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Exosomes in Cancer Disease

  • Margot ZöllerEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1381)

Abstract

Cancer diagnosis and therapy is steadily improving. Still, diagnosis is frequently late and diagnosis and follow-up procedures mostly are time-consuming and expensive. Searching for tumor-derived exosomes (TEX) in body fluids may provide an alternative, minimally invasive, yet highly reliable diagnostic tool. Beyond this, there is strong evidence that TEX could become a potent therapeutics.

Exosomes, small vesicles delivered by many cells of the organism, are found in all body fluids. Exosomes are characterized by lipid composition, common and donor cell specific proteins, mRNA, small non-coding RNA including miRNA and DNA. Particularly the protein and miRNA markers received much attention as they may allow for highly specific diagnosis and can provide hints toward tumor aggressiveness and progression, where exosome-based diagnosis and follow-up is greatly facilitated by the recovery of exosomes in body fluids, particularly the peripheral blood. Beyond this, exosomes are the most important intercellular communicators that modulate, instruct, and reprogram their surrounding as well as distant organs. In concern about TEX this includes message transfer from tumor cells toward the tumor stroma, the premetastatic niche, the hematopoietic system and, last but not least, the instruction of non-cancer stem cells by cancer-initiating cells (CIC). Taking this into account, it becomes obvious that “tailored” exosomes offer themselves as potent therapeutic delivery system.

In brief, during the last 4–5 years there is an ever-increasing, overwhelming interest in exosome research. This boom appears fully justified provided the content of the exosomes becomes most thoroughly analyzed and their mode of intercellular interaction can be unraveled in detail as this knowledge will open new doors toward cancer diagnosis and therapy including immunotherapy and CIC reprogramming.

Key words

Exosome Next-generation sequencing Pancreatic cancer 

Notes

Acknowledgement

Grant support: This investigation was supported by the German Cancer Aid (grant No: 109144) and the Wilhelm-Sander Stiftung.

References

  1. 1.
    Maryáš J, Faktor J, Dvořáková M et al (2014) Proteomics in investigation of cancer metastasis: functional and clinical consequences and methodological challenges. Proteomics 14:426–440PubMedCrossRefGoogle Scholar
  2. 2.
    Hong IS, Lee HY, Nam JS (2014) Cancer stem cells: the ‘achilles heel’ of chemo-resistant tumors. Recent Pat Anticancer Drug Discov 10:2–22CrossRefGoogle Scholar
  3. 3.
    Colak S, Medema JP (2014) Cancer stem cells--important players in tumor therapy resistance. FEBS J 281:4779–4791PubMedCrossRefGoogle Scholar
  4. 4.
    György B, Szabó TG, Pásztói M et al (2011) Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 68:2667–2688PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    O’Loughlin AJ, Woffindale CA, Wood MJ (2012) Exosomes and the emerging field of exosome-based gene therapy. Curr Gene Ther 12:262–274PubMedCrossRefGoogle Scholar
  6. 6.
    Lee Y, El Andaloussi S, Wood MJ (2012) Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet 21(R1):R125–R134PubMedCrossRefGoogle Scholar
  7. 7.
    Corrado C, Raimondo S, Chiesi A et al (2013) Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications. Int J Mol Sci 14:5338–5366PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Simons M, Raposo G (2009) Exosomes--vesicular carriers for intercellular communication. Curr Opin Cell Biol 21:575–581PubMedCrossRefGoogle Scholar
  9. 9.
    Vlassov AV, Magdaleno S, Setterquist R et al (2012) Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta 1820:940–948PubMedCrossRefGoogle Scholar
  10. 10.
    Mathivanan S, Ji H, Simpson RJ (2010) Exosomes: extracellular organelles important in intercellular communication. J Proteomics 73:1907–1920PubMedCrossRefGoogle Scholar
  11. 11.
    Kharaziha P, Ceder S, Li Q et al (2012) Tumor cell-derived exosomes: a message in a bottle. Biochim Biophys Acta 1826:103–111PubMedGoogle Scholar
  12. 12.
    Lee TH, D’Asti E, Magnus N et al (2011) Microvesicles as mediators of intercellular communication in cancer--the emerging science of cellular ‘debris’. Semin Immunopathol 33:455–467PubMedCrossRefGoogle Scholar
  13. 13.
    Simpson RJ, Lim JW, Moritz RL et al (2009) Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics 6:267–283PubMedCrossRefGoogle Scholar
  14. 14.
    Rak J (2010) Microparticles in cancer. Semin Thromb Hemost 36:888–906PubMedCrossRefGoogle Scholar
  15. 15.
    Record M, Subra C, Silvente-Poirot S et al (2011) Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol 81:1171–1182PubMedCrossRefGoogle Scholar
  16. 16.
    Martins VR, Dias MS, Hainaut P (2013) Tumor-cell-derived microvesicles as carriers of molecular information in cancer. Curr Opin Oncol 25:66–75PubMedCrossRefGoogle Scholar
  17. 17.
    Lässer C (2012) Exosomal RNA as biomarkers and the therapeutic potential of exosome vectors. Expert Opin Biol Ther 12(Suppl 1):S189–S197PubMedCrossRefGoogle Scholar
  18. 18.
    Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200:373–383PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Pap E, Pállinger E, Pásztói M et al (2009) Highlights of a new type of intercellular communication: microvesicle-based information transfer. Inflamm Res 58:1–8PubMedCrossRefGoogle Scholar
  20. 20.
    Sotelo JR, Porter KR (1959) An electron microscope study of the rat ovum. J Biophys Biochem Cytol 5:327–342PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Stahl PD, Barbieri MA (2002) Multivesicular bodies and multivesicular endosomes: the “ins and outs” of endosomal traffic. Sci STKE 2002(141):PE32PubMedGoogle Scholar
  22. 22.
    Stoorvogel W, Kleijmeer MJ, Geuze HJ et al (2002) The biogenesis and functions of exosomes. Traffic 3:321–330PubMedCrossRefGoogle Scholar
  23. 23.
    Pan BT, Johnstone RM (1983) Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33:967–977PubMedCrossRefGoogle Scholar
  24. 24.
    Denzer K, Kleijmeer MJ, Heijnen HF et al (2000) Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci 113:3365–3374PubMedGoogle Scholar
  25. 25.
    Valadi H, Ekström K, Bossios A et al (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659PubMedCrossRefGoogle Scholar
  26. 26.
    Henne WM, Buchkovich NJ, Emr SD (2011) The ESCRT pathway. Dev Cell 21:77–91PubMedCrossRefGoogle Scholar
  27. 27.
    Katzmann DJ, Odorizzi G, Emr SD (2002) Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol 3:893–905PubMedCrossRefGoogle Scholar
  28. 28.
    Colombo M, Moita C, van Niel G et al (2013) Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J Cell Sci 126(Pt 24):5553–5565PubMedCrossRefGoogle Scholar
  29. 29.
    Baietti MF, Zhang Z, Mortier E et al (2012) Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat Cell Biol 14:677–685PubMedCrossRefGoogle Scholar
  30. 30.
    Schuh AL, Audhya A (2014) The ESCRT machinery: from the plasma membrane to endosomes and back again. Crit Rev Biochem Mol Biol 49:242–261PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Buschow SI, Nolte-’t Hoen EN, van Niel G et al (2009) MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 10:1528–1542PubMedCrossRefGoogle Scholar
  32. 32.
    vanNiel G, Charrin S, Simoes S et al (2011) The tetraspanin CD63 regulates ESCRT-independent and-dependent endosomal sorting during melanogenesis. Dev Cell 21:708–721CrossRefGoogle Scholar
  33. 33.
