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Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review

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Abstract

Trafficking of biological material across membranes is an evolutionary conserved mechanism and is part of any normal cell homeostasis. Such transport is composed of active, passive, export through microparticles, and vesicular transport (exosomes) that collectively maintain proper compartmentalization of important micro- and macromolecules. In pathological states, such as cancer, aberrant activity of the export machinery results in expulsion of a number of key proteins and microRNAs resulting in their misexpression. Exosome-mediated expulsion of intracellular drugs could be another barrier in the proper action of most of the commonly used therapeutics, targeted agents, and their intracellular metabolites. Over the last decade, a number of studies have revealed that exosomes cross-talk and/or influence major tumor-related pathways, such as hypoxia-driven epithelial-to-mesenchymal transition, cancer stemness, angiogenesis, and metastasis involving many cell types within the tumor microenvironment. Emerging evidence suggests that exosome-secreted proteins can also propel fibroblast growth, resulting in desmoplastic reaction, a major barrier in effective cancer drug delivery. This comprehensive review highlights the advancements in the understanding of the biology of exosomes secretions and the consequence on cancer drug resistance. We propose that the successful combination of cancer treatments to tackle exosome-mediated drug resistance requires an interdisciplinary understanding of these cellular exclusion mechanisms, and how secreted biomolecules are involved in cellular cross-talk within the tumor microenvironment.

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Reference

  1. Kitano, H. (2004). Cancer as a robust system: implications for anticancer therapy. Nature Reviews Cancer, 4, 227–235.

    PubMed  CAS  Google Scholar 

  2. Kitano, H. (2003). Cancer robustness: tumour tactics. Nature, 426, 125.

    PubMed  CAS  Google Scholar 

  3. Miyawaki, A. (2011). Proteins on the move: insights gained from fluorescent protein technologies. Nature Reviews Molecular Cell Biology, 12, 656–668.

    PubMed  CAS  Google Scholar 

  4. Sugano, K., Kansy, M., Artursson, P., Avdeef, A., Bendels, S., Di, L., et al. (2010). Coexistence of passive and carrier-mediated processes in drug transport. Nature Reviews Drug Discovery, 9, 597–614.

    PubMed  CAS  Google Scholar 

  5. El, A. S., Mager, I., Breakefield, X. O., & Wood, M. J. (2013). Extracellular vesicles: biology and emerging therapeutic opportunities. Nature Reviews Drug Discovery, 12, 347–357.

    Google Scholar 

  6. Staals, R. H., & Pruijn, G. J. (2010). The human exosome and disease. Advances in Experimental Medicine and Biology, 702, 132–142.

    PubMed  Google Scholar 

  7. Schorey, J. S., & Bhatnagar, S. (2008). Exosome function: from tumor immunology to pathogen biology. Traffic, 9, 871–881.

    PubMed  CAS  Google Scholar 

  8. Vlassov, A. V., Magdaleno, S., Setterquist, R., & Conrad, R. (2012). Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochimica et Biophysica Acta, 1820, 940–948.

    PubMed  CAS  Google Scholar 

  9. Vinciguerra, P., & Stutz, F. (2004). mRNA export: an assembly line from genes to nuclear pores. Current Opinion in Cell Biology, 16, 285–292.

    PubMed  CAS  Google Scholar 

  10. Fevrier, B., Vilette, D., Laude, H., & Raposo, G. (2005). Exosomes: a bubble ride for prions? Traffic, 6, 10–17.

    PubMed  CAS  Google Scholar 

  11. Gibbings, D. J., Ciaudo, C., Erhardt, M., & Voinnet, O. (2009). Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nature Cell Biology, 11, 1143–1149.

    PubMed  CAS  Google Scholar 

  12. Finkelstein, A. (1964). Carrier model for active transport of ions across a mosaic membrane. Biophysical Journal, 4, 421–440.

    PubMed  CAS  Google Scholar 

  13. Diekmann, Y., & Pereira-Leal, J. B. (2013). Evolution of intracellular compartmentalization. The Biochemical Journal, 449, 319–331.

    PubMed  CAS  Google Scholar 

  14. Wright, E. M., Hirayama, B., Hazama, A., Loo, D. D., Supplisson, S., Turk, E., et al. (1993). The sodium/glucose cotransporter (SGLT1). Society of General Physiologists Series, 48, 229–241.

    PubMed  CAS  Google Scholar 

  15. Grunwald, D., Singer, R. H., & Rout, M. (2011). Nuclear export dynamics of RNA-protein complexes. Nature, 475, 333–341.

    PubMed  Google Scholar 

  16. Kim, J., Izadyar, A., Nioradze, N., & Amemiya, S. (2013). Nanoscale mechanism of molecular transport through the nuclear pore complex as studied by scanning electrochemical microscopy. Journal of the American Chemical Society, 135, 2321–2329.

    PubMed  CAS  Google Scholar 

  17. Albertini, M., Pemberton, L. F., Rosenblum, J. S., & Blobel, G. (1998). A novel nuclear import pathway for the transcription factor TFIIS. The Journal of Cell Biology, 143, 1447–1455.

    PubMed  CAS  Google Scholar 

  18. Rosenblum, J. S., Pemberton, L. F., Bonifaci, N., & Blobel, G. (1998). Nuclear import and the evolution of a multifunctional RNA-binding protein. The Journal of Cell Biology, 143, 887–899.

    PubMed  CAS  Google Scholar 

  19. Pemberton, L. F., Blobel, G., & Rosenblum, J. S. (1998). Transport routes through the nuclear pore complex. Current Opinion in Cell Biology, 10, 392–399.

    PubMed  CAS  Google Scholar 

  20. Rosenblum, J. S., Pemberton, L. F., & Blobel, G. (1997). A nuclear import pathway for a protein involved in tRNA maturation. The Journal of Cell Biology, 139, 1655–1661.

    PubMed  CAS  Google Scholar 

  21. Lee, S. J., Jiko, C., Yamashita, E., & Tsukihara, T. (2011). Selective nuclear export mechanism of small RNAs. Current Opinion in Structural Biology, 21, 101–108.

    PubMed  Google Scholar 

  22. Adam, S. A., Lobl, T. J., Mitchell, M. A., & Gerace, L. (1989). Identification of specific binding proteins for a nuclear location sequence. Nature, 337, 276–279.

    PubMed  CAS  Google Scholar 

  23. Wen, W., Meinkoth, J. L., Tsien, R. Y., & Taylor, S. S. (1995). Identification of a signal for rapid export of proteins from the nucleus. Cell, 82, 463–473.

    PubMed  CAS  Google Scholar 

  24. Denzer, K., Kleijmeer, M. J., Heijnen, H. F., Stoorvogel, W., & Geuze, H. J. (2000). Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. Journal of Cell Science, 113(Pt 19), 3365–3374.

    PubMed  CAS  Google Scholar 

  25. Trams, E. G., Lauter, C. J., Salem, N., Jr., & Heine, U. (1981). Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochimica et Biophysica Acta, 645, 63–70.

    PubMed  CAS  Google Scholar 

  26. van den Boorn, J. G., Dassler, J., Coch, C., Schlee, M., & Hartmann, G. (2013). Exosomes as nucleic acid nanocarriers. Advanced Drug Delivery Reviews, 65, 331–335.

