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Extracellular Vesicles: A Brief Overview and Its Role in Precision Medicine

  • Mingyi Shang
  • John S. Ji
  • Chao Song
  • Bao Jun Gao
  • Jason Gang Jin
  • Winston Patrick KuoEmail author
  • Hongjun Kang
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1660)

Abstract

Precision medicine has emerged as an approach to tailor therapies for an individual at the time of diagnosis and/or treatment. This emergence has been fueled by the ability to profile nucleic acids, along with proteins and lipids isolated from biofluids, a method called “liquid biopsy,” either by or in combination of one of the following components: circulating tumor cells (CTCs), cell-free DNA (cfDNA), and/or extracellular vesicles (EVs). EVs are membrane-surrounded structures released by cells in an evolutionarily conserved manner. EVs have gained much attention from both the basic and clinical research areas, as EVs appear to play a role in many diseases; however, the well-known case is cancer. The hallmark of EVs in cancer is their role as mediators of communication between cells both at physiological and pathophysiological levels; hence, EVs are thought to contribute to the creation of a microenvironmental niche that promotes cancer cell survival, as well as reprogramming distant tissue for invasion. It is important to understand the mechanistic and functional aspects at the basic science level of EVs to get a better grasp on their role in healthy and disease states. EVs range from 30–1000 nm membrane-enclosed vesicles that are released by many mammalian cell types and present in a variety of biofluids. EVs have emerged as an area of clinical interest in the era of Precision Medicine, from their role in liquid biopsy (tissue biopsy free) approach for screening, assessing tumor heterogeneity, monitoring therapeutic responses, and minimal residual disease detection to EV-based therapeutics. EVs’ diagnostic and therapeutic exploitation is under intense investigation in various indications. This chapter highlights EV biogenesis, composition of EVs, and their potential role in liquid biopsy diagnostics and therapeutics in the area of cancer.

Key words

Exosomes Biogenesis Extracellular vesicles Precision medicine Liquid biopsy Diagnostics Therapeutics 

