Exosomes are small extracellular vesicles (30–100 nm) derived from the endosomal system, which have raised considerable interest in the last decade. Several studies have shown that they mediate cell-to-cell communication in a variety of biological processes. Thus, in addition to cell-to-cell direct interaction or secretion of active molecules, they are now considered another class of signal mediators. Exosomes can be secreted by several cell types and retrieved in many body fluids, such as blood, urine, saliva and cerebrospinal fluid. In addition to proteins and lipids, they also contain nucleic acids, namely mRNA and miRNA. These features have prompted extensive research to exploit them as a source of biomarkers for several pathologies, such as cancer and neurodegenerative disorders. In this context, exosomes also appear attractive as gene delivery vehicles. Furthermore, exosome immunomodulatory and regenerative properties are also encouraging their application for further therapeutic purposes. Nevertheless, several issues remain to be addressed: exosome biogenesis and secretion mechanisms have not been clearly understood, and physiological functions, as well as pathological roles, are far from being satisfactorily elucidated.
Thery, C.; Amigorena, S.; Raposo, G.; Clayton, A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. 2006, doi:10.1002/0471143030.cb0322s30.
[6]
Booth, A.M.; Fang, Y.; Fallon, J.K.; Yang, J.M.; Hildreth, J.E.; Gould, S.J. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J. Cell. Biol. 2006, 172, 923–935, doi:10.1083/jcb.200508014.
[7]
Bobrie, A.; Colombo, M.; Raposo, G.; Thery, C. Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 2011, 12, 1659–1668, doi:10.1111/j.1600-0854.2011.01225.x.
[8]
Johnstone, R.M.; Adam, M.; Hammond, J.R.; Orr, L.; Turbide, C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J. Biol. Chem. 1987, 262, 9412–9420.
[9]
Mathivanan, S.; Simpson, R.J. ExoCarta: A compendium of exosomal proteins and RNA. Proteomics 2009, 9, 4997–5000, doi:10.1002/pmic.200900351.
[10]
Simons, M.; Raposo, G. Exosomes--vesicular carriers for intercellular communication. Curr. Opin Cell. Biol. 2009, 21, 575–581, doi:10.1016/j.ceb.2009.03.007.
[11]
Thery, C.; Ostrowski, M.; Segura, E. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 2009, 9, 581–593, doi:10.1038/nri2567.
[12]
Mathivanan, S.; Ji, H.; Simpson, R.J. Exosomes: extracellular organelles important in intercellular communication. J. Proteomics 2010, 73, 1907–1920, doi:10.1016/j.jprot.2010.06.006.
Parolini, I.; Federici, C.; Raggi, C.; Lugini, L.; Palleschi, S.; De Milito, A.; Coscia, C.; Iessi, E.; Logozzi, M.; Molinari, A.; Colone, M.; Tatti, M.; Sargiacomo, M.; Fais, S. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J. Biol. Chem. 2009, 284, 34211–34222, doi:10.1074/jbc.M109.041152.
[17]
Kobayashi, T.; Gu, F.; Gruenberg, J. Lipids, lipid domains and lipid-protein interactions in endocytic membrane traffic. Semin Cell. Dev. Biol. 1998, 9, 517–526, doi:10.1006/scdb.1998.0257.
[18]
Chu, Z.; Witte, D.P.; Qi, X. Saposin C-LBPA interaction in late-endosomes/lysosomes. Exp. Cell. Res. 2005, 303, 300–307, doi:10.1016/j.yexcr.2004.09.029.
[19]
Matsuo, H.; Chevallier, J.; Mayran, N.; Le Blanc, I.; Ferguson, C.; Faure, J.; Blanc, N.S.; Matile, S.; Dubochet, J.; Sadoul, R.; Parton, R.G.; Vilbois, F.; Gruenberg, J. Role of LBPA and Alix in multivesicular liposome formation and endosome organization. Science 2004, 303, 531–534, doi:10.1126/science.1092425.
Subra, C.; Laulagnier, K.; Perret, B.; Record, M. Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 2007, 89, 205–212, doi:10.1016/j.biochi.2006.10.014.
