Exosomes: the future of biomarkers in medicine.

Exosomes are nanovesicles secreted into the extracellular environment upon internal vesicle fusion with the plasma membrane. The molecular content of exosomes is a fingerprint of the releasing cell type and of its status. For this reason, and because they are released in easily accessible body fluids such as blood and urine, they represent a precious biomedical tool. A growing body of evidence suggests that exosomes may be used as biomarkers for the diagnosis and prognosis of malignant tumors. This article focuses on the exploitation of exosomes as diagnostic tools for human tumors and discusses possible applications of the same strategies to other pathologies, such as neurodegenerative diseases.

[1]  Declan King,et al.  High Titers of Transmissible Spongiform Encephalopathy Infectivity Associated with Extremely Low Levels of PrPSc in Vivo* , 2007, Journal of Biological Chemistry.

[2]  A. Surguchov,et al.  γ-Synuclein: seeding of α-synuclein aggregation and transmission between cells. , 2012, Biochemistry.

[3]  P. Altevogt,et al.  CD24 is a marker of exosomes secreted into urine and amniotic fluid. , 2007, Kidney international.

[4]  B. Ghetti,et al.  Accumulation of prion protein in the brain that is not associated with transmissible disease , 2007, Proceedings of the National Academy of Sciences.

[5]  M. Vidal,et al.  Exosomal sorting of the cytoplasmic domain of bovine leukemia virus TM Env protein , 2009, Cell biology international.

[6]  C. Prowse,et al.  Human platelets as a substrate source for the in vitro amplification of the abnormal prion protein (PrPSc) associated with variant Creutzfeldt‐Jakob disease , 2008, Transfusion.

[7]  P. Altevogt,et al.  Systemic presence and tumor-growth promoting effect of ovarian carcinoma released exosomes. , 2009, Cancer letters.

[8]  Paul Harrison,et al.  Classification, Functions, and Clinical Relevance of Extracellular Vesicles , 2012, Pharmacological Reviews.

[9]  R. Johnstone,et al.  Exosomes biological significance: A concise review. , 2006, Blood cells, molecules & diseases.

[10]  J. Martinez-Picado,et al.  Exosomes and retroviruses: the chicken or the egg? , 2011, Cellular microbiology.

[11]  J. Sixma,et al.  Activated Platelets Release Two Types of Membrane Vesicles: Microvesicles by Surface Shedding and Exosomes Derived From Exocytosis of Multivesicular Bodies and -Granules , 1999 .

[12]  Richard J. Simpson,et al.  Proteomics Analysis of A33 Immunoaffinity-purified Exosomes Released from the Human Colon Tumor Cell Line LIM1215 Reveals a Tissue-specific Protein Signature* , 2009, Molecular & Cellular Proteomics.

[13]  B. Quah,et al.  The immunogenicity of dendritic cell-derived exosomes. , 2005, Blood cells, molecules & diseases.

[14]  K. Takata,et al.  Localization and trafficking of aquaporin 2 in the kidney , 2008, Histochemistry and Cell Biology.

[15]  L. Zitvogel,et al.  Dendritic cell-derived exosomes for cancer immunotherapy: what's next? , 2010, Cancer research.

[16]  Cicek Gercel-Taylor,et al.  MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. , 2008, Gynecologic oncology.

[17]  Alzheimer's disease beta-amyloid peptides are released in association with exosomes. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[18]  D. Ott,et al.  CD45 immunoaffinity depletion of vesicles from Jurkat T cells demonstrates that exosomes contain CD45: no evidence for a distinct exosome/HIV-1 budding pathway , 2008, Retrovirology.

[19]  Chris Gardiner,et al.  Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission , 2011, Neurobiology of Disease.

[20]  J. F. Seybolt.  Cancer detection. , 1974, Science.

[21]  Deming Zhao,et al.  Hsp70 binds to PrPC in the process of PrPC release via exosomes from THP‐1 monocytes , 2011, Cell biology international.

[22]  A. Aguzzi,et al.  Prion infections, blood and transfusions , 2006, Nature Clinical Practice Neurology.

[23]  Robert L Moritz,et al.  Exosomes: proteomic insights and diagnostic potential , 2009, Expert review of proteomics.

[24]  Y. Matsuki,et al.  Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells*♦ , 2010, The Journal of Biological Chemistry.

[25]  Markus Tolnay,et al.  The propagation of prion-like protein inclusions in neurodegenerative diseases , 2010, Trends in Neurosciences.

