the most important facts of our current knowledge about extracellular vesicles and described some of the assumed functions in the context of cancer and HIV infection.

Key words

Exosomes Extracellular vesicles Biomarker HIV ESCRT 


  1. 1.
    Skog J et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Muratori C et al (2009) Massive secretion by T cells is caused by HIV Nef in infected cells and by Nef transfer to bystander cells. Cell Host Microbe 6:218–230CrossRefPubMedGoogle Scholar
  3. 3.
    Bollati V et al (2014) Susceptibility to particle health effects, miRNA and exosomes: rationale and study protocol of the SPHERE study. BMC Public Health 14:1137CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Trams EG et al (1981) Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim Biophys Acta 645:63–70CrossRefPubMedGoogle Scholar
  5. 5.
    Harding C, Heuser J, Stahl P (1983) Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97:329–339CrossRefPubMedGoogle Scholar
  6. 6.
    Pan BT et al (1985) Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol 101:942–948CrossRefPubMedGoogle Scholar
  7. 7.
    Skokos D et al (2001) Mast cell-dependent B and T lymphocyte activation is mediated by the secretion of immunologically active exosomes. J Immunol 166:868–876CrossRefPubMedGoogle Scholar
  8. 8.
    Wolfers J et al (2001) Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med 7:297–303CrossRefPubMedGoogle Scholar
  9. 9.
    Kadiu I et al (2012) Biochemical and biologic characterization of exosomes and microvesicles as facilitators of HIV-1 infection in macrophages. J Immunol 189:744–754CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Li J et al (2013) Exosomes mediate the cell-to-cell transmission of IFN-alpha-induced antiviral activity. Nat Immunol 14:793–803CrossRefPubMedGoogle Scholar
  11. 11.
    Chatila TA, Williams CB (2014) Regulatory T cells: exosomes deliver tolerance. Immunity 41:3–5CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Poteryaev D et al (2010) Identification of the switch in early-to-late endosome transition. Cell 141:497–508CrossRefPubMedGoogle Scholar
  13. 13.
    Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579PubMedGoogle Scholar
  14. 14.
    Williams RL, Urbe S (2007) The emerging shape of the ESCRT machinery. Nat Rev Mol Cell Biol 8:355–368CrossRefPubMedGoogle Scholar
  15. 15.
    Rusten TE, Vaccari T, Stenmark H (2012) Shaping development with ESCRTs. Nat Cell Biol 14:38–45CrossRefGoogle Scholar
  16. 16.
    Hurley JH, Hanson PI (2010) Membrane budding and scission by the ESCRT machinery: it’s all in the neck. Nat Rev Mol Cell Biol 11:556–566CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Robbins PD, Morelli AE (2014) Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 14:195–208CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Trajkovic K et al (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244–1247CrossRefPubMedGoogle Scholar
  19. 19.
    Wu BX, Clarke CJ, Hannun YA (2010) Mammalian neutral sphingomyelinases: regulation and roles in cell signaling responses. Neuromolecular Med 12:320–330CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kharaziha P et al (2012) Tumor cell-derived exosomes: a message in a bottle. Biochim Biophys Acta 1826:103–111PubMedGoogle Scholar
  21. 21.
    Ostrowski M et al (2010) Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 12:19–30; sup pp 11–13Google Scholar
  22. 22.
    Hsu C et al (2010) Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J Cell Biol 189:223–232CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Fader CM et al (2009) TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochim Biophys Acta 1793:1901–1916CrossRefPubMedGoogle Scholar
  24. 24.
    Zitvogel L et al (1998) Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 4:594–600CrossRefPubMedGoogle Scholar
  25. 25.
    Bhatnagar S et al (2007) Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood 110:3234–3244CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Raposo G et al (1997) Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol Biol Cell 8:2631–2645CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Blanchard N et al (2002) TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J Immunol 168:3235–3241CrossRefPubMedGoogle Scholar
  28. 28.
    Buschow SI et al (2009) MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 10:1528–1542CrossRefPubMedGoogle Scholar
  29. 29.
    Nolte-'t Hoen EN et al (2009) Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood 113:1977–1981CrossRefPubMedGoogle Scholar
  30. 30.
    Muntasell A et al (2007) T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes. EMBO J 26:4263–4272CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lespagnol A et al (2008) Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell Death Differ 15:1723–1733CrossRefPubMedGoogle Scholar
  32. 32.
    Yu X, Harris SL, Levine AJ (2006) The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res 66:4795–4801CrossRefPubMedGoogle Scholar
  33. 33.
    Deolindo P, Evans-Osses I, Ramirez MI (2013) Microvesicles and exosomes as vehicles between protozoan and host cell communication. Biochem Soc Trans 41:252–257CrossRefPubMedGoogle Scholar
  34. 34.
    Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19:43–51CrossRefPubMedGoogle Scholar
  35. 35.
    Conde D et al (2005) Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 106:1604–1611CrossRefPubMedGoogle Scholar
  36. 36.
    Quesenberry PJ, Aliotta JM (2010) Cellular phenotype switching and microvesicles. Adv Drug Deliv Rev 62:1141–1148CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Cocucci E et al (2007) Enlargeosome traffic: exocytosis triggered by various signals is followed by endocytosis, membrane shedding or both. Traffic 8:742–757CrossRefPubMedGoogle Scholar
  38. 38.
    Balaj L et al (2011) Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun 2:180CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Gutierrez-Vazquez C et al (2013) Transfer of extracellular vesicles during immune cell-cell interactions. Immunol Rev 251:125–142CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Thery C et al (1999) Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol 147:599–610CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Mittelbrunn M et al (2011) Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun 2:282CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Hessvik NP et al (2012) Profiling of microRNAs in exosomes released from PC-3 prostate cancer cells. Biochim Biophys Acta 1819:1154–1163CrossRefPubMedGoogle Scholar