[22]
Subra, C.; Grand, D.; Laulagnier, K.; Stella, A.; Lambeau, G.; Paillasse, M.; De Medina, P.; Monsarrat, B.; Perret, B.; Silvente-Poirot, S.; Poirot, M.; Record, M. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J. Lipid Res. 2010, 51, 2105–2120, doi:10.1194/jlr.M003657.
[23]
Valadi, H.; Ekstrom, K.; Bossios, A.; Sjostrand, M.; Lee, J.J.; Lotvall, J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell. Biol. 2007, 9, 654–659, doi:10.1038/ncb1596.
[24]
Mittelbrunn, M.; Gutierrez-Vazquez, C.; Villarroya-Beltri, C.; Gonzalez, S.; Sanchez-Cabo, F.; Gonzalez, M.A.; Bernad, A.; Sanchez-Madrid, F. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2011, 2, 282, doi:10.1038/ncomms1285.
[25]
Pegtel, D.M.; Cosmopoulos, K.; Thorley-Lawson, D.A.; van Eijndhoven, M.A.; Hopmans, E.S.; Lindenberg, J.L.; de Gruijl, T.D.; Wurdinger, T.; Middeldorp, J.M. Functional delivery of viral miRNAs via exosomes. Proc. Natl. Acad. Sci. USA 2010, 107, 6328–6333.
[26]
Guescini, M.; Genedani, S.; Stocchi, V.; Agnati, L.F. Astrocytes and Glioblastoma cells release exosomes carrying mtDNA. J. Neural. Transm. 2010, 117, 1–4, doi:10.1007/s00702-009-0288-8.
[27]
Guescini, M.; Guidolin, D.; Vallorani, L.; Casadei, L.; Gioacchini, A.M.; Tibollo, P.; Battistelli, M.; Falcieri, E.; Battistin, L.; Agnati, L.F.; Stocchi, V. C2C12 myoblasts release micro-vesicles containing mtDNA and proteins involved in signal transduction. Exp. Cell. Res. 2010, 316, 1977–1984, doi:10.1016/j.yexcr.2010.04.006.
[28]
Futter, C.E.; Pearse, A.; Hewlett, L.J.; Hopkins, C.R. Multivesicular endosomes containing internalized EGF-EGF receptor complexes mature and then fuse directly with lysosomes. J. Cell. Biol. 1996, 132, 1011–1023, doi:10.1083/jcb.132.6.1011.
[29]
Mullock, B.M.; Bright, N.A.; Fearon, C.W.; Gray, S.R.; Luzio, J.P. Fusion of lysosomes with late endosomes produces a hybrid organelle of intermediate density and is NSF dependent. J. Cell. Biol 1998, 140, 591–601, doi:10.1083/jcb.140.3.591.
[30]
Ceresa, B.P.; Schmid, S.L. Regulation of signal transduction by endocytosis. Curr. Opin. Cell. Biol. 2000, 12, 204–210, doi:10.1016/S0955-0674(99)00077-0.
Raiborg, C.; Rusten, T.E.; Stenmark, H. Protein sorting into multivesicular endosomes. Curr. Opin. Cell Biol. 2003, 15, 446–455, doi:10.1016/S0955-0674(03)00080-2.
[34]
Thery, C.; Boussac, M.; Veron, P.; Ricciardi-Castagnoli, P.; Raposo, G.; Garin, J.; Amigorena, S. Proteomic analysis of dendritic cell-derived exosomes: A secreted subcellular compartment distinct from apoptotic vesicles. J. Immunol. 2001, 166, 7309–7318.
[35]
Tamai, K.; Tanaka, N.; Nakano, T.; Kakazu, E.; Kondo, Y.; Inoue, J.; Shiina, M.; Fukushima, K.; Hoshino, T.; Sano, K.; Ueno, Y.; Shimosegawa, T.; Sugamura, K. Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein. Biochem. Biophys Res. Commun. 2010, 399, 384–390, doi:10.1016/j.bbrc.2010.07.083.
[36]
Buschow, S.I.; Nolte-'t Hoen, E.N.; van Niel, G.; Pols, M.S.; ten Broeke, T.; Lauwen, M.; Ossendorp, F.; Melief, C.J.; Raposo, G.; Wubbolts, R.; Wauben, M.H.; Stoorvogel, W. MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 2009, 10, 1528–1542, doi:10.1111/j.1600-0854.2009.00963.x.