[26]  P. Verkade,et al.  Alzheimer's disease beta-amyloid peptides are released in association with exosomes. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[27]  N. Hunter,et al.  Prion diseases are efficiently transmitted by blood transfusion in sheep. , 2008, Blood.

[28]  H. Jono,et al.  Transmission of circulating cell-free AA amyloid oligomers in exosomes vectors via a prion-like mechanism. , 2010, Biochemical and biophysical research communications.

[29]  Trairak Pisitkun,et al.  Large-scale proteomics and phosphoproteomics of urinary exosomes. , 2009, Journal of the American Society of Nephrology : JASN.

[30]  N. Hooper,et al.  The prion protein and lipid rafts. , 2006, Molecular membrane biology.

[31]  H. Valadi,et al.  Cell to Cell Signalling via Exosomes Through esRNA , 2007, Cell adhesion & migration.

[32]  S. Mathivanan,et al.  Exosomes: extracellular organelles important in intercellular communication. , 2010, Journal of proteomics.

[33]  C. Théry,et al.  Membrane vesicles as conveyors of immune responses , 2009, Nature Reviews Immunology.

[34]  A. Booth,et al.  The Trojan exosome hypothesis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[35]  P. Altevogt,et al.  Evidence for secretion of Cu,Zn superoxide dismutase via exosomes from a cell model of amyotrophic lateral sclerosis , 2007, Neuroscience Letters.

[36]  Ari Helenius,et al.  Endosome maturation , 2011, The EMBO journal.

[37]  Rong-Fong Shen,et al.  Proteomic profiling of human plasma exosomes identifies PPARgamma as an exosome-associated protein. , 2009, Biochemical and biophysical research communications.

[38]  A. McKee,et al.  Exosome-associated Tau Is Secreted in Tauopathy Models and Is Selectively Phosphorylated in Cerebrospinal Fluid in Early Alzheimer Disease* , 2011, The Journal of Biological Chemistry.

[39]  K. Kodys,et al.  Circulating microRNAs in exosomes indicate hepatocyte injury and inflammation in alcoholic, drug‐induced, and inflammatory liver diseases , 2012, Hepatology.

[40]  P. Altevogt,et al.  Body fluid derived exosomes as a novel template for clinical diagnostics , 2011, Journal of Translational Medicine.

[41]  G. Raposo,et al.  Mouse neuroblastoma cells release prion infectivity associated with exosomal vesicles , 2008, Biology of the cell.

[42]  A. Muntasell,et al.  T cell‐induced secretion of MHC class II–peptide complexes on B cell exosomes , 2007, The EMBO journal.

[43]  A. Hill,et al.  Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells , 2012, Nucleic acids research.

[44]  T. D. de Gruijl,et al.  Functional delivery of viral miRNAs via exosomes , 2010, Proceedings of the National Academy of Sciences.

[45]  Massimo Spada,et al.  High Levels of Exosomes Expressing CD63 and Caveolin-1 in Plasma of Melanoma Patients , 2009, PloS one.

[46]  J. Collinge,et al.  Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay , 2011, The Lancet.

[47]  S. Booth,et al.  Cellular prion protein is released on exosomes from activated platelets. , 2006, Blood.

[48]  A. Winslow,et al.  Exosomal cell-to-cell transmission of alpha synuclein oligomers , 2012, Molecular Neurodegeneration.

[49]  W. Schulz-Schaeffer,et al.  Upregulation of miRNA hsa-miR-342-3p in experimental and idiopathic prion disease , 2009, Molecular Neurodegeneration.

[50]  D. Theodorescu,et al.  Isolation and identification of potential urinary microparticle biomarkers of bladder cancer. , 2008, Journal of proteome research.

[51]  M. Wood,et al.  Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes , 2011, Nature Biotechnology.

[52]  J. Collinge,et al.  Plasmacytoid Dendritic Cells Sequester High Prion Titres at Early Stages of Prion Infection , 2012, PLoS pathogens.

[53]  S. Gould,et al.  Identification of an inhibitory budding signal that blocks the release of HIV particles and exosome/microvesicle proteins , 2011, Molecular biology of the cell.

[54]  Mary Andrews,et al.  Real time quaking‐induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt–Jakob disease , 2012, Annals of neurology.

[55]  J. Rossier,et al.  Transmission of the BSE Agent to Mice in the Absence of Detectable Abnormal Prion Protein , 1997, Science.