    Hemler ME (2005) Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 6:801–811PubMedCrossRefGoogle Scholar
  34. 34.
    Zöller M (2009) Tetraspanins: push and pull in suppressing and promoting metastasis. Nat Rev Cancer 9:40–55PubMedCrossRefGoogle Scholar
  35. 35.
    Rana S, Yue S, Stadel D et al (2012) Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int J Biochem Cell Biol 44:1574–1584PubMedCrossRefGoogle Scholar
  36. 36.
    Chairoungdua A, Smith DL, Pochard P et al (2010) Exosome release of beta-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol 190:1079–1091PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Trajkovic K, Hsu C, Chiantia S et al (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244–1247PubMedCrossRefGoogle Scholar
  38. 38.
    Kajimoto T, Okada T, Miya S et al (2013) Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multi-vesicular endosomes. Nat Commun 4:2712PubMedCrossRefGoogle Scholar
  39. 39.
    Laulagnier K, Grand D, Dujardin A et al (2004) PLD2 is enriched on exosomes and its activity is correlated to the release of exosomes. FEBS Lett 572:11–14PubMedCrossRefGoogle Scholar
  40. 40.
    Kirkegaard T, Roth AG, Petersen NH et al (2010) Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology. Nature 463:549–553PubMedCrossRefGoogle Scholar
  41. 41.
    Stenmark H (2009) Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 10:513–525PubMedCrossRefGoogle Scholar
  42. 42.
    Barr F, Lambright DG (2010) Rab GEFs and GAPs. Curr Opin Cell Biol 22:461–470PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Sonnichsen B, De Renzis S, Nielsen E et al (2000) Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4, Rab5, and Rab11. J Cell Biol 149:901–914PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Huotari J, Helenius A (2011) Endosome maturation. EMBO J 30:3481–3500PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Sato M, Sato K, Liou W et al (2008) Regulation of endocytic recycling by C. elegans Rab35 and its regulator RME-4, a coated-pit protein. EMBO J 27:1183–1196PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Hsu C, Morohashi Y, Yoshimura S et al (2010) Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J Cell Biol 189:223–232PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Kelly EE, Horgan CP, Goud B et al (2012) The Rab family of proteins: 25 years on. Biochem Soc Trans 40:1337–1347PubMedCrossRefGoogle Scholar
  48. 48.
    Ducharme NA, Ham AJ, Lapierre LA et al (2011) Rab11-FIP2 influences multiple components of the endosomal system in polarized MDCK cells. Cell Logist 1:57–68PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Hoshino D, Kirkbride KC, Costello K et al (2013) Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Rep 5:1159–1168PubMedCrossRefGoogle Scholar
  50. 50.
    Martin-Cofreces NB, Baixauli F, Sanchez-Madrid F (2014) Immune synapse: conductor of orchestrated organelle movement. Trends Cell Biol 24:61–72PubMedCrossRefGoogle Scholar
  51. 51.
    Pfeffer SR (2010) Two Rabs for exosome release. Nat Cell Biol 12:3–4PubMedCrossRefGoogle Scholar
  52. 52.
    Jahn R, Scheller RH (2006) SNAREs – engines for membrane fusion. Nat Rev Mol Cell Biol 7:631–643PubMedCrossRefGoogle Scholar
  53. 53.
    Südhof TC, Rizo J (2011) Synaptic vesicle exocytosis. Cold Spring Harb Perspect Biol 3:12CrossRefGoogle Scholar
  54. 54.
    Merendino AM, Bucchieri F, Campanella C et al (2010) Hsp60 is actively secreted by human tumor cells. PLoS One 5:e9247PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Parolini I, Federici C, Raggi C et al (2009) Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 284:34211–34222PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Subra C, Laulagnier K, Perret B et al (2007) Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 89:205–212PubMedCrossRefGoogle Scholar
  57. 57.
    Subra C, Grand D, Laulagnier K et al (2010) Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J Lipid Res 51:2105–2120PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Ramstedt B, Slotte JP (2002) Membrane properties of sphingomyelins. FEBS Lett 531:33–37PubMedCrossRefGoogle Scholar
  59. 59.
    Allen TM, Austin GA, Chonn A et al (1991) Uptake of liposomes by cultured mouse bone marrow macrophages: influence of liposome composition and size. Biochim Biophys Acta 1061:56–64PubMedCrossRefGoogle Scholar
  60. 60.
    Chernomordik LV, Kozlov MM (2003) Protein-lipid interplay in fusion and fission of biological membranes. Annu Rev Biochem 72:175–207PubMedCrossRefGoogle Scholar
  61. 61.
    Costanzo M, Baryshnikova A, Bellay J et al (2010) The genetic landscape of a cell. Science 327:425–431PubMedCrossRefGoogle Scholar
  62. 62.
    Muller G, Schneider M, Biemer-Daub G et al (2011) Microvesicles released from rat adipocytes and harboring glycosylphosphatidylinositol-anchored proteins transfer RNA stimulating lipid synthesis. Cell Signal 23:1207–1223PubMedCrossRefGoogle Scholar
  63. 63.
    Record M, Carayon K, Poirot M et al (2014) Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. Biochim Biophys Acta 1841:108–120PubMedCrossRefGoogle Scholar
  64. 64.
    Raimondo F, Morosi L, Chinello C et al (2011) Advances in membranous vesicle and exosome proteomics improving biological understanding and biomarker discovery. Proteomics 11:709–720PubMedCrossRefGoogle Scholar
  65. 65.
    Mathivanan S, Simpson RJ (2011) ExoCarta: a compendium of exosomal proteins and RNA. Available from: http://exocarta.org/index.html
  66. 66.
    Pols MS, Klumperman J (2009) Trafficking and function of the tetraspanin CD63. Exp Cell Res 315:1584–1592PubMedCrossRefGoogle Scholar
  67. 67.
    Choi DS, Kim DK, Kim YK et al (2013) Proteomics, transcriptomics and lipidomics of exosomes and ectosomes. Proteomics 13:1554–1571PubMedCrossRefGoogle Scholar
  68. 68.
    Xie Y, Bai O, Zhang H et al (2010) Membrane-bound HSP70-engineered myeloma cell-derived exosomes stimulate more efficient CD8(+) CTL- and NK-mediated antitumour immunity than exosomes released from heat-shocked tumour cells expressing cytoplasmic HSP70. J Cell Mol Med 14:2655–2666PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Shimoda M, Khokha R (2013) Proteolytic factors in exosomes. Proteomics 13:1624–1636PubMedCrossRefGoogle Scholar
  70. 70.
    Mu W, Rana S, Zöller M (2013) Host matrix modulation by TEX promotes motility and invasiveness. Neoplasia 15:875–887PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Henderson MC, Azorsa DO (2012) The genomic and proteomic content of cancer cell-derived exosomes. Front Oncol 2:38PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Yue S, Mu W, Erb U et al (2015) The tetraspanins CD151 and Tspan8 are essential exosome components for the crosstalk between cancer initiating cells and their surrounding. Oncotarget 6:2366PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Choi DS, Yang JS, Choi EJ et al (2012) The protein interaction network of extracellular vesicles derived from human colorectal cancer cells. J Proteome Res 11:1144–1151PubMedCrossRefGoogle Scholar
  74. 74.
    Sahu R, Kaushik S, Clement CC et al (2011) Microautophagy of cytosolic proteins by late endosomes. Dev Cell 20:131–139PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Julich H, Willms A, Lukacs-Kornek V et al (2014) Extracellular vesicle profiling and their use as potential disease specific biomarker. Front Immunol 5:413PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Andre F, Schartz NE, Movassagh M et al (2002) Malignant effusions and immunogenic tumour-derived exosomes. Lancet 360:295–305PubMedCrossRefGoogle Scholar
  77. 77.