[37]
Theos, A.C.; Truschel, S.T.; Tenza, D.; Hurbain, I.; Harper, D.C.; Berson, J.F.; Thomas, P.C.; Raposo, G.; Marks, M.S. A lumenal domain-dependent pathway for sorting to intralumenal vesicles of multivesicular endosomes involved in organelle morphogenesis. Dev. Cell. 2006, 10, 343–354, doi:10.1016/j.devcel.2006.01.012.
[38]
Bianco, F.; Perrotta, C.; Novellino, L.; Francolini, M.; Riganti, L.; Menna, E.; Saglietti, L.; Schuchman, E.H.; Furlan, R.; Clementi, E.; Matteoli, M.; Verderio, C. Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J. 2009, 28, 1043–1054, doi:10.1038/emboj.2009.45.
[39]
Kosaka, N.; Iguchi, H.; Yoshioka, Y.; Takeshita, F.; Matsuki, Y.; Ochiya, T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J. Biol. Chem. 2010, 285, 17442–17452.
[40]
Fang, Y.; Wu, N.; Gan, X.; Yan, W.; Morrell, J.C.; Gould, S.J. Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol. 2007, 5, e158, doi:10.1371/journal.pbio.0050158.
[41]
Vidal, M.; Mangeat, P.; Hoekstra, D. Aggregation reroutes molecules from a recycling to a vesicle-mediated secretion pathway during reticulocyte maturation. J. Cell. Sci. 1997, 110, 1867–1877.
[42]
Muntasell, A.; Berger, A.C.; Roche, P.A. T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes. EMBO J. 2007, 26, 4263–4272, doi:10.1038/sj.emboj.7601842.
[43]
Savina, A.; Furlan, M.; Vidal, M.; Colombo, M.I. Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J. Biol. Chem. 2003, 278, 20083–20090.
[44]
Faure, J.; Lachenal, G.; Court, M.; Hirrlinger, J.; Chatellard-Causse, C.; Blot, B.; Grange, J.; Schoehn, G.; Goldberg, Y.; Boyer, V.; Kirchhoff, F.; Raposo, G.; Garin, J.; Sadoul, R. Exosomes are released by cultured cortical neurones. Mol. Cell. Neurosci. 2006, 31, 642–648, doi:10.1016/j.mcn.2005.12.003.
[45]
Kramer-Albers, E.M.; Bretz, N.; Tenzer, S.; Winterstein, C.; Mobius, W.; Berger, H.; Nave, K.A.; Schild, H.; Trotter, J. Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: Trophic support for axons? Proteomics Clin. Appl. 2007, 1, 1446–1461, doi:10.1002/prca.200700522.
[46]
Lachenal, G.; Pernet-Gallay, K.; Chivet, M.; Hemming, F.J.; Belly, A.; Bodon, G.; Blot, B.; Haase, G.; Goldberg, Y.; Sadoul, R. Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol. Cell. Neurosci 2011, 46, 409–418, doi:10.1016/j.mcn.2010.11.004.
[47]
Skokos, D.; Botros, H.G.; Demeure, C.; Morin, J.; Peronet, R.; Birkenmeier, G.; Boudaly, S.; Mecheri, S. Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J. Immunol. 2003, 170, 3037–3045.
[48]
Skokos, D.; Goubran-Botros, H.; Roa, M.; Mecheri, S. Immunoregulatory properties of mast cell-derived exosomes. Mol. Immunol. 2002, 38, 1359–1362, doi:10.1016/S0161-5890(02)00088-3.
[49]
Blanchard, N.; Lankar, D.; Faure, F.; Regnault, A.; Dumont, C.; Raposo, G.; Hivroz, C. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J. Immunol. 2002, 168, 3235–3241.
Savina, A.; Fader, C.M.; Damiani, M.T.; Colombo, M.I. Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner. Traffic 2005, 6, 131–143, doi:10.1111/j.1600-0854.2004.00257.x.
[52]
Loomis, R.J.; Holmes, D.A.; Elms, A.; Solski, P.A.; Der, C.J.; Su, L. Citron kinase, a RhoA effector, enhances HIV-1 virion production by modulating exocytosis. Traffic 2006, 7, 1643–1653, doi:10.1111/j.1600-0854.2006.00503.x.