[56]  John McAnally,et al.  MicroRNA-206 Delays ALS Progression and Promotes Regeneration of Neuromuscular Synapses in Mice , 2009, Science.

[57]  R. Star,et al.  Exosomal Fetuin-A identified by proteomics: a novel urinary biomarker for detecting acute kidney injury. , 2006, Kidney international.

[58]  J. Klein,et al.  Comparison of three methods for isolation of urinary microvesicles to identify biomarkers of nephrotic syndrome. , 2010, Kidney international.

[59]  C. Soto,et al.  Protein misfolding cyclic amplification of infectious prions , 2012, Nature Protocols.

[60]  R. Schiffelers,et al.  Microvesicles and exosomes: opportunities for cell-derived membrane vesicles in drug delivery. , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[61]  X. Breakefield,et al.  Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer , 2009, British Journal of Cancer.

[62]  Dongmei Sun,et al.  Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[63]  G. Raposo,et al.  Retrovirus infection strongly enhances scrapie infectivity release in cell culture , 2006, The EMBO journal.

[64]  Samuel A Wickline,et al.  A systematic approach to exosome-based translational nanomedicine. , 2012, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[65]  N. Bhowmick,et al.  Identification of extracellular δ‐catenin accumulation for prostate cancer detection , 2009, The Prostate.

[66]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[67]  R. Setterquist,et al.  Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. , 2012, Biochimica et biophysica acta.

[68]  Hamid Cheshmi.  Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers , 2011 .

[69]  Douglas D. Taylor,et al.  Exosomal microRNA: a diagnostic marker for lung cancer. , 2008, Clinical lung cancer.

[70]  G. Lachenal,et al.  Exosomes are released by cultured cortical neurones , 2006, Molecular and Cellular Neuroscience.

[71]  S. Booth,et al.  A miRNA Signature of Prion Induced Neurodegeneration , 2008, PloS one.

[72]  A. Gulino,et al.  MicroRNAs as biomarkers for CNS cancer and other disorders , 2010, Brain Research.

[73]  Clotilde Théry,et al.  Exosome Secretion: Molecular Mechanisms and Roles in Immune Responses , 2011, Traffic.

[74]  James Gimzewski,et al.  Nanostructural and Transcriptomic Analyses of Human Saliva Derived Exosomes , 2010, PloS one.

[75]  Joanne L Welton,et al.  Can urinary exosomes act as treatment response markers in prostate cancer? , 2009, Journal of Translational Medicine.

[76]  Laurence Zitvogel,et al.  Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes , 1998, Nature Medicine.

[77]  R. Johnstone,et al.  Reticulocyte maturation and exosome release: transferrin receptor containing exosomes shows multiple plasma membrane functions. , 1989, Blood.

[78]  M. Ntzouni,et al.  Cell-Produced α-Synuclein Is Secreted in a Calcium-Dependent Manner by Exosomes and Impacts Neuronal Survival , 2010, The Journal of Neuroscience.

[79]  K. Uchida,et al.  Decreased abundance of urinary exosomal aquaporin-1 in renal ischemia-reperfusion injury. , 2009, American journal of physiology. Renal physiology.

[80]  R. Roden,et al.  Claudin-containing exosomes in the peripheral circulation of women with ovarian cancer , 2009, BMC Cancer.

[81]  L. O’Driscoll,et al.  Intracellular and extracellular microRNAs in breast cancer. , 2011, Clinical chemistry.

[82]  R. Simpson,et al.  Proteomic profiling of exosomes: Current perspectives , 2008, Proteomics.

[83]  B. Clotet,et al.  Capture and transfer of HIV-1 particles by mature dendritic cells converges with the exosome-dissemination pathway. , 2009, Blood.

[84]  J. Dear,et al.  Exosomal transmission of functional aquaporin 2 in kidney cortical collecting duct cells , 2011, The Journal of physiology.

[85]  H. Jäck,et al.  Serum microRNAs as powerful cancer biomarkers. , 2010, Biochimica et biophysica acta.

[86]  H. Greenberg,et al.  Membrane vesicles released by intestinal epithelial cells infected with rotavirus inhibit T-cell function. , 2010, Viral immunology.

[87]  C. Soto.  Diagnosing prion diseases: needs, challenges and hopes , 2004, Nature Reviews Microbiology.

[88]  W. Faigle,et al.  Cells release prions in association with exosomes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[89]  G. Illei,et al.  Exosomes from human saliva as a source of microRNA biomarkers. , 2010, Oral diseases.