    Runz S, Keller S, Rupp C et al (2007) Malignant ascites-derived exosomes of ovarian carcinoma patients contain CD24 and EpCAM. Gynecol Oncol 107:563–571PubMedCrossRefGoogle Scholar
  78. 78.
    Al-Nedawi K, Meehan B, Micallef J et al (2008) Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 10:619–624PubMedCrossRefGoogle Scholar
  79. 79.
    Corcoran C, Rani S, O’Brien K et al (2012) Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PLoS One 7:e50999PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Park JA, Sharif AS, Tschumperlin DJ et al (2012) Tissue factor-bearing exosome secretion from human mechanically stimulated bronchial epithelial cells in vitro and in vivo. J Allergy Clin Immunol 130:1375–1380PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Demory Beckler M, Higginbotham JN, Franklin JL et al (2013) Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol Cell Proteomics 12:343–355PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Ji H, Greening DW, Barnes TW et al (2013) Proteome profiling of exosomes derived from human primary and metastatic colorectal cancer cells reveal differential expression of key metastatic factors and signal transduction components. Proteomics 13:1672–1680PubMedCrossRefGoogle Scholar
  83. 83.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866PubMedCrossRefGoogle Scholar
  85. 85.
    Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114PubMedCrossRefGoogle Scholar
  86. 86.
    Lim LP, Lau NC, Garrett-Engele P et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773PubMedCrossRefGoogle Scholar
  87. 87.
    Tzimagiorgis G, Michailidou EZ, Kritis A et al (2011) Recovering circulating extracellular or cell-free RNA from bodily fluids. Cancer Epidemiol 35:580–589PubMedCrossRefGoogle Scholar
  88. 88.
    Ratajczak J, Miekus K, Kucia M et al (2006) Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20:847–856PubMedCrossRefGoogle Scholar
  89. 89.
    Turchinovich A, Weiz L, Langheinz A et al (2011) Characterization of extracellular circulating microRNA. Nucleic Acids Res 39:7223–7233PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Gibbings DJ, Ciaudo C, Erhardt M et al (2009) Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol 11:1143–1149PubMedCrossRefGoogle Scholar
  91. 91.
    Balaj L, Lessard R, Dai L et al (2011) Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun 2:180PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Salido-Guadarrama I, Romero-Cordoba S, Peralta-Zaragoza O et al (2014) MicroRNAs transported by exosomes in body fluids as mediators of intercellular communication in cancer. Onco Targets Ther 7:1327–1338PubMedCentralPubMedGoogle Scholar
  93. 93.
    Chen X, Liang H, Zhang J et al (2012) Horizontal transfer of microRNAs: molecular mechanisms and clinical applications. Protein Cell 3:28–37PubMedCrossRefGoogle Scholar
  94. 94.
    Skog J, Wurdinger T, van Rijn S et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139PubMedCrossRefGoogle Scholar
  96. 96.
    Han J, Lee Y, Yeom KH et al (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18:3016–3027PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Suzuki HI, Miyazono K (2011) Emerging complexity of microRNA generation cascades. J Biochem 149:15–25PubMedCrossRefGoogle Scholar
  98. 98.
    Lee YS, Pressman S, Andress AP et al (2009) Silencing by small RNAs is linked to endosomal trafficking. Nat Cell Biol 11:1150–1156PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Chen TS, Lai RC, Lee MM et al (2010) Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res 38:215–224PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Li L, Zhu D, Huang L et al (2012) Argonaute 2 complexes selectively protect the circulating microRNAs in cell-secreted microvesicles. PLoS One 7:e46957PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Doench JG, Sharp PA (2004) Specificity of microRNA target selection in translational repression. Genes Dev 18:504–511PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Pinto R, De Summa S, Petriella D et al (2014) The value of new high-throughput technologies for diagnosis and prognosis in solid tumors. Cancer Biomark 14:103–117PubMedGoogle Scholar
  103. 103.
    Braicu C, Tomuleasa C, Monroig P et al (2015) Exosomes as divine messengers: are they the Hermes of modern molecular oncology? Cell Death Differ 22:34–45PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Sato-Kuwabara Y, Melo SA, Soares FA et al (2015) The fusion of two worlds: non-coding RNAs and extracellular vesicles--diagnostic and therapeutic implications (Review). Int J Oncol 46:17–27PubMedCentralPubMedGoogle Scholar
  105. 105.
    Alečković M, Kang Y (2014) Regulation of cancer metastasis by cell-free miRNAs. Biochim Biophys Acta 1855:24–42PubMedPubMedCentralGoogle Scholar
  106. 106.
    Garg M (2015) Targeting microRNAs in epithelial-to-mesenchymal transition-induced cancer stem cells: therapeutic approaches in cancer. Expert Opin Ther Targets 19:285PubMedCrossRefGoogle Scholar
  107. 107.
    Garofalo M, Croce CM (2015) Role of microRNAs in maintaining cancer stem cells. Adv Drug Deliv Rev 81C:53–61CrossRefGoogle Scholar
  108. 108.
    Mimeault M, Batra SK (2014) Molecular biomarkers of cancer stem/progenitor cells associated with progression, metastases, and treatment resistance of aggressive cancers. Cancer Epidemiol Biomarkers Prev 23:234–254PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Katoh M (2013) Therapeutics targeting angiogenesis: genetics and epigenetics, extracellular miRNAs and signaling networks (Review). Int J Mol Med 32:763–777PubMedCentralPubMedGoogle Scholar
  110. 110.
    Park SM, Gaur AB, Lengyel E et al (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22:894–907PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Joglekar MV, Patil D, Joglekar VM et al (2009) The miR-30 family microRNAs confer epithelial phenotype to human pancreatic cells. Islets 1:137–147PubMedCrossRefGoogle Scholar
  112. 112.
    Ji Q, Hao X, Zhang M et al (2009) MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 4:e6816PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Misawa A, Katayama R, Koike S et al (2010) AP-1-Dependent miR-21 expression contributes to chemoresistance in cancer stem cell-like SP cells. Oncol Res 19:23–33PubMedCrossRefGoogle Scholar
  114. 114.
    Khew-Goodall Y, Goodall GJ (2010) Myc-modulated miR-9 makes more metastases. Nat Cell Biol 12:209–211PubMedGoogle Scholar
  115. 115.
    Liu C, Kelnar K, Liu B et al (2011) The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17:211–215PubMedCentralPubMedCrossRefGoogle Scholar
  116. 116.
    Wu ZS, Wu Q, Wang CQ et al (2011) miR-340 inhibition of breast cancer cell migration and invasion through targeting of oncoprotein c-Met. Cancer 117:2842–2852PubMedCrossRefGoogle Scholar
  117. 117.
    Nabhan JF, Hu R, Oh RS et al (2012) Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein. Proc Natl Acad Sci U S A 109:4146–4151PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Shen B, Wu N, Yang JM et al (2011) Protein targeting to exosomes/microvesicles by plasma membrane anchors. J Biol Chem 286:14383–14395PubMedCentralPubMedCrossRefGoogle Scholar
  119. 119.
    Fang Y, Wu N, Gan X et al (2007) Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol 5:e158PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Hurley JH, Emr SD (2006) The ESCRT complexes: structure and mechanism of a membrane-trafficking network. Annu Rev Biophys Biomol Struct 35:277–298PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Rana S, Claas C, Kretz CC et al (2011) Activation-induced internalization differs for the tetraspanins CD9 and Tspan8: impact on tumor cell motility. Int J Biochem Cell Biol 43:106–119PubMedCrossRefGoogle Scholar
  122. 122.