  43. 43.
    Li CC et al (2013) Glioma microvesicles carry selectively packaged coding and non-coding RNAs which alter gene expression in recipient cells. RNA Biol 10:1333–1344CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Gezer U et al (2014) Long non-coding RNAs with low expression levels in cells are enriched in secreted exosomes. Cell Biol Int 38:1076–1079PubMedGoogle Scholar
  45. 45.
    Shen B et al (2011) Protein targeting to exosomes/microvesicles by plasma membrane anchors. J Biol Chem 286:14383–14395CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Melo SA et al (2014) Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26:707–721CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Villarroya-Beltri C et al (2013) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 4:2980CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Koppers-Lalic D et al (2014) Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep 8:1649–1658CrossRefPubMedGoogle Scholar
  49. 49.
    Squadrito ML et al (2014) Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep 8:1432–1446CrossRefPubMedGoogle Scholar
  50. 50.
    Yuana Y et al (2013) Extracellular vesicles in physiological and pathological conditions. Blood Rev 27:31–39CrossRefPubMedGoogle Scholar
  51. 51.
    Peinado H et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883–891CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Alvarez-Erviti L et al (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345CrossRefPubMedGoogle Scholar
  53. 53.
    Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593CrossRefPubMedGoogle Scholar
  54. 54.
    Valadi H et al (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659CrossRefPubMedGoogle Scholar
  55. 55.
    Al-Nedawi K et al (2008) Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 10:619–624CrossRefPubMedGoogle Scholar
  56. 56.
    Montecalvo A et al (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119:756–766CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Biro E et al (2003) Human cell-derived microparticles promote thrombus formation in vivo in a tissue factor-dependent manner. J Thromb Haemost 1:2561–2568CrossRefPubMedGoogle Scholar
  58. 58.
    Zhang B et al (2015) HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells 33(7):2158–2168Google Scholar
  59. 59.
    Taylor DD, Akyol S, Gercel-Taylor C (2006) Pregnancy-associated exosomes and their modulation of T cell signaling. J Immunol 176:1534–1542CrossRefPubMedGoogle Scholar
  60. 60.
    Saenz-Cuesta M, Osorio-Querejeta I, Otaegui D (2014) Extracellular vesicles in multiple sclerosis: what are they telling us? Front Cell Neurosci 8:100CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Buzas EI et al (2014) Emerging role of extracellular vesicles in inflammatory diseases. Nat Rev Rheumatol 10:356–364CrossRefPubMedGoogle Scholar
  62. 62.
    Silverman JM, Reiner NE (2011) Exosomes and other microvesicles in infection biology: organelles with unanticipated phenotypes. Cell Microbiol 13:1–9CrossRefPubMedGoogle Scholar
  63. 63.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRefPubMedGoogle Scholar
  64. 64.
    Andreola G et al (2002) Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med 195:1303–1316CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Raisova M et al (2000) Resistance to CD95/Fas-induced and ceramide-mediated apoptosis of human melanoma cells is caused by a defective mitochondrial cytochrome c release. FEBS Lett 473:27–32CrossRefPubMedGoogle Scholar
  66. 66.
    Irmler M et al (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388:190–195CrossRefPubMedGoogle Scholar
  67. 67.
    Delcayre A, Shu H, Le Pecq JB (2005) Dendritic cell-derived exosomes in cancer immunotherapy: exploiting nature's antigen delivery pathway. Expert Rev Anticancer Ther 5:537–547CrossRefPubMedGoogle Scholar
  68. 68.
    Naslund TI et al (2013) Dendritic cell-derived exosomes need to activate both T and B cells to induce antitumor immunity. J Immunol 190:2712–2719CrossRefPubMedGoogle Scholar
  69. 69.
    Sobo-Vujanovic A et al (2014) Dendritic-cell exosomes cross-present Toll-like receptor-ligands and activate bystander dendritic cells. Cell Immunol 289:119–127CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Raposo G et al (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183:1161–1172CrossRefPubMedGoogle Scholar
  71. 71.
    Morse MA et al (2005) A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med 3:9CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Escudier B et al (2005) Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J Transl Med 3:10CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Viaud S et al (2009) Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha. PLoS One 4:e4942CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Munich S et al (2012) Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands. Oncoimmunology 1:1074–1083CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Lee JH et al (2013) HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases. Mol Cell 49:668–679CrossRefPubMedGoogle Scholar
  76. 76.
    Arenaccio C et al (2014) Exosomes from human immunodeficiency virus type 1 (HIV-1)-infected cells license quiescent CD4+ T lymphocytes to replicate HIV-1 through a Nef- and ADAM17-dependent mechanism. J Virol 88:11529–11539CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Arenaccio C et al (2014) Cell activation and HIV-1 replication in unstimulated CD4+ T lymphocytes ingesting exosomes from cells expressing defective HIV-1. Retrovirology 11:46CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Taylor DD, Gercel-Taylor C (2008) MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110:13–21CrossRefPubMedGoogle Scholar
  79. 79.
    Ogata-Kawata H et al (2014) Circulating exosomal microRNAs as biomarkers of colon cancer. PLoS One 9:e92921CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Schorey JS, Bhatnagar S (2008) Exosome function: from tumor immunology to pathogen biology. Traffic 9:871–881CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Azmi AS, Bao B, Sarkar FH (2013) Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev 32:623–642CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of DermatologyUniversity Hospital Erlangen, Friedrich-Alexander University of Erlangen-NürnbergErlangenGermany

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