    PubMed  Google Scholar 

  27. Batista, B. S., Eng, W. S., Pilobello, K. T., Hendricks-Munoz, K. D., & Mahal, L. K. (2011). Identification of a conserved glycan signature for microvesicles. Journal of Proteome Research, 10, 4624–4633.

    PubMed  CAS  Google Scholar 

  28. Caby, M. P., Lankar, D., Vincendeau-Scherrer, C., Raposo, G., & Bonnerot, C. (2005). Exosomal-like vesicles are present in human blood plasma. International Immunology, 17, 879–887.

    PubMed  CAS  Google Scholar 

  29. Almqvist, N., Lonnqvist, A., Hultkrantz, S., Rask, C., & Telemo, E. (2008). Serum-derived exosomes from antigen-fed mice prevent allergic sensitization in a model of allergic asthma. Immunology, 125, 21–27.

    PubMed  CAS  Google Scholar 

  30. Chen, C. Y., Hogan, M. C., & Ward, C. J. (2013). Purification of exosome-like vesicles from urine. Methods in Enzymology, 524, 225–241.

    PubMed  CAS  Google Scholar 

  31. Keller, S., Sanderson, M. P., Stoeck, A., & Altevogt, P. (2006). Exosomes: from biogenesis and secretion to biological function. Immunology Letters, 107, 102–108.

    PubMed  CAS  Google Scholar 

  32. Bhatnagar, S., & Schorey, J. S. (2007). Exosomes released from infected macrophages contain Mycobacterium avium glycopeptidolipids and are proinflammatory. The Journal of Biological Chemistry, 282, 25779–25789.

    PubMed  CAS  Google Scholar 

  33. Bhatnagar, S., Shinagawa, K., Castellino, F. J., & Schorey, J. S. (2007). Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood, 110, 3234–3244.

    PubMed  CAS  Google Scholar 

  34. Lee, Y., El, A. S., & Wood, M. J. (2012). Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Human Molecular Genetics, 21, R125–R134.

    PubMed  CAS  Google Scholar 

  35. Fevrier, B., & Raposo, G. (2004). Exosomes: endosomal-derived vesicles shipping extracellular messages. Current Opinion in Cell Biology, 16, 415–421.

    PubMed  CAS  Google Scholar 

  36. Cocucci, E., Racchetti, G., Podini, P., & Meldolesi, J. (2007). Enlargeosome traffic: exocytosis triggered by various signals is followed by endocytosis, membrane shedding or both. Traffic, 8, 742–757.

    PubMed  CAS  Google Scholar 

  37. Cocucci, E., Racchetti, G., Rupnik, M., & Meldolesi, J. (2008). The regulated exocytosis of enlargeosomes is mediated by a SNARE machinery that includes VAMP4. Journal of Cell Science, 121, 2983–2991.

    PubMed  CAS  Google Scholar 

  38. Cocucci, E., & Meldolesi, J. (2011). Ectosomes. Current Biology, 21, R940–R941.

    PubMed  CAS  Google Scholar 

  39. Sudhof, T. C. (2004). The synaptic vesicle cycle. Annual Review of Neuroscience, 27, 509–547.

    PubMed  Google Scholar 

  40. Sudhof, T. C., & Rothman, J. E. (2009). Membrane fusion: grappling with SNARE and SM proteins. Science, 323, 474–477.

    PubMed  Google Scholar 

  41. Ostrowski, M., Carmo, N. B., Krumeich, S., Fanget, I., Raposo, G., Savina, A., et al. (2010). Rab27a and Rab27b control different steps of the exosome secretion pathway. Nature Cell Biology, 12, 19–30.

    PubMed  CAS  Google Scholar 

  42. Bobrie, A., Krumeich, S., Reyal, F., Recchi, C., Moita, L. F., Seabra, M. C., et al. (2012). Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Research, 72, 4920–4930.

    PubMed  CAS  Google Scholar 

  43. Hsu, C., Morohashi, Y., Yoshimura, S., Manrique-Hoyos, N., Jung, S., Lauterbach, M. A., et al. (2010). Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. The Journal of Cell Biology, 189, 223–232.

    PubMed  CAS  Google Scholar 

  44. Trajkovic, K., Hsu, C., Chiantia, S., Rajendran, L., Wenzel, D., Wieland, F., et al. (2008). Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science, 319, 1244–1247.

    PubMed  CAS  Google Scholar 

  45. Parolini, I., Federici, C., Raggi, C., Lugini, L., Palleschi, S., De, M. A., et al. (2009). Microenvironmental pH is a key factor for exosome traffic in tumor cells. The Journal of Biological Chemistry, 284, 34211–34222.

    PubMed  CAS  Google Scholar 

  46. Shen, B., Fang, Y., Wu, N., & Gould, S. J. (2011). Biogenesis of the posterior pole is mediated by the exosome/microvesicle protein-sorting pathway. The Journal of Biological Chemistry, 286, 44162–44176.

    PubMed  CAS  Google Scholar 

  47. Poliakov, A., Spilman, M., Dokland, T., Amling, C. L., & Mobley, J. A. (2009). Structural heterogeneity and protein composition of exosome-like vesicles (prostasomes) in human semen. The Prostate, 69, 159–167.

    PubMed  Google Scholar 

  48. Simons, M., & Raposo, G. (2009). Exosomes–vesicular carriers for intercellular communication. Current Opinion in Cell Biology, 21, 575–581.

    PubMed  CAS  Google Scholar 

  49. Mathivanan, S., Ji, H., & Simpson, R. J. (2010). Exosomes: extracellular organelles important in intercellular communication. Journal of Proteomics, 73, 1907–1920.

    PubMed  CAS  Google Scholar 

  50. Simpson, R. J., Lim, J. W., Moritz, R. L., & Mathivanan, S. (2009). Exosomes: proteomic insights and diagnostic potential. Expert Review of Proteomics, 6, 267–283.

    PubMed  CAS  Google Scholar 

  51. Gross, J.C., Boutros, M. (2013). Secretion and extracellular space travel of Wnt proteins. Current Opinion in Genetics & Development (in press)

  52. Gross, J. C., Chaudhary, V., Bartscherer, K., & Boutros, M. (2012). Active Wnt proteins are secreted on exosomes. Nature Cell Biology, 14, 1036–1045.

    PubMed  CAS  Google Scholar 

  53. Sheldon, H., Heikamp, E., Turley, H., Dragovic, R., Thomas, P., Oon, C. E., et al. (2010). New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. Blood, 116, 2385–2394.

    PubMed  CAS  Google Scholar 

  54. Hasegawa, H., Thomas, H. J., Schooley, K., & Born, T. L. (2011). Native IL-32 is released from intestinal epithelial cells via a non-classical secretory pathway as a membrane-associated protein. Cytokine, 53, 74–83.

    PubMed  CAS  Google Scholar 

  55. Vidal, M., Sainte-Marie, J., Philippot, J. R., & Bienvenue, A. (1989). Asymmetric distribution of phospholipids in the membrane of vesicles released during in vitro maturation of guinea pig reticulocytes: evidence precluding a role for "aminophospholipid translocase". Journal of Cellular Physiology, 140, 455–462.

    PubMed  CAS  Google Scholar 

  56. Subra, C., Laulagnier, K., Perret, B., & Record, M. (2007). Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie, 89, 205–212.