References

  1. 1.
    Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12(5):323–334. doi: 10.1038/nrc3261 CrossRefPubMedGoogle Scholar
  2. 2.
    Janku F (2014) Tumor heterogeneity in the clinic: is it a real problem? Ther Adv Med Oncol 6(2):43–51. doi: 10.1177/1758834013517414 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Sadee W, Dai Z (2005) Pharmacogenetics/geno-mics and personalized medicine. Hum Mol Genet 14(2):R207–R214. doi: 10.1093/hmg/ddi261
  4. 4.
    Trams EG, Lauter CJ, Salem N Jr, Heine U (1981) Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim Biophys Acta 645(1):63–70CrossRefPubMedGoogle Scholar
  5. 5.
    Taylor DD, Chou IN, Black PH (1983) Isolation of plasma membrane fragments from cultured murine melanoma cells. Biochem Biophys Res Commun 113(2):470–476CrossRefPubMedGoogle Scholar
  6. 6.
    Taylor DD, Doellgast GJ (1979) Quantitation of peroxidase-antibody binding to membrane fragments using column chromatography. Anal Biochem 98(1):53–59Google Scholar
  7. 7.
    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(2):329–339CrossRefPubMedGoogle Scholar
  8. 8.
    Meckes DG Jr, Shair KH, Marquitz AR, Kung CP, Edwards RH, Raab-Traub N (2010) Human tumor virus utilizes exosomes for intercellular communication. Proc Natl Acad Sci U S A 107(47):20370–20375. doi: 10.1073/pnas.1014194107 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Peters PJ, Geuze HJ, Van der Donk HA, Slot JW, Griffith JM, Stam NJ, Clevers HC, Borst J (1989) Molecules relevant for T cell-target cell interaction are present in cytolytic granules of human T lymphocytes. Eur J Immunol 19(8):1469–1475. doi: 10.1002/eji.1830190819 CrossRefPubMedGoogle Scholar
  10. 10.
    Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1998) Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 4(5):594–600CrossRefPubMedGoogle Scholar
  11. 11.
    Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183(3):1161–1172CrossRefPubMedGoogle Scholar
  12. 12.
    Raposo G, Tenza D, Mecheri S, Peronet R, Bonnerot C, Desaymard C (1997) Accumulation of major histocompatibility complex class II molecules in mast cell secretory granules and their release upon degranulation. Mol Biol Cell 8(12):2631–2645CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Faure J, Lachenal G, Court M, Hirrlinger J, Chatellard-Causse C, Blot B, Grange J, Schoehn G, Goldberg Y, Boyer V, Kirchhoff F, Raposo G, Garin J, Sadoul R (2006) Exosomes are released by cultured cortical neurones. Mol Cell Neurosci 31(4):642–648. doi: 10.1016/j.mcn.2005.12.003 CrossRefPubMedGoogle Scholar
  14. 14.
    Sullivan R, Saez F, Girouard J, Frenette G (2005) Role of exosomes in sperm maturation during the transit along the male reproductive tract. Blood Cells Mol Dis 35(1):1–10. doi: 10.1016/j.bcmd.2005.03.005 CrossRefPubMedGoogle Scholar
  15. 15.
    Mears R, Craven RA, Hanrahan S, Totty N, Upton C, Young SL, Patel P, Selby PJ, Banks RE (2004) Proteomic analysis of melanoma-derived exosomes by two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. Proteomics 4(12):4019–4031. doi: 10.1002/pmic.200400876 CrossRefPubMedGoogle Scholar
  16. 16.
    Safaei R, Larson BJ, Cheng TC, Gibson MA, Otani S, Naerdemann W, Howell SB (2005) Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther 4(10):1595–1604. doi: 10.1158/1535-7163.MCT-05-0102 CrossRefPubMedGoogle Scholar
  17. 17.
    Kapsogeorgou EK, Abu-Helu RF, Moutsopoulos HM, Manoussakis MN (2005) Salivary gland epithelial cell exosomes: a source of autoantigenic ribonucleoproteins. Arthritis Rheum 52(5):1517–1521. doi: 10.1002/art.21005 CrossRefPubMedGoogle Scholar
  18. 18.
    Castellana D, Toti F, Freyssinet JM (2010) Membrane microvesicles: macromessengers in cancer disease and progression. Thromb Res 125(Suppl 2):S84–S88. doi: 10.1016/S0049-3848(10)70021-9 CrossRefPubMedGoogle Scholar
  19. 19.
    Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19(2):43–51. doi: 10.1016/j.tcb.2008.11.003 CrossRefPubMedGoogle Scholar
  20. 20.
    Mathivanan S, Lim JW, Tauro BJ, Ji H, Moritz RL, Simpson RJ (2010) Proteomics analysis of A33 immunoaffinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature. Mol Cell Proteomics 9(2):197–208. doi: 10.1074/mcp.M900152-MCP200 CrossRefPubMedGoogle Scholar
  21. 21.
    Sorkin A, Goh LK (2009) Endocytosis and intracellular trafficking of ErbBs. Exp Cell Res 315(4):683–696CrossRefPubMedGoogle Scholar
  22. 22.
    Keller S, Sanderson MP, Stoeck A, Altevogt P (2006) Exosomes: from biogenesis and secretion to biological function. Immunol Lett 107(2):102–108. doi: 10.1016/j.imlet.2006.09.005
  23. 23.
    Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2(8):569–579. doi: 10.1038/nri855
  24. 24.
