Cellular and Molecular Life Sciences

, Volume 72, Issue 4, pp 659–671 | Cite as

Formation and role of exosomes in cancer

  • Lindsey T. Brinton
  • Hillary S. Sloane
  • Mark Kester
  • Kimberly A. KellyEmail author


Exosomes offer new insight into cancer biology with both diagnostic and therapeutic implications. Because of their cell-to-cell communication, exosomes influence tumor progression, metastasis, and therapeutic efficacy. They can be isolated from blood and other bodily fluids to reveal disease processes occurring within the body, including cancerous growth. In addition to being a reservoir of cancer biomarkers, they can be re-engineered to reinstate tumor immunity. Tumor exosomes interact with various cells of the microenvironment to confer tumor-advantageous changes that are responsible for stromal activation, induction of the angiogenic switch, increased vascular permeability, and immune escape. Exosomes also contribute to metastasis by aiding in the epithelial-to-mesenchymal transition and formation of the pre-metastatic niche. Furthermore, exosomes protect tumor cells from the cytotoxic effects of chemotherapy drugs and transfer chemoresistance properties to nearby cells. Thus, exosomes are essential to many lethal elements of cancer and it is important to understand their biogenesis and role in cancer.


Signaling Immunosurveillance Fibroblast Targeted therapy Multivesicular endosome Vaccine ESCRT Biogenesis 



Multivesicular endosome


Endosomal-sorting complexes required for transport


Myeloid-derived suppressor cells


Epithelial-to-mesenchymal transition


Hypoxia-inducible factor


Granulocyte–macrophage colony-stimulating factor


Adipose stem cell


  1. 1.
    Hoyert DL, Xu J (2012) Deaths: preliminary data for 2011. Natl Vital Stat Rep 61:1–52PubMedGoogle Scholar
  2. 2.
    Heron M (2012) Deaths: leading causes for 2009. Natl Vital Stat Rep 61:1–94PubMedGoogle Scholar
  3. 3.
    DeNardo DG, Coussens LM (2007) Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 9:212PubMedCentralPubMedGoogle Scholar
  4. 4.
    Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, Aridome K, Hokita S, Aikou T (2000) Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 88:577–583PubMedGoogle Scholar
  5. 5.
    Bissell MJ, Hines WC (2011) Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17:320–329PubMedCentralPubMedGoogle Scholar
  6. 6.
    Brentnall TA (2012) Arousal of cancer-associated stromal fibroblasts: palladin-activated fibroblasts promote tumor invasion. Cell Adh Migr 6:488–494PubMedCentralPubMedGoogle Scholar
  7. 7.
    Li H, Fan X, Houghton J (2007) Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biohem 101:805–815Google Scholar
  8. 8.
    Johnson LM, Price DK, Figg WD (2013) Treatment-induced secretion of WNT16B promoted tumor growth and acquired resistance to chemotherapy: implications for potential use of inhibitors in cancer treatment. Cancer Biol Ther 14:90–91PubMedCentralPubMedGoogle Scholar
  9. 9.
    Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21:309–322PubMedGoogle Scholar
  10. 10.
    Sund M, Kalluri R (2009) Tumor stroma derived biomarkers in cancer. Cancer Metastasis Rev 28:177–183PubMedGoogle Scholar
  11. 11.
    Allen M, Louis Jones J (2011) Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J Pathol 223:162–176PubMedGoogle Scholar
  12. 12.
    Mueller MM, Fusenig NE (2004) Friends or foes: bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849PubMedGoogle Scholar
  13. 13.
    Joyce JA (2005) Therapeutic targeting of the tumor microenvironment. Cancer Cell 7:513–520PubMedGoogle Scholar
  14. 14.
    Rosenberg SA (2001) Progress in human tumour immunology and immunotherapy. Nature 411:380–384PubMedGoogle Scholar
  15. 15.
    Albini A, Sporn MB (2007) The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 7:139–147PubMedGoogle Scholar
  16. 16.
    Kucharzewska P, Belting M (2013) Emerging roles of extracellular vesicles in the adaptive response of tumour cells to microenvironmental stress. J Extracell Vesicles. doi: 10.3402/jev.v2i0.20304 PubMedCentralPubMedGoogle Scholar
  17. 17.