    PubMed  CAS  Google Scholar 

  57. Beloribi, S., Ristorcelli, E., Breuzard, G., Silvy, F., Bertrand-Michel, J., Beraud, E., et al. (2012). Exosomal lipids impact notch signaling and induce death of human pancreatic tumoral SOJ-6 cells. PloS One, 7, e47480.

    PubMed  CAS  Google Scholar 

  58. Laulagnier, K., Motta, C., Hamdi, S., Roy, S., Fauvelle, F., Pageaux, J. F., et al. (2004). Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. The Biochemical Journal, 380, 161–171.

    PubMed  CAS  Google Scholar 

  59. Yuyama, K., Sun, H., Mitsutake, S., & Igarashi, Y. (2012). Sphingolipid-modulated exosome secretion promotes clearance of amyloid-beta by microglia. The Journal of Biological Chemistry, 287, 10977–10989.

    PubMed  CAS  Google Scholar 

  60. Record, M., Subra, C., Silvente-Poirot, S., & Poirot, M. (2011). Exosomes as intercellular signalosomes and pharmacological effectors. Biochemical Pharmacology, 81, 1171–1182.

    PubMed  CAS  Google Scholar 

  61. Subra, C., Grand, D., Laulagnier, K., Stella, A., Lambeau, G., Paillasse, M., et al. (2010). Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. Journal of Lipid Research, 51, 2105–2120.

    PubMed  CAS  Google Scholar 

  62. Corrado, C., Raimondo, S., Chiesi, A., Ciccia, F., De, L. G., & Alessandro, R. (2013). Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications. International Journal of Molecular Sciences, 14, 5338–5366.

    PubMed  CAS  Google Scholar 

  63. Mathivanan, S., Fahner, C. J., Reid, G. E., & Simpson, R. J. (2012). ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Research, 40, D1241–D1244.

    PubMed  CAS  Google Scholar 

  64. Mathivanan, S., & Simpson, R. J. (2009). ExoCarta: a compendium of exosomal proteins and RNA. Proteomics, 9, 4997–5000.

    PubMed  CAS  Google Scholar 

  65. Geminard, C., De, G. A., & Vidal, M. (2002). Reticulocyte maturation: mitoptosis and exosome release. Biocell, 26, 205–215.

    PubMed  CAS  Google Scholar 

  66. Robertson, C., Booth, S. A., Beniac, D. R., Coulthart, M. B., Booth, T. F., & McNicol, A. (2006). Cellular prion protein is released on exosomes from activated platelets. Blood, 107, 3907–3911.

    PubMed  CAS  Google Scholar 

  67. Quah, B., & O'Neill, H. C. (2000). Review: the application of dendritic cell-derived exosomes in tumour immunotherapy. Cancer Biotherapy and Radiopharmaceuticals, 15, 185–194.

    PubMed  CAS  Google Scholar 

  68. Lasser, C., Eldh, M., Lotvall, J. (2012). Isolation and characterization of RNA-containing exosomes. Journal of Visualized Experiments (59):e3037.

  69. Gogolak, P., Rethi, B., Hajas, G., & Rajnavolgyi, E. (2003). Targeting dendritic cells for priming cellular immune responses. Journal of Molecular Recognition, 16, 299–317.

    PubMed  CAS  Google Scholar 

  70. Gyorgy, B., Szabo, T. G., Pasztoi, M., Pal, Z., Misjak, P., Aradi, B., et al. (2011). Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cellular and Molecular Life Sciences, 68, 2667–2688.

    PubMed  CAS  Google Scholar 

  71. Vickers, K. C., & Remaley, A. T. (2012). Lipid-based carriers of microRNAs and intercellular communication. Current Opinion in Lipidology, 23, 91–97.

    PubMed  CAS  Google Scholar 

  72. Jaiswal, R., Luk, F., Gong, J., Mathys, J. M., Grau, G. E., & Bebawy, M. (2012). Microparticle conferred microRNA profiles—implications in the transfer and dominance of cancer traits. Molecular Cancer, 11, 37.

    PubMed  CAS  Google Scholar 

  73. Gong, J., Jaiswal, R., Mathys, J. M., Combes, V., Grau, G. E., & Bebawy, M. (2012). Microparticles and their emerging role in cancer multidrug resistance. Cancer Treatment Reviews, 38, 226–234.

    PubMed  CAS  Google Scholar 

  74. Gonzalez-Begne, M., Lu, B., Han, X., Hagen, F. K., Hand, A. R., Melvin, J. E., et al. (2009). Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). Journal of Proteome Research, 8, 1304–1314.

    PubMed  CAS  Google Scholar 

  75. Akerfelt, M., Morimoto, R. I., & Sistonen, L. (2010). Heat shock factors: integrators of cell stress, development and lifespan. Nature Reviews Molecular Cell Biology, 11, 545–555.

    PubMed  CAS  Google Scholar 

  76. Akerfelt, M., Trouillet, D., Mezger, V., & Sistonen, L. (2007). Heat shock factors at a crossroad between stress and development. Annals of the New York Academy of Sciences, 1113, 15–27.

    PubMed  CAS  Google Scholar 

  77. De, M. A. (1999). Heat shock proteins: facts, thoughts, and dreams. Shock, 11, 1–12.

    Google Scholar 

  78. Bolhassani, A., & Rafati, S. (2013). Mini-chaperones: potential immuno-stimulators in vaccine design. Human Vaccines & Immunotherapeutics, 9, 153–161.

    CAS  Google Scholar 

  79. Bolhassani, A., & Rafati, S. (2008). Heat-shock proteins as powerful weapons in vaccine development. Expert Review of Vaccines, 7, 1185–1199.

    PubMed  CAS  Google Scholar 

  80. Mathew, A., Bell, A., & Johnstone, R. M. (1995). Hsp-70 is closely associated with the transferrin receptor in exosomes from maturing reticulocytes. The Biochemical Journal, 308(Pt 3), 823–830.

    PubMed  CAS  Google Scholar 

  81. Lancaster, G. I., & Febbraio, M. A. (2005). Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. The Journal of Biological Chemistry, 280, 23349–23355.

    PubMed  CAS  Google Scholar 

  82. Clayton, A., Turkes, A., Navabi, H., Mason, M. D., & Tabi, Z. (2005). Induction of heat shock proteins in B-cell exosomes. Journal of Cell Science, 118, 3631–3638.

    PubMed  CAS  Google Scholar 

  83. Lv, L. H., Wan, Y. L., Lin, Y., Zhang, W., Yang, M., Li, G. L., et al. (2012). Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in vitro. The Journal of Biological Chemistry, 287, 15874–15885.

    PubMed  CAS  Google Scholar 

  84. Cho, J. A., Lee, Y. S., Kim, S. H., Ko, J. K., & Kim, C. W. (2009). MHC independent anti-tumor immune responses induced by Hsp70-enriched exosomes generate tumor regression in murine models. Cancer Letters, 275, 256–265.

    PubMed  CAS  Google Scholar 

  85. Mukhopadhyay, U. K., & Mak, A. S. (2009). p53: is the guardian of the genome also a suppressor of cell invasion? Cell Cycle, 8, 2481.

    PubMed  CAS  Google Scholar 

  86. Muller, P. A., & Vousden, K. H. (2013). p53 mutations in cancer. Nature Cell Biology, 15, 2–8.

    PubMed  CAS  Google Scholar 

  87. Wade, M., Li, Y. C., & Wahl, G. M. (2013). MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nature Reviews. Cancer, 13, 83–96.