    Pant S, Hilton H, Burczynski ME (2012) The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities. Biochem Pharmacol 83:1484–1494PubMedCrossRefGoogle Scholar
  123. 123.
    Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F et al (2013) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 4:2980PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Munro TP, Magee RJ, Kidd GJ et al (1999) Mutational analysis of a heterogeneous nuclear ribonucleoprotein A2 response element for RNA trafficking. J Biol Chem 274:34389–34395PubMedCrossRefGoogle Scholar
  125. 125.
    Hollas H, Aukrust I, Grimmer S et al (2006) Annexin A2 recognises a specific region in the 3′-UTR of its cognate messenger RNA. Biochim Biophys Acta 1763:1325–1334PubMedCrossRefGoogle Scholar
  126. 126.
    Thery C, Amigorena S, Raposo G et al (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol 3:22PubMedGoogle Scholar
  127. 127.
    Taylor DD, Gercel-Taylor C, Lyons KS et al (2003) T-cell apoptosis and suppression of T-cell receptor/CD3-zeta by Fas ligand-containing membrane vesicles shed from ovarian tumors. Clin Cancer Res 9:5113–5119PubMedGoogle Scholar
  128. 128.
    Lai RC, Arslan F, Lee MM et al (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4:214–222PubMedCrossRefGoogle Scholar
  129. 129.
    Petersen KE, Manangon E, Hood JL et al (2014) A review of exosome separation techniques and characterization of B16-F10 mouse melanoma exosomes with AF4-UV-MALS-DLS-TEM. Anal Bioanal Chem 406:7855–7866PubMedCentralPubMedCrossRefGoogle Scholar
  130. 130.
    Brownlee Z, Lynn KD, Thorpe PE et al (2014) A novel “salting-out” procedure for the isolation of tumor-derived exosomes. J Immunol Methods 407:120–126PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Clayton A, Court J, Navabi H et al (2001) Analysis of antigen presenting cell derived exosomes, based on immuno- magnetic isolation and flowcytometry. J Immunol Methods 247:163–174PubMedCrossRefGoogle Scholar
  132. 132.
    Chen C, Skog J, Hsu CH et al (2010) Microfluidic isolation and transcriptome analysis of serum microvesicles. Lab Chip 10:505–511PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Navabi H, Croston D, Hobot J et al (2005) Preparation of human ovarian cancer ascites-derived exosomes for a clinical trial. Blood Cells Mol Dis 35:149–152PubMedCrossRefGoogle Scholar
  134. 134.
    Lamparski HG, Metha-Damani A, Yao JY et al (2002) Production and characterization of clinical grade exosomes derived from dendritic cells. J Immunol Methods 270:211–226PubMedCrossRefGoogle Scholar
  135. 135.
    Orozco AF, Lewis DE (2010) Flow cytometric analysis of circulating microparticles in plasma. Cytometry A 77:502–514PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Yurkovetsky Z, Skates S, Lomakin A et al (2010) Development of a multimarker assay for early detection of ovarian cancer. J Clin Oncol 28:2159–2166PubMedCentralPubMedCrossRefGoogle Scholar
  137. 137.
    Deatherage BL, Cookson BT (2012) Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect Immun 80:1948–1957PubMedCentralPubMedCrossRefGoogle Scholar
  138. 138.
    Mariotto AB, Noone AM, Howlader N et al (2014) Cancer survival: an overview of measures, uses, and interpretation. J Natl Cancer Inst Monogr 2014:145–186PubMedCrossRefGoogle Scholar
  139. 139.
    Paulson AS, Tran Cao HS, Tempero MA et al (2013) Therapeutic advances in pancreatic cancer. Gastroenterology 144:1316–1326PubMedCrossRefGoogle Scholar
  140. 140.
    Madhavan B, Yue S, Galli U et al (2015) Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. Int J Cancer 136:2616PubMedCrossRefGoogle Scholar
  141. 141.
    Logozzi M, DeMilito A, Lugini L et al (2009) High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One 4:e5219PubMedCentralPubMedCrossRefGoogle Scholar
  142. 142.
    Weber JA, Baxter DH, Zhang S et al (2010) The microRNA spectrum in 12 body fluids. Clin Chem 56:1733–1741PubMedCrossRefGoogle Scholar
  143. 143.
    Mitchell PS, Parkin RK, Krih EM et al (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105:10513–10518PubMedCentralPubMedCrossRefGoogle Scholar
  144. 144.
    Jia S, Zocco D, Samuels ML et al (2014) Emerging technologies in extracellular vesicle-based molecular diagnostics. Expert Rev Mol Diagn 14:307–321PubMedCrossRefGoogle Scholar
  145. 145.
    Sun Y, Liu J (2014) Potential of cancer cell-derived exosomes in clinical application: a review of recent research advances. Clin Ther 36:863–872PubMedCrossRefGoogle Scholar
  146. 146.
    Di C, Zhao Y (2015) Multiple drug resistance due to resistance to stem cells and stem cell treatment progress in cancer (Review). Exp Ther Med 9:289–293PubMedCentralPubMedGoogle Scholar
  147. 147.
    Elshamy WM, Duhé RJ (2013) Overview: cellular plasticity, cancer stem cells and metastasis. Cancer Lett 341:2–8PubMedCrossRefGoogle Scholar
  148. 148.
    Tirino V, Desiderio V, Paino F et al (2013) Cancer stem cells in solid tumors: an overview and new approaches for their isolation and characterization. FASEB J 27:13–24PubMedCrossRefGoogle Scholar
  149. 149.
    Wang H, Rana S, Giese N et al (2013) Tspan8, CD44v6 and alpha6beta4 are biomarkers of migrating pancreatic cancer-initiating cells. Int J Cancer 133:416–426PubMedCrossRefGoogle Scholar
  150. 150.
    Marcelo CL, Peramo A, Ambati A et al (2012) Characterization of a unique technique for culturing primary adult human epithelial progenitor/“stem cells”. BMC Dermatol 12:8PubMedCentralPubMedCrossRefGoogle Scholar
  151. 151.
    Papini S, Cecchetti D, Campani D et al (2003) Isolation and clonal analysis of human epidermal keratinocyte stem cells in long-term culture. Stem Cells 21:481–494PubMedCrossRefGoogle Scholar
  152. 152.
    Tauro BJ, Greening DW, Mathias RA et al (2012) Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. Methods 56:293–304PubMedCrossRefGoogle Scholar
  153. 153.
    Chen CL, Lai YF, Tang P et al (2012) Comparative and targeted proteomic analyses of urinary microparticles from bladder cancer and hernia patients. J Proteome Res 11:5611–5629PubMedGoogle Scholar
  154. 154.
    Kim G, Yoo CE, Kim M et al (2012) Noble polymeric surface conjugated with zwitterionic moieties and antibodies for the isolation of exosomes from human serum. Bioconjug Chem 23:2114–2120PubMedCrossRefGoogle Scholar
  155. 155.
    Lässer C, Eldh M, Lötvall J (2012) Isolation and characterization of RNA-containing exosomes. J Vis Exp 59:e3037PubMedGoogle Scholar
  156. 156.
    Kalra H, Simpson RJ, Ji H et al (2012) Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol 10:e1001450PubMedCentralPubMedCrossRefGoogle Scholar
  157. 157.
    Skvortsov S, Debbage P, Skvortsova I (2014) Proteomics of cancer stem cells. Int J Radiat Biol 90:653–658PubMedCrossRefGoogle Scholar
  158. 158.