    Khan S, Jutzy JM, Aspe JR, McGregor DW, Neidigh JW, Wall NR (2011) Survivin is released from cancer cells via exosomes. Apoptosis 16:1–12PubMedCentralPubMedGoogle Scholar
  18. 18.
    Théry C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593PubMedGoogle Scholar
  19. 19.
    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 4:1921–1926PubMedCentralPubMedGoogle Scholar
  20. 20.
    Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19:43–51PubMedGoogle Scholar
  21. 21.
    Kahlert C, Melo SA, Protopopov A, Tang J, Seth S, Koch M, Zhang J, Weitz J, Chin L, Futreal A, Kalluri R (2014) Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem 289:3869–3875PubMedGoogle Scholar
  22. 22.
    Mathivanan S, Fahner CJ, Reid GE, Simpson RJ (2012) ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucl Acids Res 40:D1241–D1244PubMedCentralPubMedGoogle Scholar
  23. 23.
    Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brügger B, Simons M (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244–1247PubMedGoogle Scholar
  24. 24.
    Michael A, Bajracharya SD, Yuen PS, Zhou H, Star RA, Illei GG, Alevizos I (2010) Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis 16:34–38PubMedCentralPubMedGoogle Scholar
  25. 25.
    Trams EG, Lauter CJ, Salem N Jr, Heine U (1981) Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim Biophys Acta 645:63–70PubMedGoogle Scholar
  26. 26.
    Théry C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2:569–579PubMedGoogle Scholar
  27. 27.
    De Broe ME, Wieme RJ, Logghe GN, Roels F (1977) Spontaneous shedding of plasma membrane fragments by human cells in vivo and in vitro. Clin Chim Acta 81:237–245PubMedGoogle Scholar
  28. 28.
    Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C, Sánchez-Madrid F, Mittelbrunn M (2014) Sorting it out: regulation of exosome loading. Semin Cancer Biol 28C:3–13Google Scholar
  29. 29.
    Colombo M, Moita C, van Niel G, Kowal J, Vigneron J, Benaroch P, Manel N, Moita LF, Théry C, Raposo G (2013) Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J Cell Sci 126:5553–5565PubMedGoogle Scholar
  30. 30.
    Kajimoto T, Okada T, Miya S, Zhang L, Nakamura S (2013) Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes. Nat Commun 4:2712PubMedGoogle Scholar
  31. 31.
    Perez-Hernandez D, Gutiérrez-Vázquez C, Jorge I, López-Martín S, Ursa A, Sánchez-Madrid F, Vázquez J, Yáñez-Mó M (2013) The intercellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. J Biol Chem 288:11649–11661PubMedCentralPubMedGoogle Scholar
  32. 32.
    Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J, Martin-Cofreces N, Martinez-Herrera DJ, Pascual-Montano A, Mittelbrunn M, Sánchez-Madrid F (2013) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 4:2980PubMedCentralPubMedGoogle Scholar
  33. 33.
    Yu X, Harris SL, Levine AJ (2006) The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res 66:4795–4801PubMedGoogle Scholar
  34. 34.
    Lespagnol A, Duflaut D, Beekman C, Blanc L, Fiucci G, Marine JC, Vidal M, Amson R, Telerman A (2008) Exosome secretion, including DNA damage-induced p53-dependent secretory pathway, is severly compromised in TSAP6/Steap3-null mice. Cell Death Differ 15:1723–1733PubMedGoogle Scholar
  35. 35.
    Thompson CA, Purushothaman A, Ramani VC, Vlodavsky I, Sanderson RD (2013) Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. J Biol Chem 288(14):10093–10099PubMedCentralPubMedGoogle Scholar
  36. 36.
    Riches A, Campbell E, Borger E, Powis S (2014) Regulation of exosome release from mammary epithelial and breast cancer cells: a new regulatory pathway. Eur J Cancer 50:1025–1034PubMedGoogle Scholar
  37. 37.
    Tolmachova T, Anders R, Stinchcombe J, Bossi G, Griffiths GM, Huxley C, Seabra MC (2004) A general role for Rab27a in secretory cells. Mol Biol Cell 15:332–344PubMedCentralPubMedGoogle Scholar
  38. 38.