    PubMed  CAS  Google Scholar 

  88. Azmi, A. S. (2011). Pharmaceutical reactivation of p53 pathways in cancer. Current Pharmaceutical Design, 17, 534–535.

    PubMed  CAS  Google Scholar 

  89. Yu, X., Harris, S. L., & Levine, A. J. (2006). The regulation of exosome secretion: a novel function of the p53 protein. Cancer Research, 66, 4795–4801.

    PubMed  CAS  Google Scholar 

  90. Yu, X., Riley, T., & Levine, A. J. (2009). The regulation of the endosomal compartment by p53 the tumor suppressor gene. The FEBS Journal, 276, 2201–2212.

    PubMed  CAS  Google Scholar 

  91. Lespagnol, A., Duflaut, D., Beekman, C., Blanc, L., Fiucci, G., Marine, J. C., et al. (2008). Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell Death and Differentiation, 15, 1723–1733.

    PubMed  CAS  Google Scholar 

  92. Honegger, A., Leitz, J., Bulkescher, J., Hoppe-Seyler, K., Hoppe-Seyler, F. (2013). Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and amounts of extracellular microvesicles released from HPV-positive cancer cells. International Journal of Cancer (in press)

  93. Hupalowska, A., & Miaczynska, M. (2012). The new faces of endocytosis in signaling. Traffic, 13, 9–18.

    PubMed  CAS  Google Scholar 

  94. Song, M. S., Salmena, L., & Pandolfi, P. P. (2012). The functions and regulation of the PTEN tumour suppressor. Nature Reviews Molecular Cell Biology, 13, 283–296.

    PubMed  CAS  Google Scholar 

  95. Wrighton, K. H. (2011). Tumour suppressors: role of nuclear PTEN revealed. Nature Reviews. Cancer, 11, 154.

    PubMed  CAS  Google Scholar 

  96. Vanhaesebroeck, B., Stephens, L., & Hawkins, P. (2012). PI3K signalling: the path to discovery and understanding. Nature Reviews Molecular Cell Biology, 13, 195–203.

    PubMed  CAS  Google Scholar 

  97. Putz, U., Howitt, J., Doan, A., Goh, C. P., Low, L. H., Silke, J., et al. (2012). The tumor suppressor PTEN is exported in exosomes and has phosphatase activity in recipient cells. Science Signaling, 5, ra70.

    PubMed  Google Scholar 

  98. Leslie, N. R. (2012). PTEN: an intercellular peacekeeper? Science Signaling, 5, e50.

    Google Scholar 

  99. Ristorcelli, E., Beraud, E., Mathieu, S., Lombardo, D., & Verine, A. (2009). Essential role of Notch signaling in apoptosis of human pancreatic tumoral cells mediated by exosomal nanoparticles. International Journal of Cancer, 125, 1016–1026.

    CAS  Google Scholar 

  100. Cho, K. R., & Vogelstein, B. (1992). Suppressor gene alterations in the colorectal adenoma-carcinoma sequence. Journal of Cellular Biochemistry. Supplement, 16G, 137–141.

    PubMed  CAS  Google Scholar 

  101. Aust, D. E., Terdiman, J. P., Willenbucher, R. F., Chang, C. G., Molinaro-Clark, A., Baretton, G. B., et al. (2002). The APC/beta-catenin pathway in ulcerative colitis-related colorectal carcinomas: a mutational analysis. Cancer, 94, 1421–1427.

    PubMed  CAS  Google Scholar 

  102. Lim, J. W., Mathias, R. A., Kapp, E. A., Layton, M. J., Faux, M. C., Burgess, A. W., et al. (2012). Restoration of full-length APC protein in SW480 colon cancer cells induces exosome-mediated secretion of DKK-4. Electrophoresis, 33, 1873–1880.

    PubMed  CAS  Google Scholar 

  103. Seton-Rogers, S. (2013). Microenvironment: making connections. Nature Reviews. Cancer, 13, 222–223.

    CAS  Google Scholar 

  104. He, L., & Hannon, G. J. (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nature Reviews Genetics, 5, 522–531.

    PubMed  CAS  Google Scholar 

  105. Mitchell, P. S., Parkin, R. K., Kroh, E. M., Fritz, B. R., Wyman, S. K., Pogosova-Agadjanyan, E. L., et al. (2008). Circulating microRNAs as stable blood-based markers for cancer detection. Proceedings of the National Academy of Sciences of the United States of America, 105, 10513–10518.

    PubMed  CAS  Google Scholar 

  106. Cortez, M. A., Bueso-Ramos, C., Ferdin, J., Lopez-Berestein, G., Sood, A. K., & Calin, G. A. (2011). MicroRNAs in body fluids—the mix of hormones and biomarkers. Nature Reviews. Clinical Oncology, 8, 467–477.

    PubMed  CAS  Google Scholar 

  107. Lund, E., Guttinger, S., Calado, A., Dahlberg, J. E., & Kutay, U. (2004). Nuclear export of microRNA precursors. Science, 303, 95–98.

    PubMed  CAS  Google Scholar 

  108. Stoorvogel, W. (2012). Functional transfer of microRNA by exosomes. Blood, 119, 646–648.

    PubMed  CAS  Google Scholar 

  109. Gallo, A., Tandon, M., Alevizos, I., & Illei, G. G. (2012). The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PloS One, 7, e30679.

    PubMed  CAS  Google Scholar 

  110. Russo, F., Di, B. S., Nigita, G., Macca, V., Lagana, A., Giugno, R., et al. (2012). miRandola: extracellular circulating microRNAs database. PloS One, 7, e47786.

    PubMed  CAS  Google Scholar 

  111. Boon, R. A., & Vickers, K. C. (2013). Intercellular transport of microRNAs. Arteriosclerosis, Thrombosis, and Vascular Biology, 33, 186–192.

    PubMed  CAS  Google Scholar 

  112. Valadi, H., Ekstrom, K., Bossios, A., Sjostrand, M., Lee, J. J., & Lotvall, J. O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology, 9, 654–659.

    PubMed  CAS  Google Scholar 

  113. Lotvall, J., & Valadi, H. (2007). Cell to cell signalling via exosomes through esRNA. Cell Adhesion & Migration, 1, 156–158.

    Google Scholar 

  114. Koga, Y., Yasunaga, M., Moriya, Y., Akasu, T., Fujita, S., Yamamoto, S., et al. (2011). Exosome can prevent RNase from degrading microRNA in feces. Journal of Gastrointestinal Oncology, 2, 215–222.

    PubMed  CAS  Google Scholar 

  115. Chen, T. S., Lai, R. C., Lee, M. M., Choo, A. B., Lee, C. N., & Lim, S. K. (2010). Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Research, 38, 215–224.

    PubMed  CAS  Google Scholar 

  116. Flynt, A. S., Greimann, J. C., Chung, W. J., Lima, C. D., & Lai, E. C. (2010). MicroRNA biogenesis via splicing and exosome-mediated trimming in Drosophila. Molecular Cell, 38, 900–907.