    Nazarenko I, Rana S, Baumann A, McAlear J, Hellwig A, Trendelenburg M, Lochnit G, Preissner KT, Zoller M (2010) Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res 70(4):1668–1678. doi: 10.1158/0008-5472.CAN-09-2470 CrossRefPubMedGoogle Scholar
  25. 25.
    Sorkin A, von Zastrow M (2009) Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol 10(9):609–622. doi: 10.1038/nrm2748 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ohno H (2006) Clathrin-associated adaptor protein complexes. J Cell Sci 119(Pt 18):3719–3721. doi: 10.1242/jcs.03085 CrossRefPubMedGoogle Scholar
  27. 27.
    Praefcke GJ, Ford MG, Schmid EM, Olesen LE, Gallop JL, Peak-Chew SY, Vallis Y, Babu MM, Mills IG, McMahon HT (2004) Evolving nature of the AP2 alpha-appendage hub during clathrin-coated vesicle endocytosis. EMBO J 23(22):4371–4383. doi: 10.1038/sj.emboj.7600445 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    van Dam EM, Stoorvogel W (2002) Dynamin-dependent transferrin receptor recycling by endosome-derived clathrin-coated vesicles. Mol Biol Cell 13(1):169–182. doi: 10.1091/mbc.01-07-0380 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lakkaraju A, Rodriguez-Boulan E (2008) Itinerant exosomes: emerging roles in cell and tissue polarity. Trends Cell Biol 18(5):199–209. doi: 10.1016/j.tcb.2008.03.002 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    van Niel G, Wubbolts R, Ten Broeke T, Buschow SI, Ossendorp FA, Melief CJ, Raposo G, van Balkom BW, Stoorvogel W (2006) Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination. Immunity 25(6):885–894. doi: 10.1016/j.immuni.2006.11.001 CrossRefPubMedGoogle Scholar
  31. 31.
    Piper RC, Luzio JP (2001) Late endosomes: sorting and partitioning in multivesicular bodies. Traffic 2(9):612–621CrossRefPubMedGoogle Scholar
  32. 32.
    Yeo SC, Xu L, Ren J, Boulton VJ, Wagle MD, Liu C, Ren G, Wong P, Zahn R, Sasajala P, Yang H, Piper RC, Munn AL (2003) Vps20p and Vta1p interact with Vps4p and function in multivesicular body sorting and endosomal transport in Saccharomyces cerevisiae. J Cell Sci 116(Pt 19):3957–3970. doi: 10.1242/jcs.00751 CrossRefPubMedGoogle Scholar
  33. 33.
    Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9(8):581–593. doi: 10.1038/nri2567 CrossRefPubMedGoogle Scholar
  34. 34.
    Rink J, Ghigo E, Kalaidzidis Y, Zerial M (2005) Rab conversion as a mechanism of progression from early to late endosomes. Cell 122(5):735–749. doi: 10.1016/j.cell.2005.06.043 CrossRefPubMedGoogle Scholar
  35. 35.
    Savina A, Vidal M, Colombo MI (2002) The exosome pathway in K562 cells is regulated by Rab11. J Cell Sci 115(Pt 12):2505–2515PubMedGoogle Scholar
  36. 36.
    Feng D, Zhao WL, Ye YY, Bai XC, Liu RQ, Chang LF, Zhou Q, Sui SF (2010) Cellular internalization of exosomes occurs through phagocytosis. Traffic 11(5):675–687. doi: 10.1111/j.1600-0854.2010.01041.x CrossRefPubMedGoogle Scholar
  37. 37.
    Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brugger B, Simons M (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319(5867):1244–1247. doi: 10.1126/science.1153124 CrossRefPubMedGoogle Scholar
  38. 38.
    Futter CE, Pearse A, Hewlett LJ, Hopkins CR (1996) Multivesicular endosomes containing internalized EGF-EGF receptor complexes mature and then fuse directly with lysosomes. J Cell Biol 132(6):1011–1023CrossRefPubMedGoogle Scholar
  39. 39.
    Logozzi M, De Milito A, Lugini L, Borghi M, Calabro L, Spada M, Perdicchio M, Marino ML, Federici C, Iessi E, Brambilla D, Venturi G, Lozupone F, Santinami M, Huber V, Maio M, Rivoltini L, Fais S (2009) High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One 4(4):e5219. doi: 10.1371/journal.pone.0005219 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C (2005) Exosomal-like vesicles are present in human blood plasma. Int Immunol 17(7):879–887. doi: 10.1093/intimm/dxh267 CrossRefPubMedGoogle Scholar
  41. 41.
    Pisitkun T, Shen RF, Knepper MA (2004) Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A 101(36):13368–13373. doi: 10.1073/pnas.0403453101 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Vella LJ, Greenwood DL, Cappai R, Scheerlinck JP, Hill AF (2008) Enrichment of prion protein in exosomes derived from ovine cerebral spinal fluid. Vet Immunol Immunopathol 124(3–4):385–393. doi: 10.1016/j.vetimm.2008.04.002 CrossRefPubMedGoogle Scholar
  43. 43.
    Sharma S, Rasool HI, Palanisamy V, Mathisen C, Schmidt M, Wong DT, Gimzewski JK (2010) Structural-mechanical characterization of nanoparticle exosomes in human saliva, using correlative AFM, FESEM, and force spectroscopy. ACS Nano 4(4):1921–1926. doi: 10.1021/nn901824n CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Qazi KR, Torregrosa Paredes P, Dahlberg B, Grunewald J, Eklund A, Gabrielsson S (2010) Proinflammatory exosomes in bronchoalveolar lavage fluid of patients with sarcoidosis. Thorax 65(11):1016–1024. doi: 10.1136/thx.2009.132027