    Wang Y, Gao X, Wei F et al (2014) Diagnostic and prognostic value of circulating miR-21 for cancer: a systematic review and meta-analysis. Gene 533:389–397PubMedCrossRefGoogle Scholar
  159. 159.
    Zhang QH, Sun HM, Zheng RZ et al (2013) Meta-analysis of microRNA-183 family expression in human cancer studies comparing cancer tissues with noncancerous tissues. Gene 527:26–32PubMedCrossRefGoogle Scholar
  160. 160.
    Fu X, Han Y, Wu Y et al (2011) Prognostic role of microRNA-21 in various carcinomas: a systematic review and meta-analysis. Eur J Clin Invest 41:1245–1253PubMedCrossRefGoogle Scholar
  161. 161.
    Liu R, Chen X, Du Y et al (2012) Serum microRNA expression profile as a biomarker in the diagnosis and prognosis of pancreatic cancer. Clin Chem 58:610–618PubMedCrossRefGoogle Scholar
  162. 162.
    Altevogt P, Bretz NP, Ridinger J et al (2014) Novel insights into exosome-induced, tumor-associated inflammation and immunomodulation. Semin Cancer Biol 28:51–57PubMedCrossRefGoogle Scholar
  163. 163.
    Zöller M (2011) CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer 11:254–267PubMedCrossRefGoogle Scholar
  164. 164.
    Wang W, Li J, Zhu W et al (2014) MicroRNA-21 and the clinical outcomes of various carcinomas: a systematic review and meta-analysis. BMC Cancer 14:819PubMedCentralPubMedCrossRefGoogle Scholar
  165. 165.
    Thuma F, Zöller M (2014) Outsmart TEX to steal the cancer initiating cell its niche. Semin Cancer Biol 28:39–50PubMedCrossRefGoogle Scholar
  166. 166.
    Azmi AS, Bao B, Sarkar FH (2013) Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev 32:623–642PubMedCrossRefGoogle Scholar
  167. 167.
    Montecalvo A, Larregina AT, Shufesky WJ et al (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119:756–766PubMedCentralPubMedCrossRefGoogle Scholar
  168. 168.
    Tian T, Wang Y, Wang H et al (2010) Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. J Cell Biochem 111:488–496PubMedCrossRefGoogle Scholar
  169. 169.
    van der Pol E, Hoekstra AG, Sturk A et al (2010) Optical and non-optical methods for detection and characterization of microparticles and exosomes. J Thromb Haemost 8:2596–2607PubMedCrossRefGoogle Scholar
  170. 170.
    Feng D, Zhao WL, Ye YY et al (2010) Cellular internalization of exosomes occurs through phagocytosis. Traffic 11:675–687PubMedCrossRefGoogle Scholar
  171. 171.
    Mulcahy LA, Pink RC, Carter DR (2014) Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles 4:3Google Scholar
  172. 172.
    Taylor MJ, Lampe M, Merrifield CJ (2012) A feedback loop between dynamin and actin recruitment during clathrin-mediated endocytosis. PLoS Biol 10:e1001302PubMedCentralPubMedCrossRefGoogle Scholar
  173. 173.
    Parton RG, Simons K (2007) The multiple faces of caveolae. Nat Rev Mol Cell Biol 8:185–194PubMedCrossRefGoogle Scholar
  174. 174.
    Kerr MC, Teasdale RD (2009) Defining macropinocytosis. Traffic 10:364–371PubMedCrossRefGoogle Scholar
  175. 175.
    Chernomordik LV, Kozlov MM (2008) Mechanics of membrane fusion. Nat Struct Mol Biol 15:675–683PubMedCentralPubMedCrossRefGoogle Scholar
  176. 176.
    Barrès C, Blanc L, Bette-Bobillo P et al (2010) Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages. Blood 115:696–705PubMedCrossRefGoogle Scholar
  177. 177.
    Svensson KJ, Christianson HC, Wittrup A et al (2013) Exosome uptake depends on ERK1/2-heat shock protein 27 signalling and lipid raft-mediated endocytosis negatively regulated by caveolin-1. J Biol Chem 288:17713–17724PubMedCentralPubMedCrossRefGoogle Scholar
  178. 178.
    Franzen CA, Simms PE, Van Huis AF et al (2014) Characterization of uptake and internalization of exosomes by bladder cancer cells. Biomed Res Int 2014:619829PubMedCentralPubMedCrossRefGoogle Scholar
  179. 179.
    Escola JM, Kleijmeer MJ, Stoorvogel W et al (1998) Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem 273:20121–20127PubMedCrossRefGoogle Scholar
  180. 180.
    Nazarenko I, Rana S, Baumann A et al (2010) Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res 70:1668–1678PubMedCrossRefGoogle Scholar
  181. 181.
    Zech D, Rana S, Büchler MW et al (2012) Tumor-exosomes and leukocyte activation: an ambivalent crosstalk. Cell Commun Signal 10:37PubMedCentralPubMedCrossRefGoogle Scholar
  182. 182.
    Morelli AE, Larregina AT, Shufesky WJ et al (2004) Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood 104:3257–3266PubMedCrossRefGoogle Scholar
  183. 183.
    Nolte-’t Hoen EN, Buschow SI, Anderton SM et al (2009) Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood 113:1977–1981PubMedCrossRefGoogle Scholar
  184. 184.
    Gu X, Erb U, Büchler MW et al (2015) Improved vaccine efficacy of tumor exosome compared to tumor lysate loaded dendritic cells in mice. Int J Cancer 136:E74–E84PubMedCrossRefGoogle Scholar
  185. 185.
    Valapala M, Vishwanatha JK (2011) Lipid raft endocytosis and exosomal transport facilitate extracellular trafficking of annexin A2. J Biol Chem 286:30911–30925PubMedCentralPubMedCrossRefGoogle Scholar
  186. 186.
    Van Gool SW, Vandenberghe P, de Boer M et al (1996) CD80, CD86 and CD40 provide accessory signals in a multiple-step T-cell activation model. Immunol Rev 153:47–83PubMedCrossRefGoogle Scholar
  187. 187.
    Prydz K, Tveit H, Vedeler A et al (2013) Arrivals and departures at the plasma membrane: direct and indirect transport routes. Cell Tissue Res 352:5–20PubMedCrossRefGoogle Scholar
  188. 188.
    Vega-Ramos J, Villadangos JA (2013) Consequences of direct and indirect activation of dendritic cells on antigen presentation: functional implications and clinical considerations. Mol Immunol 55:175–178PubMedCrossRefGoogle Scholar
  189. 189.
    Lakkaraju A, Rodriguez-Boulan E (2008) Itinerant exosomes: emerging roles in cell and tissue polarity. Trends Cell Biol 18:199–209PubMedCentralPubMedCrossRefGoogle Scholar
  190. 190.
    Stanley S (2014) Biological nanoparticles and their influence on organisms. Curr Opin Biotechnol 28:69–74PubMedCrossRefGoogle Scholar
  191. 191.
    Mathivanan S, Lim JW, Tauro BJ et al (2010) Proteomic analysis of A33-immunoaffinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature. Mol Cell Proteomics 9:197–208PubMedCentralPubMedCrossRefGoogle Scholar
  192. 192.
    Kosaka N, Iguchi H, Yoshioka Y et al (2010) Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 285:17442–17452PubMedCentralPubMedCrossRefGoogle Scholar
  193. 193.
    Sevenich L, Joyce JA (2014) Pericellular proteolysis in cancer. Genes Dev 28:2331–2347PubMedCentralPubMedCrossRefGoogle Scholar
  194. 194.