    PubMed  CAS  Google Scholar 

  117. Rabinowits, G., Gercel-Taylor, C., Day, J. M., Taylor, D. D., & Kloecker, G. H. (2009). Exosomal microRNA: a diagnostic marker for lung cancer. Clinical Lung Cancer, 10, 42–46.

    PubMed  CAS  Google Scholar 

  118. Mizoguchi, M., Guan, Y., Yoshimoto, K., Hata, N., Amano, T., Nakamizo, A., et al. (2013). Clinical implications of microRNAs in human glioblastoma. Frontiers in Oncology, 3, 19.

    PubMed  CAS  Google Scholar 

  119. Tanaka, Y., Kamohara, H., Kinoshita, K., Kurashige, J., Ishimoto, T., Iwatsuki, M., et al. (2013). Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer, 119, 1159–1167.

    PubMed  CAS  Google Scholar 

  120. Hessvik, N. P., Sandvig, K., & Llorente, A. (2013). Exosomal miRNAs as biomarkers for prostate cancer. Frontiers in Genetics, 4, 36.

    PubMed  CAS  Google Scholar 

  121. Hessvik, N. P., Phuyal, S., Brech, A., Sandvig, K., & Llorente, A. (2012). Profiling of microRNAs in exosomes released from PC-3 prostate cancer cells. Biochimica et Biophysica Acta, 1819, 1154–1163.

    PubMed  CAS  Google Scholar 

  122. da Silveira, J. C., Veeramachaneni, D. N., Winger, Q. A., Carnevale, E. M., & Bouma, G. J. (2012). Cell-secreted vesicles in equine ovarian follicular fluid contain miRNAs and proteins: a possible new form of cell communication within the ovarian follicle. Biology of Reproduction, 86, 71.

    PubMed  Google Scholar 

  123. Lasser, C. (2012). Exosomal RNA as biomarkers and the therapeutic potential of exosome vectors. Expert Opinion on Biological Therapy, 12(Suppl 1), S189–S197.

    PubMed  Google Scholar 

  124. Tauro, B. J., Greening, D. W., Mathias, R. A., Ji, H., Mathivanan, S., Scott, A. M., 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, 293–304.

    PubMed  CAS  Google Scholar 

  125. Alvarez, M. L., Khosroheidari, M., Kanchi, R. R., & DiStefano, J. K. (2012). Comparison of protein, microRNA, and mRNA yields using different methods of urinary exosome isolation for the discovery of kidney disease biomarkers. Kidney International, 82, 1024–1032.

    PubMed  CAS  Google Scholar 

  126. Umezu, T., Ohyashiki, K., Kuroda, M., Ohyashiki, J.H. (2013) Leukemia cell to endothelial cell communication via exosomal miRNAs. Oncogene (in press)

  127. Bobrie, A., Colombo, M., Raposo, G., & Thery, C. (2011). Exosome secretion: molecular mechanisms and roles in immune responses. Traffic, 12, 1659–1668.

    PubMed  CAS  Google Scholar 

  128. Pegtel, D. M., van de Garde, M. D. B., & Middeldorp, J. M. (2011). Viral miRNAs exploiting the endosomal-exosomal pathway for intercellular cross-talk and immune evasion. Biochimica et Biophysica Acta, 1809, 715–721.

    PubMed  CAS  Google Scholar 

  129. Palma, J., Yaddanapudi, S. C., Pigati, L., Havens, M. A., Jeong, S., Weiner, G. A., et al. (2012). MicroRNAs are exported from malignant cells in customized particles. Nucleic Acids Research, 40, 9125–9138.

    PubMed  CAS  Google Scholar 

  130. Yang, M., Chen, J., Su, F., Yu, B., Su, F., Lin, L., et al. (2011). Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Molecular Cancer, 10, 117.

    PubMed  CAS  Google Scholar 

  131. Bullerdiek, J., & Flor, I. (2012). Exosome-delivered microRNAs of "chromosome 19 microRNA cluster" as immunomodulators in pregnancy and tumorigenesis. Molecular Cytogenetics, 5, 27.

    PubMed  CAS  Google Scholar 

  132. Meads, M. B., Gatenby, R. A., & Dalton, W. S. (2009). Environment-mediated drug resistance: a major contributor to minimal residual disease. Nature Reviews. Cancer, 9, 665–674.

    PubMed  CAS  Google Scholar 

  133. Shain, K. H., Landowski, T. H., & Dalton, W. S. (2000). The tumor microenvironment as a determinant of cancer cell survival: a possible mechanism for de novo drug resistance. Current Opinion in Oncology, 12, 557–563.

    PubMed  CAS  Google Scholar 

  134. Li, H., Yang, B.B. (2013). Friend or foe: the role of microRNA in chemotherapy resistance. Acta Pharmacologica Sinica (in press)

  135. Holzel, M., Bovier, A., & Tuting, T. (2013). Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nature Reviews. Cancer, 13, 365–376.

    PubMed  Google Scholar 

  136. McMillin, D. W., Negri, J. M., & Mitsiades, C. S. (2013). The role of tumour-stromal interactions in modifying drug response: challenges and opportunities. Nature Reviews Drug Discovery, 12, 217–228.

    PubMed  CAS  Google Scholar 

  137. Khan, S., Aspe, J. R., Asumen, M. G., Almaguel, F., Odumosu, O., cevedo-Martinez, S., et al. (2009). Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential. British Journal of Cancer, 100, 1073–1086.

    PubMed  CAS  Google Scholar 

  138. Pilzer, D., Gasser, O., Moskovich, O., Schifferli, J. A., & Fishelson, Z. (2005). Emission of membrane vesicles: roles in complement resistance, immunity and cancer. Springer Seminars in Immunopathology, 27, 375–387.

    PubMed  CAS  Google Scholar 

  139. Pilzer, D., & Fishelson, Z. (2005). Mortalin/GRP75 promotes release of membrane vesicles from immune attacked cells and protection from complement-mediated lysis. International Immunology, 17, 1239–1248.

    PubMed  CAS  Google Scholar 

  140. Zhang, H. G., Liu, C., Su, K., Yu, S., Zhang, L., Zhang, S., et al. (2006). A membrane form of TNF-alpha presented by exosomes delays T cell activation-induced cell death. The Journal of Immunology, 176, 7385–7393.

    PubMed  CAS  Google Scholar 

  141. Bodey, B., Bodey, B., Jr., & Kaiser, H. E. (1997). Dendritic type, accessory cells within the mammalian thymic microenvironment. Antigen presentation in the dendritic neuro-endocrine-immune cellular network. In Vivo, 11, 351–370.

    PubMed  CAS  Google Scholar 

  142. Aung, T., Chapuy, B., Vogel, D., Wenzel, D., Oppermann, M., Lahmann, M., et al. (2011). Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3. Proceedings of the National Academy of Sciences of the United States of America, 108, 15336–15341.

    PubMed  CAS  Google Scholar 

  143. Hupfeld, T., Chapuy, B., Schrader, V., Beutler, M., Veltkamp, C., Koch, R., et al. (2013). Tyrosinekinase inhibition facilitates cooperation of transcription factor SALL4 and ABC transporter A3 towards intrinsic CML cell drug resistance. British Journal of Haematology, 161, 204–213.

    PubMed  CAS  Google Scholar 

  144. Safaei, R., Larson, B. J., Cheng, T. C., Gibson, M. A., Otani, S., Naerdemann, W., et al. (2005). Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Molecular Cancer Therapeutics, 4, 1595–1604.