  45. 45.
    Welton JL, Khanna S, Giles PJ, Brennan P, Brewis IA, Staffurth J, Mason MD, Clayton A (2010) Proteomics analysis of bladder cancer exosomes. Mol Cell Proteomics 9(6):1324–1338. doi: 10.1074/mcp.M000063-MCP201 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Rabinowits G, Gercel-Taylor C, Day JM, Taylor DD, Kloecker GH (2009) Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer 10(1):42–46. doi: 10.3816/CLC.2009.n.006
  47. 47.
    Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10(12):1470–1476. doi: 10.1038/ncb1800
  48. 48.
    de Kok JB, Verhaegh GW, Roelofs RW, Hessels D, Kiemeney LA, Aalders TW, Swinkels DW, Schalken JA (2002) DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res 62(9):2695–2698PubMedGoogle Scholar
  49. 49.
    Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310(5748):644–648. doi: 10.1126/science.1117679 CrossRefPubMedGoogle Scholar
  50. 50.
    Nilsson J, Skog J, Nordstrand A, Baranov V, Mincheva-Nilsson L, Breakefield XO, Widmark A (2009) Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer 100(10):1603–1607. doi: 10.1038/sj.bjc.6605058 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Taylor DD, Gercel-Taylor C (2008) MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110(1):13–21. doi: 10.1016/j.ygyno.2008.04.033
  52. 52.
    El Andaloussi S, Lakhal S, Mager I, Wood MJ (2013) Exosomes for targeted siRNA delivery across biological barriers. Adv Drug Deliv Rev 65(3):391–397. doi: 10.1016/j.addr.2012.08.008
  53. 53.
    Lai RC, Yeo RW, Tan KH, Lim SK (2013) Exosomes for drug delivery–a novel application for the mesenchymal stem cell. Biotechnol Adv 31(5):543–551. doi: 10.1016/j.biotechadv.2012.08.008
  54. 54.
    Vickers KC, Remaley AT (2012) Lipid-based carriers of microRNAs and intercellular communication. Curr Opin Lipidol 23(2):91–97. doi: 10.1097/MOL.0b013e328350a425 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D, Zhang HG (2010) A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther 18(9):1606–1614. doi: 10.1038/mt.2010.105
  56. 56.
    O'Loughlin AJ, Woffindale CA, Wood MJ (2012) Exosomes and the emerging field of exosome-based gene therapy. Curr Gene Ther 12(4):262–274CrossRefPubMedGoogle Scholar
  57. 57.
    Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T, Gotoh N, Kuroda M (2013) Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther 21(1):185–191. doi: 10.1038/mt.2012.180 CrossRefPubMedGoogle Scholar
  58. 58.
    Karlsson MR, Kahu H, Hanson LA, Telemo E, Dahlgren UI (2000) Tolerance and bystander suppression, with involvement of CD25-positive cells, is induced in rats receiving serum from ovalbumin-fed donors. Immunology 100(3):326–333CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Karlsson MR, Kahu H, Hanson LA, Telemo E, Dahlgren UI (2002) An established immune response against ovalbumin is suppressed by a transferable serum factor produced after ovalbumin feeding: a role of CD25+ regulatory cells. Scand J Immunol 55(5):470–477CrossRefPubMedGoogle Scholar
  60. 60.
    Martinez MC, Andriantsitohaina R (2011) Microparticles in angiogenesis: therapeutic potential. Circ Res 109(1):110–119. doi: 10.1161/CIRCRESAHA.110.233049 CrossRefPubMedGoogle Scholar
  61. 61.
    Chaput N, Flament C, Viaud S, Taieb J, Roux S, Spatz A, Andre F, LePecq JB, Boussac M, Garin J, Amigorena S, Thery C, Zitvogel L (2006) Dendritic cell derived-exosomes: biology and clinical implementations. J Leukoc Biol 80(3):471–478. doi: 10.1189/jlb.0206094 CrossRefPubMedGoogle Scholar
  62. 62.
    Viaud S, Ploix S, Lapierre V, Thery C, Commere PH, Tramalloni D, Gorrichon K, Virault-Rocroy P, Tursz T, Lantz O, Zitvogel L, Chaput N (2011) Updated technology to produce highly immunogenic dendritic cell-derived exosomes of clinical grade: a critical role of interferon-gamma. J Immunother 34(1):65–75. doi: 10.1097/CJI.0b013e3181fe535b CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2017

Authors and Affiliations

  • Mingyi Shang
    • 1
  • John S. Ji
    • 2
  • Chao Song
    • 3
  • Bao Jun Gao
    • 3
  • Jason Gang Jin
    • 3
  • Winston Patrick Kuo
    • 3
    • 4
    Email author
  • Hongjun Kang
    • 5
  1. 1.Department of RadiologyShanghai Tongren HospitalShanghaiChina
  2. 2.Environmental Health ScienceDuke Kunshan UniversityShanghaiChina
  3. 3.CloudHealth Genomics, LtdShanghaiChina
  4. 4.Weschester Biotech ProjectAsbury ParkUSA
  5. 5.Department of Critical Care MedicineChinese PLA General HospitalBeijingChina

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