[53]
Ostrowski, M.; Carmo, N.B.; Krumeich, S.; Fanget, I.; Raposo, G.; Savina, A.; Moita, C.F.; Schauer, K.; Hume, A.N.; Freitas, R.P.; Goud, B.; Benaroch, P.; Hacohen, N.; Fukuda, M.; Desnos, C.; Seabra, M.C.; Darchen, F.; Amigorena, S.; Moita, L.F.; Thery, C. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell. Biol. 2010, 12, 11–13,19–30.
[54]
Hsu, C.; Morohashi, Y.; Yoshimura, S.; Manrique-Hoyos, N.; Jung, S.; Lauterbach, M.A.; Bakhti, M.; Gronborg, M.; Mobius, W.; Rhee, J.; Barr, F.A.; Simons, M. Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J. Cell. Biol. 2010, 189, 223–232, doi:10.1083/jcb.200911018.
[55]
Laulagnier, K.; Vincent-Schneider, H.; Hamdi, S.; Subra, C.; Lankar, D.; Record, M. Characterization of exosome subpopulations from RBL-2H3 cells using fluorescent lipids. Blood Cells Mol. Dis. 2005, 35, 116–121.
[56]
Laulagnier, K.; Grand, D.; Dujardin, A.; Hamdi, S.; Vincent-Schneider, H.; Lankar, D.; Salles, J.P.; Bonnerot, C.; Perret, B.; Record, M. PLD2 is enriched on exosomes and its activity is correlated to the release of exosomes. FEBS Lett. 2004, 572, 11–14, doi:10.1016/j.febslet.2004.06.082.
[57]
Alonso, R.; Mazzeo, C.; Rodriguez, M.C.; Marsh, M.; Fraile-Ramos, A.; Calvo, V.; Avila-Flores, A.; Merida, I.; Izquierdo, M. Diacylglycerol kinase alpha regulates the formation and polarisation of mature multivesicular bodies involved in the secretion of Fas ligand-containing exosomes in T lymphocytes. Cell. Death Differ. 2011, 18, 1161–1173, doi:10.1038/cdd.2010.184.
[58]
Chaineau, M.; Danglot, L.; Galli, T. Multiple roles of the vesicular-SNARE TI-VAMP in post-Golgi and endosomal trafficking. FEBS Lett. 2009, 583, 3817–3826, doi:10.1016/j.febslet.2009.10.026.
[59]
Fader, C.M.; Sanchez, D.G.; Mestre, M.B.; Colombo, M.I. TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochim. Biophys Acta 2009, 1793, 1901–1916, doi:10.1016/j.bbamcr.2009.09.011.
[60]
Yu, X.; Harris, S.L.; Levine, A.J. The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res. 2006, 66, 4795–4801, doi:10.1158/0008-5472.CAN-05-4579.
[61]
Lespagnol, A.; Duflaut, D.; Beekman, C.; Blanc, L.; Fiucci, G.; Marine, J.C.; Vidal, M.; Amson, R.; Telerman, A. Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell. Death Differ. 2008, 15, 1723–1733, doi:10.1038/cdd.2008.104.
[62]
Amzallag, N.; Passer, B.J.; Allanic, D.; Segura, E.; Thery, C.; Goud, B.; Amson, R.; Telerman, A. TSAP6 facilitates the secretion of translationally controlled tumor protein/histamine-releasing factor via a nonclassical pathway. J. Biol. Chem. 2004, 279, 46104–46112.
[63]
Segura, E.; Guerin, C.; Hogg, N.; Amigorena, S.; Thery, C. CD8+ dendritic cells use LFA-1 to capture MHC-peptide complexes from exosomes in vivo. J. Immunol. 2007, 179, 1489–1496.
[64]
Nolte-'t Hoen, E.N.; Buschow, S.I.; Anderton, S.M.; Stoorvogel, W.; Wauben, M.H. Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood 2009, 113, 1977–1981, doi:10.1182/blood-2008-08-174094.
Feng, D.; Zhao, W.L.; Ye, Y.Y.; Bai, X.C.; Liu, R.Q.; Chang, L.F.; Zhou, Q.; Sui, S.F. Cellular internalization of exosomes occurs through phagocytosis. Traffic 2010, 11, 675–687, doi:10.1111/j.1600-0854.2010.01041.x.