    Arduise C, Abache T, Li L et al (2008) Tetraspanins regulate ADAM10-mediated cleavage of TNF-alpha and epidermal growth factor. J Immunol 181:7002–7013PubMedCrossRefGoogle Scholar
  195. 195.
    Gutiérrez-López MD, Gilsanz A, Yáñez-Mó M et al (2011) The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9. Cell Mol Life Sci 68:3275–3292PubMedCrossRefGoogle Scholar
  196. 196.
    Le Naour F, André M, Boucheix C et al (2006) Membrane microdomains and proteomics: lessons from tetraspanin microdomains and comparison with lipid rafts. Proteomics 6:6447–6454PubMedCrossRefGoogle Scholar
  197. 197.
    Yanez-Mo M, Barreiro O, Gonzalo P et al (2008) MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells. Blood 112:3217–3226PubMedCrossRefGoogle Scholar
  198. 198.
    Hendrix A, Westbroek W, Bracke M et al (2010) An ex(o)citing machinery for invasive tumor growth. Cancer Res 70:9533–9537PubMedCrossRefGoogle Scholar
  199. 199.
    Grange C, Tapparo M, Collino F et al (2011) Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 71:5346–5356PubMedCrossRefGoogle Scholar
  200. 200.
    Lo Cicero A, Majkowska I, Nagase H et al (2012) Microvesicles shed by oligodendroglioma cells and rheumatoid synovial fibroblasts contain aggrecanase activity. Matrix Biol 31:229–233PubMedCrossRefGoogle Scholar
  201. 201.
    Ngora H, Galli UM, Miyazaki K et al (2012) Membrane-bound and exosomal metastasis-associated C4.4A promotes migration by associating with the α(6)β(4) integrin and MT1-MMP. Neoplasia 14:95–107PubMedCentralPubMedCrossRefGoogle Scholar
  202. 202.
    Lages E, Ipas H, Guttin A et al (2012) MicroRNAs: molecular features and role in cancer. Front Biosci 17:2508–2540CrossRefGoogle Scholar
  203. 203.
    Sangaletti S, Colombo MP (2008) Matricellular proteins at the crossroad of inflammation and cancer. Cancer Lett 267:245–253PubMedCrossRefGoogle Scholar
  204. 204.
    Clayton A, Mitchell JP, Court J et al (2007) Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res 67:7458–7466PubMedCrossRefGoogle Scholar
  205. 205.
    Rana S, Malinowska K, Zöller M (2013) Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia 15:281–295PubMedCentralPubMedCrossRefGoogle Scholar
  206. 206.
    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 5:537–547PubMedCrossRefGoogle Scholar
  207. 207.
    Artavanis-Tsakonas K, Kasperkovitz PV, Papa E et al (2011) The tetraspanin CD82 is specifically recruited to fungal and bacterial phagosomes prior to acidification. Infect Immun 79:1098–1106PubMedCentralPubMedCrossRefGoogle Scholar
  208. 208.
    Tumne A, Prasad VS, Chen Y et al (2009) Noncytotoxic suppression of human immunodeficiency virus type 1 transcription by exosomes secreted from CD8+ T cells. J Virol 83:4354–4364PubMedCentralPubMedCrossRefGoogle Scholar
  209. 209.
    Tan A, De La Peña H, Seifalian AM (2010) The application of exosomes as a nanoscale cancer vaccine. Int J Nanomedicine 5:889–900PubMedCentralPubMedGoogle Scholar
  210. 210.
    Taylor DD, Gercel-Taylor C (2011) Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol 33:441–454PubMedCrossRefGoogle Scholar
  211. 211.
    Filipazzi P, Bürdek M, Villa A et al (2012) Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Semin Cancer Biol 22:342–349PubMedCrossRefGoogle Scholar
  212. 212.
    Whiteside TL (2014) Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes). Biochem Soc Trans 41:245–251CrossRefGoogle Scholar
  213. 213.
    Khalil AA, Kabapy NF, Deraz SF et al (2011) Heat shock proteins in oncology: diagnostic biomarkers or therapeutic targets? Biochim Biophys Acta 1816:89–104PubMedGoogle Scholar
  214. 214.
    Elsner L, Muppala V, Gehrmann M et al (2007) The heat shock protein HSP70 promotes mouse NK cell activity against tumors that express inducible NKG2D ligands. J Immunol 179:5523–5533PubMedCrossRefGoogle Scholar
  215. 215.
    Dai S, Wan T, Wang B et al (2005) More efficient induction of HLA-A*0201-restricted and carcinoembryonic antigen (CEA)-specific CTL response by immunization with exosomes prepared from heat-stressed CEA-positive tumor cells. Clin Cancer Res 11:7554–7563PubMedCrossRefGoogle Scholar
  216. 216.
    Hurwitz MD, Kaur P, Nagaraja GM et al (2010) Radiation therapy induces circulating serum Hsp72 in patients with prostate cancer. Radiother Oncol 95:350–358PubMedCentralPubMedCrossRefGoogle Scholar
  217. 217.
    Chen T, Guo J, Yang M et al (2011) Chemokine-containing exosomes are released from heat-stressed tumor cells via lipid raft-dependent pathway and act as efficient tumor vaccine. J Immunol 186:2219–2228PubMedCrossRefGoogle Scholar
  218. 218.
    Zeelenberg IS, van Maren WW, Boissonnas A et al (2011) Antigen localization controls T cell-mediated tumor immunity. J Immunol 187:1281–1288PubMedCrossRefGoogle Scholar
  219. 219.
    Robbins PD, Morelli AE (2014) Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 14:195–208PubMedCentralPubMedCrossRefGoogle Scholar
  220. 220.
    Pitt JM, Charrier M, Viaud S et al (2014) Dendritic cell-derived exosomes as immunotherapies in the fight against cancer. J Immunol 193:1006–1011PubMedCrossRefGoogle Scholar
  221. 221.
    Claas C, Seiter S, Claas A et al (1998) Association between the rat homologue of CO-029, a metastasis-associated tetraspanin molecule and consumption coagulopathy. J Cell Biol 141:267–280PubMedCentralPubMedCrossRefGoogle Scholar
  222. 222.
    Gesierich S, Berezovskiy I, Ryschich E et al (2006) Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029. Cancer Res 66:7083–7094PubMedCrossRefGoogle Scholar
  223. 223.
    Hood JL, San Roman S, Wickline SA (2011) Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 71:3792–3801PubMedCrossRefGoogle Scholar
  224. 224.
    Al-Nedawi K, Meehan B, Rak J (2009) Microvesicles: messengers and mediators of tumor progression. Cell Cycle 8:2014–2018PubMedCrossRefGoogle Scholar
  225. 225.
    Mineo M, Garfield SH, Taverna S et al (2012) Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a Src-dependent fashion. Angiogenesis 15:33–45PubMedCentralPubMedCrossRefGoogle Scholar
  226. 226.
    Hong BS, Cho JH, Kim H et al (2009) Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells. BMC Genomics 10:556PubMedCentralPubMedCrossRefGoogle Scholar
  227. 227.
    Peinado H, Alečković M, Lavotshkin S et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883–891PubMedCentralPubMedCrossRefGoogle Scholar
  228. 228.
    Verweij FJ, Middeldorp JM, Pegtel DM (2012) Intracellular signaling controlled by the endosomal-exosomal pathway. Commun Integr Biol 5:88–93PubMedCentralPubMedCrossRefGoogle Scholar
  229. 229.
    Antonyak MA, Li B, Boroughs LK (2011) Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells. Proc Natl Acad Sci U S A 108:4852–4857PubMedCentralPubMedCrossRefGoogle Scholar
  230. 230.