    Barral DC, Ramalho JS, Anders R, Hume AN, Knapton HJ, Tolmachova T, Collinson LM, Goulding D, Authi KS, Seabra MC (2002) Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome. J Clin Invest 110:247–257PubMedCentralPubMedGoogle Scholar
  39. 39.
    Shin SJ, Smith JA, Rezniczek GA, Pan S, Chen R, Brentnall TA, Wiche G, Kelly KA (2013) Unexpected gain of function for the scaffolding protein plectin due to mislocalization in pancreatic cancer. Proc Natl Acad Sci USA 110:19414–19419PubMedCentralPubMedGoogle Scholar
  40. 40.
    Savina A, Vidal M, Colombo MI (2002) The exosome pathway in K562 cells is regulated by Rab11. J Cell Sci 115:2505–2515PubMedGoogle Scholar
  41. 41.
    Savina A, Fader CM, Damiani MT, Colombo MI (2005) Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner. Traffic 6:131–143PubMedGoogle Scholar
  42. 42.
    Hoshino D, Kirkbride KC, Costello K, Clark ES, Sinha S, Grega-Larson N, Tyska MJ, Weaver AM (2013) Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Rep 5:1159–1168PubMedGoogle Scholar
  43. 43.
    Tlsty TD, Hein PW (2001) Know thy neighbor: stromal cells can contribute oncogenic signals. Curr Opin Genet Dev 11:54–59PubMedGoogle Scholar
  44. 44.
    Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348PubMedGoogle Scholar
  45. 45.
    Camps JL, Chang SM, Hsu TC, Freeman MR, Hong SJ, Zhau HE, von Eschenbach AC, Chung LW (1990) Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc Natl Acad Sci USA 87:75–79PubMedCentralPubMedGoogle Scholar
  46. 46.
    Gleave M, Hsieh JT, Gao CA, von Eschenbach AC, Chung LW (1991) Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. Cancer Res 51:3753–3761PubMedGoogle Scholar
  47. 47.
    Kanekura T, Chen X, Kanzaki T (2002) Basigin (CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinases by fibroblasts. Int J Cancer 99:520–528PubMedGoogle Scholar
  48. 48.
    Sameshima T, Nabeshima K, Toole BP, Yokogami K, Okada Y, Goya T, Koono M, Wakisaka S (2000) Glioma cell extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) stimulates production of membrane-type matrix metalloproteinases and activated gelatinase A in co-cultures with brain-derived fibroblasts. Cancer Lett 157:177–184PubMedGoogle Scholar
  49. 49.
    Gu J, Qian H, Shen L, Zhang X, Zhu W, Huang L, Yan Y, Mao F, Zhao C, Shi Y, Xu W (2012) Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-β/Smad pathway. PLoS One. doi: 10.1371/journal.pone.0052465 Google Scholar
  50. 50.
    Webber J, Steadman R, Mason MD, Tabi Z, Clayton A (2010) Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res 70:9621–9630PubMedGoogle Scholar
  51. 51.
    Webber JP, Spary LK, Sanders AJ, Chowdhury R, Jiang WG, Steadman R, Wymant J, Jones AT, Kynsaston H, Mason MD, Tabi Z, Clayton A (2014) Differentiation of tumou-promoting stromal myofibroblasts by cancer exosomes. Oncogene. doi: 10.1038/onc.2013.560 PubMedGoogle Scholar
  52. 52.
    Atula S, Grenman R, Syrjänen S (1997) Fibroblasts can modulate the phenotype of malignant epithelial cells in vitro. Exp Cell Res 235(1):180–187PubMedGoogle Scholar
  53. 53.
    Gesierich S, Berezovskiy I, Ryschich E, Zöller M (2006) Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029. Cancer Res 66:7083–7094PubMedGoogle Scholar
  54. 54.
    Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410PubMedGoogle Scholar
  55. 55.
    Giordano FJ, Johnson RS (2001) Angiogenesis: the role of the microenvironment in flipping the switch. Curr Opin Genet Dev 11:35–40PubMedGoogle Scholar
  56. 56.
    Park JE, Tan HS, Datta A, Lai RC, Zhang H, Meng W, Lim SK, Sze SK (2010) Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteomics 9:1085–1099PubMedCentralPubMedGoogle Scholar
  57. 57.
    Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, 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 10:1470–1476PubMedCentralPubMedGoogle Scholar
  58. 58.
    Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringnér M, Mörgelin M, Bourseau-Guilmain E, Bengzon J, Belting M (2013) Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci USA 110:7312–7317PubMedCentralPubMedGoogle Scholar
  59. 59.
    Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, Yu Y, Chow A, O’Connor ST, Chin AR, Yen Y, Wang Y, Marcusson EG, Chu P, Wu J, Wu X, Li AX, Li Z, Gao H, Ren X, Boldin MP, Lin PC, Wang SE (2014) Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25:501–515PubMedGoogle Scholar
  60. 60.
    Lakshmi Narendra B, Eshvendar Reddy K, Shantikumar S, Ramakrishna S (2013) Immune system: a double-edged sword in cancer. Inflamm Res 62:823–834PubMedGoogle Scholar
  61. 61.
    Kawamoto H, Minato N (2004) Myeloid cells. Int J Biochem Cell Biol 36:1374–1379PubMedGoogle Scholar
  62. 62.
    Skokos D, Botros HG, Demeure C, Morin J, Peronet R, Birkenmeier G, Boudaly S, Mécheri S (2003) Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol 170:3037–3045PubMedGoogle Scholar
  63. 63.
    Théry C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1999) Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol 147:599–610PubMedCentralPubMedGoogle Scholar
  64. 64.
    Valenti R, Huber V, Iero M, Filipazzi P, Parmiani G, Rivoltini L (2007) Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res 67:2912–2915PubMedGoogle Scholar
  65. 65.
    Xiang X, Poliakov A, Liu C, Liu Y, Deng ZB, Wang J, Cheng Z, Shah SV, Wang GJ, Zhang L, Grizzie WE, Mobley J, Zhang HG (2009) Induction of myeloid-derived suppressor cells by tumor exosomes. Int J Cancer 124:2621–2633PubMedCentralPubMedGoogle Scholar
  66. 66.
    Yu S, Liu C, Su K, Wang J, Liu Y, Zhang L, Li C, Cong Y, Kimberly R, Grizzle WE, Falkson C, Zhang HG (2007) Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J Immunol 178:6867–6875PubMedGoogle Scholar
  67. 67.
    Serafini P, Borrello I, Bronte V (2006) Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol 16:53–65PubMedGoogle Scholar
  68. 68.
    Liu Y, Xiang X, Zhuang X, Zhang S, Liu C, Cheng Z, Michalek S, Grizzle W, Zhang HG (2010) Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. Am J Pathol 176:2490–2499PubMedCentralPubMedGoogle Scholar
  69. 69.
    Hong EH, Chang SY, Lee BR, Kim YS, Lee JM, Kang CY, Kweon MN, Ko HJ (2013) Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid-derived suppressor cells. Int J Cancer 132:2839–2848PubMedGoogle Scholar
  70. 70.
    Xiang X, Liu Y, Zhuang X, Zhang S, Michalek S, Taylor DD, Grizzle W, Zhang HG (2010) TLR2-mediated expansion of MDSCs is dependent on the source of tumor exosomes. Am J Pathol 177:1606–1610PubMedCentralPubMedGoogle Scholar
  71. 71.
    Luczyński W, Krawczuk-Rybak M, Stasiak-Barmuta A (2008) Myeloid-derived suppressor cells: the new mechanism of immunosuppression in cancer. Postepy Hig Med Dosw 62:18–22Google Scholar
  72. 72.
    Ye SB, Li ZL, Luo DH, Huang BJ, Chen YS, Zhang XS, Cui J, Zeng YX, Li J (2014) Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma. Oncotarget [Epub ahead of print]Google Scholar
  73. 73.
    Clayton A, Mitchell JP, Court J, Mason MD, Tabi Z (2007) Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res 67:7458–7466PubMedGoogle Scholar
  74. 74.
    Abusamra AJ, Zhong A, Zheng X, Li M, Ichim TE, Chin JL, Min WP (2005) Tumor exosomes expressing Fas ligand mediate CD8 + T-cell apoptosis. Blood Cells Mol Dis 35:169–173PubMedGoogle Scholar
  75. 75.
    Klibi J, Niki T, Riedel A, Pioche-Durieu C, Souquere S, Rubinstein E, Le Moulec S, Guigay J, Hirashima M, Guemira F, Adhikary D, Mautner J, Busson P (2009) Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cels. Blood 113:1957–1966PubMedGoogle Scholar
  76. 76.