[67]
Stoeck, A.; Keller, S.; Riedle, S.; Sanderson, M.P.; Runz, S.; Le Naour, F.; Gutwein, P.; Ludwig, A.; Rubinstein, E.; Altevogt, P. A role for exosomes in the constitutive and stimulus-induced ectodomain cleavage of L1 and CD44. Biochem. J. 2006, 393, 609–618, doi:10.1042/BJ20051013.
[68]
Hakulinen, J.; Junnikkala, S.; Sorsa, T.; Meri, S. Complement inhibitor membrane cofactor protein (MCP; CD46) is constitutively shed from cancer cell membranes in vesicles and converted by a metalloproteinase to a functionally active soluble form. Eur J. Immunol. 2004, 34, 2620–2629, doi:10.1002/eji.200424969.
[69]
Hawari, F.I.; Rouhani, F.N.; Cui, X.; Yu, Z.X.; Buckley, C.; Kaler, M.; Levine, S.J. 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 2004, 101, 1297–1302.
[70]
Skog, J.; Wurdinger, T.; van Rijn, S.; Meijer, D.H.; Gainche, L.; Sena-Esteves, M.; Curry, W.T., Jr.; Carter, B.S.; Krichevsky, A.M.; Breakefield, X.O. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell. Biol. 2008, 10, 1470–1476, doi:10.1038/ncb1800.
[71]
Fitzner, D.; Schnaars, M.; van Rossum, D.; Krishnamoorthy, G.; Dibaj, P.; Bakhti, M.; Regen, T.; Hanisch, U.K.; Simons, M. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J. Cell. Sci. 2011, 124, 447–458, doi:10.1242/jcs.074088.
[72]
Admyre, C.; Johansson, S.M.; Paulie, S.; Gabrielsson, S. Direct exosome stimulation of peripheral human T cells detected by ELISPOT. Eur. J. Immunol. 2006, 36, 1772–1781, doi:10.1002/eji.200535615.
[73]
Thery, C.; Duban, L.; Segura, E.; Veron, P.; Lantz, O.; Amigorena, S. Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nat. Immunol. 2002, 3, 1156–1162, doi:10.1038/ni854.
[74]
Segura, E.; Nicco, C.; Lombard, B.; Veron, P.; Raposo, G.; Batteux, F.; Amigorena, S.; Thery, C. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood 2005, 106, 216–223, doi:10.1182/blood-2005-01-0220.
[75]
Montecalvo, A.; Shufesky, W.J.; Stolz, D.B.; Sullivan, M.G.; Wang, Z.; Divito, S.J.; Papworth, G.D.; Watkins, S.C.; Robbins, P.D.; Larregina, A.T.; Morelli, A.E. Exosomes as a short-range mechanism to spread alloantigen between dendritic cells during T cell allorecognition. J. Immunol. 2008, 180, 3081–3090.
[76]
Qazi, K.R.; Gehrmann, U.; Domange Jordo, E.; Karlsson, M.C.; Gabrielsson, S. Antigen-loaded exosomes alone induce Th1-type memory through a B-cell-dependent mechanism. Blood 2009, 113, 2673–2683, doi:10.1182/blood-2008-04-153536.
[77]
Bhatnagar, S.; Schorey, J.S. Exosomes released from infected macrophages contain Mycobacterium avium glycopeptidolipids and are proinflammatory. J. Biol. Chem. 2007, 282, 25779–25789, doi:10.1074/jbc.M702277200.
[78]
Walker, J.D.; Maier, C.L.; Pober, J.S. Cytomegalovirus-infected human endothelial cells can stimulate allogeneic CD4+ memory T cells by releasing antigenic exosomes. J. Immunol. 2009, 182, 1548–1559.
[79]
Wolfers, J.; Lozier, A.; Raposo, G.; Regnault, A.; Thery, C.; Masurier, C.; Flament, C.; Pouzieux, S.; Faure, F.; Tursz, T.; Angevin, E.; Amigorena, S.; Zitvogel, L. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat. Med. 2001, 7, 297–303.
[80]
Dai, S.; Wan, T.; Wang, B.; Zhou, X.; Xiu, F.; Chen, T.; Wu, Y.; Cao, X. 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. 2005, 11, 7554–7563, doi:10.1158/1078-0432.CCR-05-0810.