    Khan S, Jutzy JM, Aspe JR et al (2011) Survivin is released from cancer cells via exosomes. Apoptosis 16:1–12PubMedCentralPubMedCrossRefGoogle Scholar
  231. 231.
    Webber J, Steadman R, Mason MD et al (2010) Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res 70:9621–9630PubMedCrossRefGoogle Scholar
  232. 232.
    Cho JA, Park H, Lim EH et al (2012) Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. Int J Oncol 40:130–138PubMedGoogle Scholar
  233. 233.
    Wysoczynski M, Ratajczak MZ (2009) Lung cancer secreted microvesicles: underappreciated modulators of microenvironment in expanding tumors. Int J Cancer 125:1595–1603PubMedCentralPubMedCrossRefGoogle Scholar
  234. 234.
    Jung T, Castellana D, Klingbeil P et al (2009) CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 11:1093–1105PubMedCentralPubMedCrossRefGoogle Scholar
  235. 235.
    McCready J, Sims JD, Chan D et al (2010) Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation. BMC Cancer 10:294PubMedCentralPubMedCrossRefGoogle Scholar
  236. 236.
    Huan J, Hornick NI, Shurtleff MJ et al (2013) RNA trafficking by acute myelogenous leukemia exosomes. Cancer Res 73:918–929PubMedCrossRefGoogle Scholar
  237. 237.
    Janowska-Wieczorek A, Wysoczynski M, Kijowski J et al (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113:752–760PubMedCrossRefGoogle Scholar
  238. 238.
    Cai Z, Yang F, Yu L et al (2012) Activated T cell exosomes promote tumor invasion via Fas signaling pathway. J Immunol 188:5954–5961PubMedCrossRefGoogle Scholar
  239. 239.
    Luga V, Zhang L, Viloria-Petit AM et al (2012) Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151:1542–1556PubMedCrossRefGoogle Scholar
  240. 240.
    Umezu T, Ohyashiki K, Kuroda M et al (2013) Leukemia cell to endothelial cell communication via exosomal miRNAs. Oncogene 32:2747–2755PubMedCrossRefGoogle Scholar
  241. 241.
    Fabbri M, Paone A, Calore F et al (2012) MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A 109:E2110–E2116PubMedCentralPubMedCrossRefGoogle Scholar
  242. 242.
    Hupalowska A, Miaczynska M (2012) The new faces of endocytosis in signaling. Traffic 13:9–18PubMedCrossRefGoogle Scholar
  243. 243.
    Bobrie A, Krumeich S, Reyal F et al (2012) Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res 72:4920–4930PubMedCrossRefGoogle Scholar
  244. 244.
    Pan Q, Ramakrishnaiah V, Henry S et al (2012) Hepatic cell-to-cell transmission of small silencing RNA can extend the therapeutic reach of RNA interference (RNAi). Gut 61:1330–1339PubMedCrossRefGoogle Scholar
  245. 245.
    Higginbotham JN, Demory Beckler M, Gephart JD et al (2011) Amphiregulin exosomes increase cancer cell invasion. Curr Biol 21:779–786PubMedCentralPubMedCrossRefGoogle Scholar
  246. 246.
    Meckes DG Jr, Shair KH, Marquitz AR et al (2010) Human tumor virus utilizes exosomes for intercellular communication. Proc Natl Acad Sci U S A 107:20370–20375PubMedCentralPubMedCrossRefGoogle Scholar
  247. 247.
    Gourzones C, Gelin A, Bombik I et al (2010) Extra-cellular release and blood diffusion of BART viral micro-RNAs produced by EBV-infected nasopharyngeal carcinoma cells. Virol J 7:271PubMedCentralPubMedCrossRefGoogle Scholar
  248. 248.
    Yang M, Chen J, Su F et al (2011) Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer 10:117PubMedCentralPubMedCrossRefGoogle Scholar
  249. 249.
    Zhang Y, Liu D, Chen X et al (2010) Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 39:133–144PubMedCrossRefGoogle Scholar
  250. 250.
    Roninson IB (1987) Molecular mechanism of multidrug resistance in tumor cells. Clin Physiol Biochem 5:140–151PubMedGoogle Scholar
  251. 251.
    Bebawy M, Combes V, Lee E et al (2009) Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells. Leukemia 23:1643–1649PubMedCrossRefGoogle Scholar
  252. 252.
    Puisieux A, Brabletz T, Caramel J (2014) Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol 16:488–494PubMedCrossRefGoogle Scholar
  253. 253.
    Vella LJ (2014) The emerging role of exosomes in epithelial-mesenchymal-transition in cancer. Front Oncol 4:361PubMedCentralPubMedCrossRefGoogle Scholar
  254. 254.
    Garnier D, Magnus N, Lee TH et al (2012) Cancer cells induced to express mesenchymal phenotype release exosome-like extracellular vesicles carrying tissue factor. J Biol Chem 287:43565–43572PubMedCentralPubMedCrossRefGoogle Scholar
  255. 255.
    Tauro BJ, Mathias RA, Greening DW et al (2013) Oncogenic H-ras reprograms Madin-Darby canine kidney (MDCK) cell-derived exosomal proteins following epithelial-mesenchymal transition. Mol Cell Proteomics 12:2148–2159PubMedCentralPubMedCrossRefGoogle Scholar
  256. 256.
    Jeppesen DK, Nawrocki A, Jensen SG et al (2014) Quantitative proteomics of fractionated membrane and lumen exosome proteins from isogenic metastatic and nonmetastatic bladder cancer cells reveal differential expression of EMT factors. Proteomics 14:699–712PubMedCrossRefGoogle Scholar
  257. 257.
    Ramteke A, Ting H, Agarwal C et al (2015) Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog 54:554PubMedCrossRefPubMedCentralGoogle Scholar
  258. 258.
    Bijnsdorp IV, Geldof AA, Lavaei M et al. (2013) Exosomal ITGA3 interferes with non-cancerous prostate cell functions and is increased in urine exosomes of metastatic prostate cancer patients. J Extracell Vesicles 2. doi:  10.3402/jev.v2i0.22097
  259. 259.
    Mathias RA, Chen YS, Wang B et al (2010) Extracellular remodelling during oncogenic Ras-induced epithelial-mesenchymal transition facilitates MDCK cell migration. J Proteome Res 9:1007–1019PubMedCrossRefGoogle Scholar
  260. 260.
    Atay S, Banskota S, Crow J et al (2014) Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion. Proc Natl Acad Sci U S A 111:711–716PubMedCentralPubMedCrossRefGoogle Scholar
  261. 261.
    Garnier D, Magnus N, Meehan B et al (2013) Qualitative changes in the proteome of extracellular vesicles accompanying cancer cell transition to mesenchymal state. Exp Cell Res 319:2747–2757PubMedCrossRefGoogle Scholar
  262. 262.
    Aga M, Bradley JM, Wanchu R et al (2014) Differential effects of caveolin-1 and -2 knockdown on aqueous outflow and altered extracellular matrix turnover in caveolin-silenced trabecular meshwork cells. Invest Ophthalmol Vis Sci 55:5497–5509PubMedCentralPubMedCrossRefGoogle Scholar
  263. 263.
    Philip R, Heiler S, Mu W et al (2015) Claudin-7 promotes the epithelial-mesenchymal transition in human colorectal cancer. Oncotarget 6:2046PubMedCentralPubMedCrossRefGoogle Scholar
  264. 264.
    Josson S, Gururajan M, Hu P et al (2014) miR-409-3p/-5p promotes tumorigenesis, epithelial-to-mesenchymal transition, and bone metastasis of human prostate cancer. Clin Cancer Res 20:4636–4646PubMedCentralPubMedCrossRefGoogle Scholar
  265. 265.