    Yang C, Chalasani G, Ng YH, Robbins PD (2012) Exosomes released from Mycoplasma infected tumor cells activate inhibitory B cells. PLoS One. doi: 10.1371/journal.pone.0036138 Google Scholar
  77. 77.
    Qin Z, Richter G, Schüler T, Ibe S, Cao X, Blankenstein T (1998) B cells inhibit induction of T cell-dependent tumor immunity. Nat Med 4:627–630PubMedGoogle Scholar
  78. 78.
    Mincheva-Nilsson L, Baranov V (2014) Cancer exosomes and NKG2D receptor-ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance. Semin Cancer Biol. doi: 10.1016/j.semcancer.2014.02.010 PubMedGoogle Scholar
  79. 79.
    Ashiru O, Boutet P, Fernández-Messina L, Agüera-González S, Skepper JN, Valés-Gómez M, Reyburn HT (2010) Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes. Cancer Res 70:481–489PubMedCentralPubMedGoogle Scholar
  80. 80.
    Gehrmann U, Näslund TI, Hiltbrunner S, Larssen P, Gabrielsson S (2014) Harnessing the exosome-induced immune response for cancer immunotherapy. Semin Cancer Biol. doi: 10.1016/j.semcancer.2014.05.003 PubMedGoogle Scholar
  81. 81.
    Altevogt P, Bretz NP, Ridinger J, Utikal J, Umansky V (2014) Novel insights into exosome-induced, tumor-associated inflammation and immunomodulation. Semin Cancer Biol. doi: 10.1016/j.semcancer.2014.04.008 PubMedGoogle Scholar
  82. 82.
    Fidler IJ (2002) The organ microenvironment and cancer metastasis. Differentiation 70:498–505PubMedGoogle Scholar
  83. 83.
    Jeppesen DK, Nawrocki A, Jensen SG, Thorsen K, Whitehead B, Howard KA, Dyrskjøt L, Ørntoft TF, Larsen MR, Ostenfeld MS (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 14:699–712PubMedGoogle Scholar
  84. 84.
    Chow A, Zhou W, Liu L, Fong MY, Champer J, Van Haute D, Chin AR, Ren X, Gugiu BG, Meng Z, Huang W, Ngo V, Kortylewski M, Wang SE (2014) Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB. Sci Rep 4:5750PubMedCentralPubMedGoogle Scholar
  85. 85.
    Kimbro KS, Simons JW (2006) Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr Relat Cancer 13:739–749PubMedGoogle Scholar
  86. 86.
    Wang T, Gilkes DM, Takano N, Xiang L, Luo W, Bishop CJ, Chaturvedi P, Green JJ, Semenza FL (2014) Hypoxia-inducible factors and RAB22 mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci USA [Epub ahead of print]Google Scholar
  87. 87.
    Irmisch A, Huelsken J (2013) Metastasis: new insights into organ-specific extravasation and metastatic niches. Exp Cell Res. doi: 10.1016/j.yexcr.2013.02.012 PubMedGoogle Scholar
  88. 88.
    Wong CC, Gilkes DM, Zhang H, Chen J, Wei H, Chaturvedi P, Fraley SI, Wong CM, Khoo US, Ng IO, Wirtz D, Semenza GL (2011) Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci USA 108:16369–16374PubMedCentralPubMedGoogle Scholar
  89. 89.
    Thuma F, Zöller M (2014) Outsmart tumor exosomes to steal the cancer initiating cell its niche. Semin Cancer Biol. doi: 10.1016/j.semcancer.2014.02.011 PubMedGoogle Scholar
  90. 90.
    Abd Elmageed ZY, Yang Y, Thomas R, Ranjan M, Mondal D, Moroz K, Fang Z, Rezk BM, Moparty K, Sikka SC, Sartor O, Abdel-Mageed AB (2014) Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes. Stem Cells 32:983–997PubMedGoogle Scholar
  91. 91.
    Wang T, Diaz AJ, Yen Y (2014) The role of peroxiredoxin II in chemoresistance of breast cancer cells. Breast Cancer 6:73–80PubMedCentralPubMedGoogle Scholar
  92. 92.