    PubMed  CAS  Google Scholar 

  145. Yin, J., Yan, X., Yao, X., Zhang, Y., Shan, Y., Mao, N., et al. (2012). Secretion of annexin A3 from ovarian cancer cells and its association with platinum resistance in ovarian cancer patients. Journal of Cellular and Molecular Medicine, 16, 337–348.

    PubMed  CAS  Google Scholar 

  146. Ciravolo, V., Huber, V., Ghedini, G. C., Venturelli, E., Bianchi, F., Campiglio, M., et al. (2012). Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. Journal of Cellular Physiology, 227, 658–667.

    PubMed  CAS  Google Scholar 

  147. Hosseini-Beheshti, E., Pham, S., Adomat, H., Li, N., & Tomlinson Guns, E. S. (2012). Exosomes as biomarker enriched microvesicles: characterization of exosomal proteins derived from a panel of prostate cell lines with distinct AR phenotypes. Molecular & Cellular Proteomics, 11, 863–885.

    CAS  Google Scholar 

  148. Bard, M. P., Hegmans, J. P., Hemmes, A., Luider, T. M., Willemsen, R., Severijnen, L. A., et al. (2004). Proteomic analysis of exosomes isolated from human malignant pleural effusions. American Journal of Respiratory Cell and Molecular Biology, 31, 114–121.

    PubMed  CAS  Google Scholar 

  149. Hegmans, J. P., Bard, M. P., Hemmes, A., Luider, T. M., Kleijmeer, M. J., Prins, J. B., et al. (2004). Proteomic analysis of exosomes secreted by human mesothelioma cells. The American Journal of Pathology, 164, 1807–1815.

    PubMed  CAS  Google Scholar 

  150. Mears, R., Craven, R. A., Hanrahan, S., Totty, N., Upton, C., Young, S. L., et al. (2004). Proteomic analysis of melanoma-derived exosomes by two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. Proteomics, 4, 4019–4031.

    PubMed  CAS  Google Scholar 

  151. Nguyen, D. X., Bos, P. D., & Massague, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nature Reviews. Cancer, 9, 274–284.

    PubMed  CAS  Google Scholar 

  152. Nguyen, D. X., & Massague, J. (2007). Genetic determinants of cancer metastasis. Nature Reviews Genetics, 8, 341–352.

    PubMed  CAS  Google Scholar 

  153. Grange, C., Tapparo, M., Collino, F., Vitillo, L., Damasco, C., Deregibus, M. C., et al. (2011). Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Research, 71, 5346–5356.

    PubMed  CAS  Google Scholar 

  154. Hood, J. L., Pan, H., Lanza, G. M., & Wickline, S. A. (2009). Paracrine induction of endothelium by tumor exosomes. Laboratory Investigation, 89, 1317–1328.

    PubMed  Google Scholar 

  155. Hood, J. L., San, R. S., & Wickline, S. A. (2011). Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Research, 71, 3792–3801.

    PubMed  CAS  Google Scholar 

  156. Rana, S., Malinowska, K., & Zoller, M. (2013). Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia, 15, 281–295.

    PubMed  CAS  Google Scholar 

  157. Di, V. D., Morello, M., Dudley, A. C., Schow, P. W., Adam, R. M., Morley, S., et al. (2012). Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. The American Journal of Pathology, 181, 1573–1584.

    Google Scholar 

  158. Bao, B., Azmi, A. S., Ali, S., Ahmad, A., Li, Y., Banerjee, S., et al. (2012). The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness. Biochimica et Biophysica Acta, 1826, 272–296.

    PubMed  CAS  Google Scholar 

  159. Casazza, A., Di, C. G., Wenes, M., Finisguerra, V., Deschoemaeker, S., and Mazzone, M. (2013) Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene.

  160. Salnikov, A. V., Liu, L., Platen, M., Gladkich, J., Salnikova, O., Ryschich, E., et al. (2012). Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential. PloS One, 7, e46391.

    PubMed  CAS  Google Scholar 

  161. Chaturvedi, P., Gilkes, D. M., Wong, C. C., Luo, W., Zhang, H., Wei, H., et al. (2013). Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. The Journal of Clinical Investigation, 123, 189–205.

    PubMed  CAS  Google Scholar 

  162. Wilson, W. R., & Hay, M. P. (2011). Targeting hypoxia in cancer therapy. Nature Reviews. Cancer, 11, 393–410.

    PubMed  CAS  Google Scholar 

  163. Rapisarda, A., & Melillo, G. (2012). Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nature Reviews. Clinical Oncology, 9, 378–390.

    PubMed  CAS  Google Scholar 

  164. King, H. W., Michael, M. Z., & Gleadle, J. M. (2012). Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer, 12, 421.

    PubMed  CAS  Google Scholar 

  165. Kucharzewska, P., Christianson, H.C., Welch, J.E., Svensson, K.J., Fredlund, E., Ringner, M., et al. (2013) Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proceedings of the National Academy of Sciences of the United States of America (in press)

  166. Borges, F. T., Melo, S. A., Ozdemir, B. C., Kato, N., Revuelta, I., Miller, C. A., et al. (2013). TGF-beta1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. Journal of the American Society of Nephrology, 24, 385–392.

    PubMed  CAS  Google Scholar 

  167. Park, J. E., Tan, H. S., Datta, A., Lai, R. C., Zhang, H., Meng, W., et al. (2010). Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Molecular & Cellular Proteomics, 9, 1085–1099.

    CAS  Google Scholar 

  168. Svensson, K. J., Kucharzewska, P., Christianson, H. C., Skold, S., Lofstedt, T., Johansson, M. C., et al. (2011). Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells. Proceedings of the National Academy of Sciences of the United States of America, 108, 13147–13152.

    PubMed  CAS  Google Scholar 

  169. Svensson, K. J., & Belting, M. (2013). Role of extracellular membrane vesicles in intercellular communication of the tumour microenvironment. Biochemical Society Transactions, 41, 273–276.

    PubMed  CAS  Google Scholar 

  170. Thiery, J. P., & Sleeman, J. P. (2006). Complex networks orchestrate epithelial-mesenchymal transitions. Nature Reviews Molecular Cell Biology, 7, 131–142.

    PubMed  CAS  Google Scholar 

  171. Thiery, J. P. (2002). Epithelial-mesenchymal transitions in tumour progression. Nature Reviews. Cancer, 2, 442–454.

    PubMed  CAS  Google Scholar 

  172. Masuda, S., & Izpisua Belmonte, J. C. (2013). The microenvironment and resistance to personalized cancer therapy. Nature Reviews. Clinical Oncology, 10.

  173. Garnier, D., Magnus, N., Lee, T. H., Bentley, V., Meehan, B., Milsom, C., et al. (2012). Cancer cells induced to express mesenchymal phenotype release exosome-like extracellular vesicles carrying tissue factor. The Journal of Biological Chemistry, 287, 43565–43572.

    PubMed  CAS  Google Scholar 

  174. Roccaro, A.M., Sacco, A., Maiso, P., Azab, A.K., Tai, Y.T., Reagan, M., et al. (2013) BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. Journal of Clinical Investigation (in press)

  175. Katsuno, Y., Lamouille, S., & Derynck, R. (2013). TGF-beta signaling and epithelial-mesenchymal transition in cancer progression. Current Opinion in Oncology, 25, 76–84.