    Marcus ME, Leonard JN (2013) FedExosomes: engineering therapeutic biological nanoparticles that truly deliver. Pharmaceuticals (Basel) 6:659–680CrossRefGoogle Scholar
  266. 266.
    Xin H, Li Y, Buller B et al (2012) Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 30:1556–1564PubMedCentralPubMedCrossRefGoogle Scholar
  267. 267.
    Arslan F, Lai RC, Smeets MB et al (2013) Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res 10:301–312PubMedCrossRefGoogle Scholar
  268. 268.
    Marleau AM, Chen CS, Joyce JA et al (2012) Exosome removal as a therapeutic adjuvant in cancer. J Transl Med 10:134PubMedCentralPubMedCrossRefGoogle Scholar
  269. 269.
    Christianson HC, Svensson KJ, van Kuppevelt TH et al (2013) Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci U S A 110:17380–17385PubMedCentralPubMedCrossRefGoogle Scholar
  270. 270.
    Atai NA, Balaj L, van Veen H et al (2013) Heparin blocks transfer of extracellular vesicles between donor and recipient cells. J Neurooncol 115:343–351PubMedCrossRefGoogle Scholar
  271. 271.
    Fabian MR, Sonenberg N, Filipowicz W (2010) Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 79:351–379PubMedCrossRefGoogle Scholar
  272. 272.
    Chen VY, Posada MM, Blazer LL et al (2006) The role of the VPS4A-exosome pathway in the intrinsic egress route of a DNA-binding anticancer drug. Pharm Res 23:1687–1695PubMedCrossRefGoogle Scholar
  273. 273.
    Li J, Sherman-Baust CA, Tsai-Turton M et al (2009) Claudin-containing exosomes in the peripheral circulation of women with ovarian cancer. BMC Cancer 9:244PubMedCentralPubMedCrossRefGoogle Scholar
  274. 274.
    Shen C, Hao SG, Zhao CX et al (2011) Antileukaemia immunity: effect of exosomes against NB4 acute promyelocytic leukaemia cells. J Int Med Res 39:740–747PubMedCrossRefGoogle Scholar
  275. 275.
    Johnsen KB, Gudbergsson JM, Skov MN (2014) A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy. Biochim Biophys Acta 1846:75–87PubMedGoogle Scholar
  276. 276.
    Ohno S, Takanashi M, Sudo K et al (2013) Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther 21:185–191PubMedCentralPubMedCrossRefGoogle Scholar
  277. 277.
    Kosaka N, Iguchi H, Yoshioka Y et al (2012) Competitive interactions of cancer cells and normal cells via secretory microRNAs. J Biol Chem 287:1397–1405PubMedCentralPubMedCrossRefGoogle Scholar
  278. 278.
    Mizrak A, Bolukbasi MF, Ozdener GB et al (2013) Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol Ther 21:101–108PubMedCentralPubMedCrossRefGoogle Scholar
  279. 279.
    Wahlgren J, De L, Karlson T et al (2012) Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res 40:e130PubMedCentralPubMedCrossRefGoogle Scholar
  280. 280.
    El-Andaloussi S, Lee Y, Lakhal-Littleton S et al (2012) Exosome-mediated delivery of siRNA in vitro and in vivo. Nat Protoc 7:2112–2126PubMedCrossRefGoogle Scholar
  281. 281.
    Alvarez-Erviti L, Seow Y, Yin H et al (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345PubMedCrossRefGoogle Scholar
  282. 282.
    Hartman ZC, Wei J, Glass OK et al (2011) Increasing vaccine potency through exosome antigen targeting. Vaccine 29:9361–9367PubMedCentralPubMedCrossRefGoogle Scholar
  283. 283.
    Bolukbasi MF, Mizrak A, Ozdener GB et al (2012) miR-1289 and “Zipcode”-like Sequence Enrich mRNAs in Microvesicles. Mol Ther Nucleic Acids 1:e10PubMedCentralPubMedCrossRefGoogle Scholar
  284. 284.
    de Medina P, Paillasse MR, Segala G et al (2010) Identification and pharmacological characterization of cholesterol-5,6-epoxide hydrolase as a target for tamoxifen and AEBS ligands. Proc Natl Acad Sci U S A 107:13520–13525PubMedCentralPubMedCrossRefGoogle Scholar
  285. 285.
    Sun D, Zhuang X, Xiang X et al (2010) A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther 18:1606–1614PubMedCentralPubMedCrossRefGoogle Scholar
  286. 286.
    Ristorcelli E, Beraud E, Verrando P et al (2008) Human tumor nanoparticles induce apoptosis of pancreatic cancer cells. FASEB J 22:3358–3369PubMedCrossRefGoogle Scholar
  287. 287.
    Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562PubMedCrossRefGoogle Scholar
  288. 288.
    Esquela-Kerscher A, Trang P, Wiggins JF et al (2008) The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle 7:759–764PubMedCrossRefGoogle Scholar
  289. 289.
    Kelnar K, Peltier HJ, Leatherbury N et al (2014) Quantification of therapeutic miRNA mimics in whole blood from nonhuman primates. Anal Chem 86:1534–1542PubMedCentralPubMedCrossRefGoogle Scholar
  290. 290.
    Bader AG (2012) miR-34 - a microRNA replacement therapy is headed to the clinic. Front Genet 3:120PubMedCentralPubMedCrossRefGoogle Scholar
  291. 291.
    Kota J, Chivukula RR, O’Donnell KA et al (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137:1005–1017PubMedCentralPubMedCrossRefGoogle Scholar
  292. 292.
    Ajit SK (2012) Circulating microRNAs as biomarkers, therapeutic targets, and signaling molecules. Sensors (Basel) 12:3359–3369CrossRefGoogle Scholar
  293. 293.
    Si ML, Zhu S, Wu H et al (2007) miR-21-mediated tumor growth. Oncogene 26:2799–2803PubMedCrossRefGoogle Scholar
  294. 294.
    Zhang L, Wrana JL (2014) The emerging role of exosomes in Wnt secretion and transport. Curr Opin Genet Dev 27:14–19PubMedCrossRefGoogle Scholar
  295. 295.
    Gangoda L, Boukouris S, Liem M et al (2015) Extracellular vesicles including exosomes are mediators of signal transduction: are they protective or pathogenic? Proteomics 15:260–271PubMedCentralPubMedCrossRefGoogle Scholar
  296. 296.
    Wolfson B, Eades G, Zhou Q (2014) Roles of microRNA-140 in stem cell-associated early stage breast cancer. World J Stem Cells 6:591–597PubMedCentralPubMedCrossRefGoogle Scholar
  297. 297.
    Ruiss R, Jochum S, Mocikat R et al (2011) EBV-gp350 confers B-cell tropism to tailored exosomes and is a neo-antigen in normal and malignant B cells--a new option for the treatment of B-CLL. PLoS One 6:e25294PubMedCentralPubMedCrossRefGoogle Scholar
  298. 298.
    Rajendran L, Knölker HJ, Simons K (2010) Subcellular targeting strategies for drug design and delivery. Nat Rev Drug Discov 9:29–42PubMedCrossRefGoogle Scholar
  299. 299.
    Kooijmans SA, Vader P, van Dommelen SM et al (2012) Exosome mimetics: a novel class of drug delivery systems. Int J Nanomedicine 7:1525–1541PubMedCentralPubMedGoogle Scholar
  300. 300.
    van der Meel R, Fens MH, Vader P et al (2014) Extracellular vesicles as drug delivery systems: lessons from the liposome field. J Control Release 195:72–85PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Tumor Cell BiologyUniversity Hospital of SurgeryHeidelbergGermany

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