    Chen WX, Liu XM, Lv MM, Chen L, Zhao JH, Zhong SL, Ji MH, Hu Q, Luo Z, Wu JZ, Tang JH (2014) Exosomes from drug-resistance breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS One. doi: 10.1371/journal.pone.0095240 Google Scholar
  93. 93.
    Corcoran C, Rani S, O’Brien K, O’Neill A, Prencipe M, Sheikh R, Webb G, McDermott R, Watson W, Crown J, O’Driscoll L (2012) Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PLoS One 7(12):e50999PubMedCentralPubMedGoogle Scholar
  94. 94.
    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):1595–1604PubMedGoogle Scholar
  95. 95.
    Federici C, Petrucci F, Caimi S, Cesolini A, Logozzi M, Borghi M, D’Ilio S, Lugini L, Violante N, Azzarito T, Majorani C, Brambilla D, Fais S (2014) Exosome release and low pH belong to a framework of resistance of human melanoma cells to cisplatin. PLoS One. doi: 10.1371/journal.pone.0088193 Google Scholar
  96. 96.
    Gonzales PA, Zhou H, Pisitkun T, Wang NS, Star RA, Knepper MA, Yuen PS (2010) Isolation and purification of exosomes in urine. Methods Mol Biol 641:89–99PubMedGoogle Scholar
  97. 97.
    Zhou Q, Li M, Wang X, Li Q, Wang T, Zhu Q, Zhou X, Wang X, Gao X, Li X (2012) Immune-related microRNAs are abundant in breast milk exosomes. Int J Bio Sci 8:118–123Google Scholar
  98. 98.
    Peng P, Yan Y, Keng S (2011) Exosomes in the ascites of ovarian cancer patients: origin and effects on anti-tumor immunity. Oncol Rep 25:749–762PubMedGoogle Scholar
  99. 99.
    Asea A, Jean-Pierre C, Kaur P, Rao P, Linhares IM, Skupski D, Witkin SS (2008) Heat shock protein-containing exosomes in mid-trimester amniotic fluids. J Reprod Immunol 79:12–17PubMedGoogle Scholar
  100. 100.
    Rodriguez M, Silva J, López-Alfonso A, López-Muñiz MB, Peña C, Domínguez G, García JM, López-Gónzalez A, Méndez M, Provencio M, García V, Bonilla F (2014) Different exosome cargo from plasma/bronchoalveolar lavage in non-small-cell lung cancer. Genes Chromosome Cancer 53:713–724Google Scholar
  101. 101.
    Teplyuk NM, Mollenhauer B, Gabriely G, Giese A, Kim E, Smolsky M, Kim RY, Saria MG, Pastorino S, Kesari S, Krichevsky AM (2012) MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. Neuro Oncol 14:689–700PubMedCentralPubMedGoogle Scholar
  102. 102.
    Vojtech L, Woo S, Hughes S, Levy C, Ballweber L, Sauteraud RP, Strobi J, Westerberg K, Gottardo R, Tewari M, Hladik F (2014) Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions. Nucleic Acids Res 42:7290–7304PubMedCentralPubMedGoogle Scholar
  103. 103.
    Skriner K, Adolph K, Jungblut PR, Burmester GR (2006) Association of citrullinated proteins with synovial exosomes. Arthritis Rheum 54:3809–3814PubMedGoogle Scholar
  104. 104.
    Properzi F, Logozzi M, Fais S (2013) Exosomes: the future of biomarkers in medicine. Biomark Med 7:769–778PubMedGoogle Scholar
  105. 105.
    Rabinowits G, Gerçel-Taylor C, Day JM, Taylor DD, Kloecker GH (2009) Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer 10(1):42–46PubMedGoogle Scholar
  106. 106.
    Taylor DD, Gercel-Taylor C (2008) MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110(1):13–21PubMedGoogle Scholar
  107. 107.
    Properzi F, Logozzi M, Fais S (2013) Exosomes: the future of biomarkers in medicine. Biomark Med 7(5):769–778PubMedGoogle Scholar
  108. 108.
    Choi DS, Park JO, Jang SC, Yoon YJ, Jung JW, Choi DY, Kim JW, Kang JS, Park J, Hwang D, Lee KH, Park SH, Kim YK, Desiderio DM, Kim KP, Gho YS (2011) Proteomic analysis of microvesicles derived from human colorectal cancer ascites. Proteomics 11(13):2745–2751PubMedGoogle Scholar
  109. 109.