    PubMed  CAS  Google Scholar 

  176. Xu, J., Lamouille, S., & Derynck, R. (2009). TGF-beta-induced epithelial to mesenchymal transition. Cell Research, 19, 156–172.

    PubMed  CAS  Google Scholar 

  177. Lamouille, S., Connolly, E., Smyth, J. W., Akhurst, R. J., & Derynck, R. (2012). TGF-beta-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. Journal of Cell Science, 125, 1259–1273.

    PubMed  CAS  Google Scholar 

  178. Cho, J. A., Park, H., Lim, E. H., & Lee, K. W. (2012). Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. International Journal of Oncology, 40, 130–138.

    PubMed  CAS  Google Scholar 

  179. Clayton, A., Mitchell, J. P., Court, J., Mason, M. D., & Tabi, Z. (2007). Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Research, 67, 7458–7466.

    PubMed  CAS  Google Scholar 

  180. Cheng, C. F., Fan, J., Fedesco, M., Guan, S., Li, Y., Bandyopadhyay, B., et al. (2008). Transforming growth factor alpha (TGFalpha)-stimulated secretion of HSP90alpha: using the receptor LRP-1/CD91 to promote human skin cell migration against a TGFbeta-rich environment during wound healing. Molecular and Cellular Biology, 28, 3344–3358.

    PubMed  CAS  Google Scholar 

  181. Clayton, A., Mitchell, J. P., Court, J., Linnane, S., Mason, M. D., & Tabi, Z. (2008). Human tumor-derived exosomes down-modulate NKG2D expression. The Journal of Immunology, 180, 7249–7258.

    PubMed  CAS  Google Scholar 

  182. Cho, J. A., Park, H., Lim, E. H., Kim, K. H., Choi, J. S., Lee, J. H., et al. (2011). Exosomes from ovarian cancer cells induce adipose tissue-derived mesenchymal stem cells to acquire the physical and functional characteristics of tumor-supporting myofibroblasts. Gynecologic Oncology, 123, 379–386.

    PubMed  CAS  Google Scholar 

  183. Klaus, A., & Birchmeier, W. (2008). Wnt signalling and its impact on development and cancer. Nature Reviews. Cancer, 8, 387–398.

    PubMed  CAS  Google Scholar 

  184. Anastas, J. N., & Moon, R. T. (2013). WNT signalling pathways as therapeutic targets in cancer. Nature Reviews. Cancer, 13, 11–26.

    PubMed  CAS  Google Scholar 

  185. Haegel, H., Larue, L., Ohsugi, M., Fedorov, L., Herrenknecht, K., & Kemler, R. (1995). Lack of beta-catenin affects mouse development at gastrulation. Development (Cambridge, England), 121, 3529–3537.

    CAS  Google Scholar 

  186. Morin, P. J. (1999). beta-catenin signaling and cancer. BioEssays, 21, 1021–1030.

    PubMed  CAS  Google Scholar 

  187. Korkut, C., Ataman, B., Ramachandran, P., Ashley, J., Barria, R., Gherbesi, N., et al. (2009). Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless. Cell, 139, 393–404.

    PubMed  CAS  Google Scholar 

  188. Koles, K., Nunnari, J., Korkut, C., Barria, R., Brewer, C., Li, Y., et al. (2012). Mechanism of evenness interrupted (Evi)-exosome release at synaptic boutons. The Journal of Biological Chemistry, 287, 16820–16834.

    PubMed  CAS  Google Scholar 

  189. Chairoungdua, A., Smith, D. L., Pochard, P., Hull, M., & Caplan, M. J. (2010). Exosome release of beta-catenin: a novel mechanism that antagonizes Wnt signaling. The Journal of Cell Biology, 190, 1079–1091.

    PubMed  CAS  Google Scholar 

  190. Li, D., Ren, Y. N., Yang, J., Yang, Y. M., Li, C. Y., Xie, R. F., et al. (2011). A preliminary study on the influence of human plasma exosomes-like vesicles on macrophage Wnt5A-Ca(2)+ pathway. Zhonghua Xue Ye Xue Za Zhi, 32, 404–407.

    PubMed  CAS  Google Scholar 

  191. Hooper, C., Sainz-Fuertes, R., Lynham, S., Hye, A., Killick, R., Warley, A., et al. (2012). Wnt3a induces exosome secretion from primary cultured rat microglia. BMC Neuroscience, 13, 144.

    PubMed  CAS  Google Scholar 

  192. Luga, V., Zhang, L., Viloria-Petit, A. M., Ogunjimi, A. A., Inanlou, M. R., Chiu, E., et al. (2012). Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell, 151, 1542–1556.

    PubMed  CAS  Google Scholar 

  193. Stumpf, W. E. (2005). Drug localization and targeting with receptor microscopic autoradiography. Journal of Pharmacological and Toxicological Methods, 51, 25–40.

    PubMed  CAS  Google Scholar 

  194. Jones, P. M., & George, A. M. (2004). The ABC transporter structure and mechanism: perspectives on recent research. Cellular and Molecular Life Sciences, 61, 682–699.

    PubMed  CAS  Google Scholar 

  195. Lee, C. H. (2010). Reversing agents for ATP-binding cassette drug transporters. Methods in Molecular Biology, 596, 325–340.

    PubMed  CAS  Google Scholar 

  196. Corcoran, C., Rani, S., O'Brien, K., O'Neill, A., Prencipe, M., Sheikh, R., et al. (2012). Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PloS One, 7, e50999.

    PubMed  CAS  Google Scholar 

  197. Shedden, K., Xie, X. T., Chandaroy, P., Chang, Y. T., & Rosania, G. R. (2003). Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profiles. Cancer Research, 63, 4331–4337.

    PubMed  CAS  Google Scholar 

  198. Kooijmans, S. A., Vader, P., van Dommelen, S. M., van Solinge, W. W., & Schiffelers, R. M. (2012). Exosome mimetics: a novel class of drug delivery systems. International Journal of Nanomedicine, 7, 1525–1541.

    PubMed  CAS  Google Scholar 

  199. Harding, C. V., Heuser, J. E., & Stahl, P. D. (2013). Exosomes: looking back three decades and into the future. The Journal of Cell Biology, 200, 367–371.

    PubMed  CAS  Google Scholar 

  200. Zitvogel, L., Regnault, A., Lozier, A., Wolfers, J., Flament, C., Tenza, D., et al. (1998). Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nature Medicine, 4, 594–600.

    PubMed  CAS  Google Scholar 

  201. Zitvogel, L., Fernandez, N., Lozier, A., Wolfers, J., Regnault, A., Raposo, G., et al. (1999). Dendritic cells or their exosomes are effective biotherapies of cancer. European Journal of Cancer, 35(Suppl 3), S36–S38.

    PubMed  CAS  Google Scholar 

  202. Thery, C., Regnault, A., Garin, J., Wolfers, J., Zitvogel, L., Ricciardi-Castagnoli, P., et al. (1999). Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. The Journal of Cell Biology, 147, 599–610.

    PubMed  CAS  Google Scholar 

  203. Wolfers, J., Lozier, A., Raposo, G., Regnault, A., Thery, C., Masurier, C., et al. (2001). Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nature Medicine, 7, 297–303.