[81]
Dai, S.; Zhou, X.; Wang, B.; Wang, Q.; Fu, Y.; Chen, T.; Wan, T.; Yu, Y.; Cao, X. Enhanced induction of dendritic cell maturation and HLA-A*0201-restricted CEA-specific CD8(+) CTL response by exosomes derived from IL-18 gene-modified CEA-positive tumor cells. J. Mol. Med. (Berl) 2006, 84, 1067–1076.
[82]
Andreola, G.; Rivoltini, L.; Castelli, C.; Huber, V.; Perego, P.; Deho, P.; Squarcina, P.; Accornero, P.; Lozupone, F.; Lugini, L.; Stringaro, A.; Molinari, A.; Arancia, G.; Gentile, M.; Parmiani, G.; Fais, S. Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J. Exp. Med. 2002, 195, 1303–1316.
[83]
Taylor, D.D.; Gercel-Taylor, C.; Lyons, K.S.; Stanson, J.; Whiteside, T.L. T-cell apoptosis and suppression of T-cell receptor/CD3-zeta by Fas ligand-containing membrane vesicles shed from ovarian tumors. Clin. Cancer Res. 2003, 9, 5113–5119.
[84]
Huber, V.; Fais, S.; Iero, M.; Lugini, L.; Canese, P.; Squarcina, P.; Zaccheddu, A.; Colone, M.; Arancia, G.; Gentile, M.; Seregni, E.; Valenti, R.; Ballabio, G.; Belli, F.; Leo, E.; Parmiani, G.; Rivoltini, L. Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: Role in immune escape. Gastroenterology 2005, 128, 1796–1804, doi:10.1053/j.gastro.2005.03.045.
[85]
Clayton, A.; Mitchell, J.P.; Court, J.; Mason, M.D.; Tabi, Z. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res. 2007, 67, 7458–7466, doi:10.1158/0008-5472.CAN-06-3456.
[86]
Clayton, A.; Mitchell, J.P.; Court, J.; Linnane, S.; Mason, M.D.; Tabi, Z. Human tumor-derived exosomes down-modulate NKG2D expression. J. Immunol. 2008, 180, 7249–7258.
[87]
Liu, C.; Yu, S.; Zinn, K.; Wang, J.; Zhang, L.; Jia, Y.; Kappes, J.C.; Barnes, S.; Kimberly, R.P.; Grizzle, W.E.; Zhang, H.G. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J. Immunol. 2006, 176, 1375–1385.
[88]
Szajnik, M.; Czystowska, M.; Szczepanski, M.J.; Mandapathil, M.; Whiteside, T.L. Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS One 2010, 5, e11469.
[89]
Valenti, R.; Huber, V.; Filipazzi, P.; Pilla, L.; Sovena, G.; Villa, A.; Corbelli, A.; Fais, S.; Parmiani, G.; Rivoltini, L. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res. 2006, 66, 9290–9298, doi:10.1158/0008-5472.CAN-06-1819.
[90]
Taylor, D.D.; Akyol, S.; Gercel-Taylor, C. Pregnancy-associated exosomes and their modulation of T cell signaling. J. Immunol. 2006, 176, 1534–1542.
Demory Beckler, M.; Higginbotham, J.N.; Franklin, J.L.; Ham, A.J.; Halvey, P.J.; Imasuen, I.E.; Whitwell, C.; Li, M.; Liebler, D.C.; Coffey, R.J. Proteomic Analysis of Exosomes from Mutant KRAS Colon Cancer Cells Identifies Intercellular Transfer of Mutant KRAS. Mol. Cell. Proteomics 2013, 12, 343–355, doi:10.1074/mcp.M112.022806.
[95]
Hong, B.S.; Cho, J.H.; Kim, H.; Choi, E.J.; Rho, S.; Kim, J.; Kim, J.H.; Choi, D.S.; Kim, Y.K.; Hwang, D.; Gho, Y.S. Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells. BMC Genomics 2009, 10, 556.
[96]
Yang, M.; Chen, J.; Su, F.; Yu, B.; Lin, L.; Liu, Y.; Huang, J.D.; Song, E. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol. Cancer 2011, 10, 117.