    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):1603–1607PubMedCentralPubMedGoogle Scholar
  110. 110.
    Bryant RJ, Pawlowski T, Catto JW, Marsden G, Vessella RL, Rhees B, Kuslich C, Visakorpi T, Hamdy FC (2012) Changes in circulating microRNA levels associated with prostate cancer. Br J Cancer 106(4):768–774PubMedCentralPubMedGoogle Scholar
  111. 111.
    Corcoran C, Friel AM, Duffy MJ, Crown J, O’Driscoll L (2011) Intracellular and extracellular microRNAs in breast cancer. Clin Chem 57(1):18–32PubMedGoogle Scholar
  112. 112.
    Kosaka N, Iguchi H, Ochiya T (2010) Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci 101(10):2087–2092PubMedGoogle Scholar
  113. 113.
    Natasha G, Gundogan B, Tan A, Farhatnia Y, Wu W, Rajadas J, Seifalian AM (2014) Exosomes as immunotheranostic nanoparticles. Clin Ther 36:820–829PubMedGoogle Scholar
  114. 114.
    Hao S, Liu Y, Yuan J, Zhang X, He T, Wu X, Wei Y, Sun D, Xiang J (2007) Novel exosome-targeted CD4 + T cell vaccine counteracting CD4 + 25 + regulatory T cell-mediated immune suppression and stimulating efficient central memory CD8 + CTL response. J Immunol 179:2731–2740PubMedCentralPubMedGoogle Scholar
  115. 115.
    Dai S, Wei D, Wu Z, Zhou X, Wei X, Huang H, Li G (2008) Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther 16:782–790PubMedGoogle Scholar
  116. 116.
    Escudier B, Dorval T, Chaput N, André F, Caby MP, Novault S, Flament C, Leboulaire C, Borg C, Amigorena S, Boccaccio C, Bonnerot C, Dhellin O, Movassagh M, Piperno S, Robert C, Serra V, Valente N, Le Pecq JB, Spatz A, Lantz O, Tursz T, Angevin E, Zitvogel L (2005) Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J Transl Med 3:10PubMedCentralPubMedGoogle Scholar
  117. 117.
    Morse MA, Garst J, Osada T, Khan S, Hobeika A, Clay TM, Valente N, Shreeniwas R, Sutton MA, Delcayre A, Hsu DH, Le Pecq JB, Lyerly HK (2005) A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med 3:9PubMedCentralPubMedGoogle Scholar
  118. 118.
    Pitt JM, Charrier M, Viaud S, André F, Besse B, Chaput N, Zitvogel L (2014) Dendritic cell-derived exosomes as immunotherapies in the fight against cancer. J Immunol 193:1006–1011PubMedGoogle Scholar
  119. 119.
    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 9:1324–1338PubMedCentralPubMedGoogle Scholar
  120. 120.
    Choi DS, Kim DK, Kim YK, Gho YS (2013) Proteomics, transcriptomics and lipidomics of exosomes and ectosomes. Proteomics 13(10–11):1554–1571PubMedGoogle Scholar
  121. 121.
    Llorente A, Skotland T, Sylvänne T, Kauhanen D, Róg T, Orlowski A, Vattulainen I, Ekroos K (1831) Sandvig K (2013) Molecular lipidomics of exosomes released by PC-3 prostate cancer cells. Biochim Biophys Acta 7:1302–1309Google Scholar
  122. 122.
    Laulagnier K, Motta C, Hamdi S, Roy S, Fauvelle F, Pageaux JF, Kobayashi T, Salles JP, Perret B, Bonnerot C, Record M (2004) Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. Biochem J 380(Pt 1):161–171PubMedCentralPubMedGoogle Scholar
  123. 123.
    He M, Crow J, Roth M, Zeng Y, Godwin AK (2014) Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology. Lab Chip 14(19):3773–3780PubMedCentralPubMedGoogle Scholar
  124. 124.
    Petersen KE, Manangon E, Hood JL, Wickline SA, Fernandez DP, Johnson WP, Gale BK (2014) A review of exosome separation techniques and characterization of B16-F10 mouse melanoma exosomes with AF4-UV-MALS-DLS-TEM. Anal Bioanal Chem [Epub ahead of print]Google Scholar
  125. 125.