    PubMed  CAS  Google Scholar 

  204. Lamparski, H. G., Metha-Damani, A., Yao, J. Y., Patel, S., Hsu, D. H., Ruegg, C., et al. (2002). Production and characterization of clinical grade exosomes derived from dendritic cells. Journal of Immunological Methods, 270, 211–226.

    PubMed  CAS  Google Scholar 

  205. Chaput, N., Schartz, N. E., Andre, F., Taieb, J., Novault, S., Bonnaventure, P., et al. (2004). Exosomes as potent cell-free peptide-based vaccine. II. Exosomes in CpG adjuvants efficiently prime naive Tc1 lymphocytes leading to tumor rejection. The Journal of Immunology, 172, 2137–2146.

    PubMed  CAS  Google Scholar 

  206. Taieb, J., Chaput, N., Schartz, N., Roux, S., Novault, S., Menard, C., et al. (2006). Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines. The Journal of Immunology, 176, 2722–2729.

    PubMed  CAS  Google Scholar 

  207. Tian, X., Zhu, M., & Nie, G. (2013). How can nanotechnology help membrane vesicle-based cancer immunotherapy development? Human Vaccines & Immunotherapeutics, 9, 222–225.

    CAS  Google Scholar 

  208. Hood, J. L., & Wickline, S. A. (2012). A systematic approach to exosome-based translational nanomedicine. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 4, 458–467.

    PubMed  CAS  Google Scholar 

  209. Sokolova, V., Ludwig, A. K., Hornung, S., Rotan, O., Horn, P. A., Epple, M., et al. (2011). Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy. Colloids and Surfaces. B, Biointerfaces, 87, 146–150.

    PubMed  CAS  Google Scholar 

  210. Marchesano, V., Hernandez, Y., Salvenmoser, W., Ambrosone, A., Tino, A., Hobmayer, B., et al. (2013). Imaging inward and outward trafficking of gold nanoparticles in whole animals. ACS Nano, 7, 2431–2442.

    PubMed  CAS  Google Scholar 

  211. Tan, A., De La, P. H., & Seifalian, A. M. (2010). The application of exosomes as a nanoscale cancer vaccine. International Journal of Nanomedicine, 5, 889–900.

    PubMed  CAS  Google Scholar 

  212. Ristorcelli, E., Beraud, E., Verrando, P., Villard, C., Lafitte, D., Sbarra, V., et al. (2008). Human tumor nanoparticles induce apoptosis of pancreatic cancer cells. The FASEB Journal, 22, 3358–3369.

    CAS  Google Scholar 

  213. Lakhal, S., & Wood, M. J. (2011). Exosome nanotechnology: an emerging paradigm shift in drug delivery: exploitation of exosome nanovesicles for systemic in vivo delivery of RNAi heralds new horizons for drug delivery across biological barriers. BioEssays, 33, 737–741.

    PubMed  CAS  Google Scholar 

  214. varez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., & Wood, M. J. (2011). Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology, 29, 341–345.

    Google Scholar 

  215. Zhu, M., Tian, X., Song, X., Li, Y., Tian, Y., Zhao, Y., et al. (2012). Nanoparticle-induced exosomes target antigen-presenting cells to initiate Th1-type immune activation. Small, 8, 2841–2848.

    PubMed  CAS  Google Scholar 

  216. Halliwell, B. (2007). Dietary polyphenols: good, bad, or indifferent for your health? Cardiovascular Research, 73, 341–347.

    PubMed  CAS  Google Scholar 

  217. Raffoul, J. J., Kucuk, O., Sarkar, F. H., & Hillman, G. G. (2012). Dietary agents in cancer chemoprevention and treatment. Journal of Oncology, 2012, 749310.

    PubMed  Google Scholar 

  218. Sarkar, F. H., & Li, Y. (2009). Harnessing the fruits of nature for the development of multi-targeted cancer therapeutics. Cancer Treatment Reviews, 35, 597–607.

    PubMed  CAS  Google Scholar 

  219. Asher, G. N., & Spelman, K. (2013). Clinical utility of curcumin extract. Alternative Therapies in Health and Medicine, 19, 20–22.

    PubMed  Google Scholar 

  220. Ahmad, I. U., Forman, J. D., Sarkar, F. H., Hillman, G. G., Heath, E., Vaishampayan, U., et al. (2010). Soy isoflavones in conjunction with radiation therapy in patients with prostate cancer. Nutrition and Cancer, 62, 996–1000.

    PubMed  CAS  Google Scholar 

  221. Heath, E. I., Heilbrun, L. K., Li, J., Vaishampayan, U., Harper, F., Pemberton, P., et al. (2010). A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3′-diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. American Journal of Translational Research, 2, 402–411.

    PubMed  CAS  Google Scholar 

  222. Ahmad, A., Sakr, W. A., & Rahman, K. M. (2012). Novel targets for detection of cancer and their modulation by chemopreventive natural compounds. Frontiers in Bioscience (Elite Edition), 4, 410–425.

    Google Scholar 

  223. Zhang, H. G., Kim, H., Liu, C., Yu, S., Wang, J., Grizzle, W. E., et al. (2007). Curcumin reverses breast tumor exosomes mediated immune suppression of NK cell tumor cytotoxicity. Biochimica et Biophysica Acta, 1773, 1116–1123.

    PubMed  CAS  Google Scholar 

  224. Zhuang, X., Xiang, X., Grizzle, W., Sun, D., Zhang, S., Axtell, R. C., et al. (2011). Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Molecular Therapy, 19, 1769–1779.

    PubMed  CAS  Google Scholar 

  225. Escudier, B., Dorval, T., Chaput, N., Andre, F., Caby, M. P., Novault, S., et al. (2005). Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial. Journal of Translational Medicine, 3, 10.

    PubMed  Google Scholar 

  226. Marleau, A. M., Chen, C. S., Joyce, J. A., & Tullis, R. H. (2012). Exosome removal as a therapeutic adjuvant in cancer. Journal of Translational Medicine, 10, 134.

    PubMed  CAS  Google Scholar 

  227. Tauro, B. J., Greening, D. W., Mathias, R. A., Mathivanan, S., Ji, H., & Simpson, R. J. (2013). Two distinct populations of exosomes are released from LIM1863 colon carcinoma cell-derived organoids. Molecular & Cellular Proteomics, 12, 587–598.

    CAS  Google Scholar 

  228. Ogawa, Y., Taketomi, Y., Murakami, M., Tsujimoto, M., & Yanoshita, R. (2013). Small RNA transcriptomes of two types of exosomes in human whole saliva determined by next generation sequencing. Biological and Pharmaceutical Bulletin, 36, 66–75.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, Wayne State University School of Medicine, 4100 John R, HWCRC 740, Detroit, MI, 48201, USA

    Asfar S. Azmi, Bin Bao & Fazlul H. Sarkar

  2. Department of Oncology, Karmanos Cancer Institute, 4100 John R, HWCRC 740, Detroit, MI, 48201, USA

    Fazlul H. Sarkar

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  1. Asfar S. Azmi
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  2. Bin Bao
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  3. Fazlul H. Sarkar
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Correspondence to Asfar S. Azmi or Fazlul H. Sarkar.

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Azmi, A.S., Bao, B. & Sarkar, F.H. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev 32, 623–642 (2013). https://doi.org/10.1007/s10555-013-9441-9

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