[97]
Garcia, E.; Pion, M.; Pelchen-Matthews, A.; Collinson, L.; Arrighi, J.F.; Blot, G.; Leuba, F.; Escola, J.M.; Demaurex, N.; Marsh, M.; Piguet, V. HIV-1 trafficking to the dendritic cell-T-cell infectious synapse uses a pathway of tetraspanin sorting to the immunological synapse. Traffic 2005, 6, 488–501, doi:10.1111/j.1600-0854.2005.00293.x.
[98]
Wiley, R.D.; Gummuluru, S. Immature dendritic cell-derived exosomes can mediate HIV-1 trans infection. Proc. Natl. Acad. Sci. USA 2006, 103, 738–743, doi:10.1073/pnas.0507995103.
[99]
Izquierdo-Useros, N.; Naranjo-Gomez, M.; Archer, J.; Hatch, S.C.; Erkizia, I.; Blanco, J.; Borras, F.E.; Puertas, M.C.; Connor, J.H.; Fernandez-Figueras, M.T.; Moore, L.; Clotet, B.; Gummuluru, S.; Martinez-Picado, J. Capture and transfer of HIV-1 particles by mature dendritic cells converges with the exosome-dissemination pathway. Blood 2009, 113, 2732–2741, doi:10.1182/blood-2008-05-158642.
[100]
Von Bartheld, C.S.; Altick, A.L. Multivesicular bodies in neurons: Distribution, protein content, and trafficking functions. Prog. Neurobiol. 2011, 93, 313–340, doi:10.1016/j.pneurobio.2011.01.003.
[101]
Kraev, I.V.; Godukhin, O.V.; Patrushev, I.V.; Davies, H.A.; Popov, V.I.; Stewart, M.G. Partial kindling induces neurogenesis, activates astrocytes and alters synaptic morphology in the dentate gyrus of freely moving adult rats. Neuroscience 2009, 162, 254–267, doi:10.1016/j.neuroscience.2009.05.020.
[102]
Fevrier, B.; Vilette, D.; Archer, F.; Loew, D.; Faigle, W.; Vidal, M.; Laude, H.; Raposo, G. Cells release prions in association with exosomes. Proc. Natl. Acad. Sci. USA 2004, 101, 9683–9688.
[103]
Vella, L.J.; Sharples, R.A.; Lawson, V.A.; Masters, C.L.; Cappai, R.; Hill, A.F. Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J. Pathol. 2007, 211, 582–590, doi:10.1002/path.2145.
[104]
Alvarez-Erviti, L.; Couch, Y.; Richardson, J.; Cooper, J.M.; Wood, M.J. Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line. Neurosci. Res. 2011, 69, 337–342, doi:10.1016/j.neures.2010.12.020.
[105]
Emmanouilidou, E.; Melachroinou, K.; Roumeliotis, T.; Garbis, S.D.; Ntzouni, M.; Margaritis, L.H.; Stefanis, L.; Vekrellis, K. Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J. Neurosci. 2010, 30, 6838–6851, doi:10.1523/JNEUROSCI.5699-09.2010.
[106]
Rajendran, L.; Honsho, M.; Zahn, T.R.; Keller, P.; Geiger, K.D.; Verkade, P.; Simons, K. Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc. Natl. Acad. Sci. USA 2006, 103, 11172–11177.
[107]
Sharples, R.A.; Vella, L.J.; Nisbet, R.M.; Naylor, R.; Perez, K.; Barnham, K.J.; Masters, C.L.; Hill, A.F. Inhibition of gamma-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes. FASEB J. 2008, 22, 1469–1478.
[108]
Vingtdeux, V.; Hamdane, M.; Loyens, A.; Gele, P.; Drobeck, H.; Begard, S.; Galas, M.C.; Delacourte, A.; Beauvillain, J.C.; Buee, L.; Sergeant, N. Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies. J. Biol. Chem. 2007, 282, 18197–18205, doi:10.1074/jbc.M609475200.
[109]
Ghidoni, R.; Paterlini, A.; Albertini, V.; Glionna, M.; Monti, E.; Schiaffonati, L.; Benussi, L.; Levy, E.; Binetti, G. Cystatin C is released in association with exosomes: A new tool of neuronal communication which is unbalanced in Alzheimer's disease. Neurobiol. Aging 2011, 32, 1435–1442, doi:10.1016/j.neurobiolaging.2009.08.013.