    Mizutani K, Terazawa R, Kameyama K, Kato T, Horie K, Tsuchiya T, Seike K, Ehara H, Fujita Y, Kawakami K, Ito M, Deguchi T (2014) Isolation of prostate cancer-related exosomes. Anticancer Res 34(7):3419–3423PubMedGoogle Scholar
  126. 126.
    De Broe ME, Borgers M, Wieme RJ (1975) The separation and characterization of liver plasma membrane fragments circulating in the blood of patients with cholestasis. Clin Chim Acta 59(3):369–372PubMedGoogle Scholar
  127. 127.
    Brocklehurst D, Wilde CE, Doar JW (1978) The incidence and likely origins of serum particulate alkaline phosphatase and lipoprotein-X in liver disease. Clin Chim Acta 88(3):509–515PubMedGoogle Scholar
  128. 128.
    Harding C, Stahl P (1983) Transferrin recycling in reticulocytes: pH and iron are important determinants of ligand binding and processing. Biochem Biophys Res Commun 113(2):650–658PubMedGoogle Scholar
  129. 129.
    Pan BT, Johnstone RM (1983) Fate of the transferrin receptor during maturation of sheep reticulocyte in vitro: selective externalization of the receptor. Cell 33(3):967–978PubMedGoogle Scholar
  130. 130.
    Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C (1987) Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 262(19):9412–9420PubMedGoogle Scholar
  131. 131.
    Harding CV, Heuser JE, Stahl PD (2013) Exosomes: looking back three decades and into the future. J Cell Biol 200(4):367–371PubMedCentralPubMedGoogle Scholar
  132. 132.
    Johnstone RM, Matthew A, Mason AB, Teng K (1991) Exosome formation during maturation of mammalian and avian reticulocytes: evidence that exosome release is a major route for externalization of obsolete membrane proteins. J Cell Physiol 147:27–36PubMedGoogle Scholar
  133. 133.
    Gruenberg J (2001) The endocytic pathway: a mosaic of domains. Nat Rev Mol Cell Biol 2:721–730PubMedGoogle Scholar
  134. 134.
    Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ (1996) B lymophocytes secrete antigen-presenting vesicles. J Exp Med 183:1161–1172PubMedGoogle Scholar
  135. 135.
    Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ (2006) Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20:1487–1495PubMedGoogle Scholar
  136. 136.
    Théry C (2011) Exosomes: secreted vesicles and intercellular communications. F1000 Biol Rep 3:15PubMedCentralPubMedGoogle Scholar
  137. 137.
    Gould SJ, Raposo G (2013) As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles. doi: 10.3402/jev.v2i0.20389 PubMedCentralPubMedGoogle Scholar
  138. 138.
    Orozco AF, Lewis DE (2010) Flow cytometric analysis of circulating microparticles in plasma. Cytometry 77:502–514PubMedCentralPubMedGoogle Scholar
  139. 139.
    Morelli AE, Larregina AT, Shufesky WJ, Sullivan ML, Stolz DB, Papworth GD, Zahorchak AF, Logar AJ, Wang Z, Watkins SC, Falo LD Jr, Thomson AW (2004) Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood 104:3257–3266PubMedGoogle Scholar
  140. 140.
    Hawari FI, Rouhani FN, Cui X, Yu ZX, Buckley C, Kaler M, Levine SJ (2004) Release of full-length 55-kDa TNF receptor 1 in exosome-like vesicles: a mechanism for generation of soluble cytokine receptors. Proc Natl Acad Sci USA 101:1297–1302PubMedCentralPubMedGoogle Scholar
  141. 141.
    Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, Geuze HJ (1998) Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem 273:20121–20127PubMedGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  • Lindsey T. Brinton
    • 1
    • 2
  • Hillary S. Sloane
    • 3
  • Mark Kester
    • 4
  • Kimberly A. Kelly
    • 1
    • 2
    Email author
  1. 1.Department of Biomedical EngineeringUniversity of VirginiaCharlottesvilleUSA
  2. 2.Robert M. Berne Cardiovascular Research CenterUniversity of Virginia School of MedicineCharlottesvilleUSA
  3. 3.Department of ChemistryUniversity of VirginiaCharlottesvilleUSA
  4. 4.Department of PharmacologyUniversity of Virginia School of MedicineCharlottesvilleUSA

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