Exosomes for Non‐Invasive Cancer Monitoring

Exosomes, membrane‐bound phospholipid vesicles having diameters of 50–200 nm, are secreted by all cell types and circulate in human body fluids. These vesicles are known to carry cellular constituents that are specific to the originating cells (e.g., cytoplasmic/membrane proteins, RNA, and DNA). Thus, exosomes, which are both structurally stable and abundant, are robust indicators of cancers and, as a result, they have been utilized to monitor this disease in a manner that is less invasive than gold standard tissue biopsies. In this review, the history of exosomes and the specific biomarkers present in exosomes that enable accurate monitoring of various diseases are described. In addition, methods for analysis of exosomes and identification of biomarkers are presented with special emphasis being given to isolation and signaling strategies. Lastly, integrated, microfluidic systems developed for exosome‐based cancer diagnosis are described and future directions that research in this area will likely take are presented.

[1]  M. Merchant,et al.  MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression , 2017, Nature Communications.

[2]  C. Sheridan Exosome cancer diagnostic reaches market , 2016, Nature Biotechnology.

[3]  M. Oksvold,et al.  Magnetic bead-based isolation of exosomes. , 2015, Methods in molecular biology.

[4]  Christian Pilarsky,et al.  Glypican-1 identifies cancer exosomes and detects early pancreatic cancer , 2015, Nature.

[5]  Kristie L. Rose,et al.  Proteomics characterization of exosome cargo. , 2015, Methods.

[6]  S. Fan,et al.  Exosomes containing differential expression of microRNA and mRNA in osteosarcoma that can predict response to chemotherapy , 2017, Oncotarget.

[7]  H. Iinuma,et al.  Exosomal microRNA in plasma as a non-invasive biomarker for the recurrence of non-small cell lung cancer. , 2017, Oncology letters.

[8]  Zhiqiang Gao,et al.  Advances in exosome quantification techniques , 2017 .

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

[10]  X. Qu,et al.  Cancer biomarker detection: recent achievements and challenges. , 2015, Chemical Society reviews.

[11]  R. Jamal,et al.  Exosomes As Potential Biomarkers and Targeted Therapy in Colorectal Cancer: A Mini-Review , 2017, Front. Pharmacol..

[12]  L. Bujanda,et al.  Non-invasive biomarkers in pancreatic cancer diagnosis: what we need versus what we have. , 2016, Annals of translational medicine.

[13]  Lei Wang,et al.  GPC1 exosome and its regulatory miRNAs are specific markers for the detection and target therapy of colorectal cancer , 2017, Journal of cellular and molecular medicine.

[14]  Tiantian Zhang,et al.  Nucleic Acid Aptamers: An Emerging Tool for Biotechnology and Biomedical Sensing , 2015, Sensors.

[15]  Lei Dong,et al.  Circulating Long RNAs in Serum Extracellular Vesicles: Their Characterization and Potential Application as Biomarkers for Diagnosis of Colorectal Cancer , 2016, Cancer Epidemiology, Biomarkers & Prevention.

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

[17]  K. R. Jakobsen,et al.  Exosomal proteins as potential diagnostic markers in advanced non-small cell lung carcinoma , 2015, Journal of extracellular vesicles.

[18]  T. D. de Reijke,et al.  Prostate cancer biomarker profiles in urinary sediments and exosomes. , 2014, The Journal of urology.

[19]  Yu Wang,et al.  Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer. , 2017, Biochemical and biophysical research communications.

[20]  C. Théry,et al.  Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. , 2014, Annual review of cell and developmental biology.

[21]  Joshua M. Weiss,et al.  Extracellular Vesicles in Cancer: Cell-to-Cell Mediators of Metastasis. , 2016, Cancer cell.

[22]  Y. Toiyama,et al.  Diagnostic Potential of Cell-Free and Exosomal MicroRNAs in the Identification of Patients with High-Risk Colorectal Adenomas , 2016, PloS one.

[23]  D. Hwang,et al.  Proteomic analysis of microvesicles derived from human colorectal cancer ascites , 2011, Proteomics.

[24]  J. Gatti,et al.  Identification, Proteomic Profiling, and Origin of Ram Epididymal Fluid Exosome-Like Vesicles1 , 2005, Biology of reproduction.

[25]  Tosifusa Toda,et al.  Proteomic analysis of two types of exosomes in human whole saliva. , 2011, Biological & pharmaceutical bulletin.

[26]  C. Melief,et al.  B lymphocytes secrete antigen-presenting vesicles , 1996, The Journal of experimental medicine.

[27]  David W. Greening,et al.  Extracellular vesicles in cancer — implications for future improvements in cancer care , 2018, Nature Reviews Clinical Oncology.

[28]  D. Terrian,et al.  Senescence-associated exosome release from human prostate cancer cells. , 2008, Cancer research.

[29]  Alicia Llorente,et al.  Lipids in exosomes: Current knowledge and the way forward. , 2017, Progress in lipid research.

[30]  P. Brambilla,et al.  Differential protein profiling of renal cell carcinoma urinary exosomes. , 2013, Molecular bioSystems.

[31]  Yusuke Yoshioka,et al.  Ultra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen , 2014, Nature Communications.

[32]  Pasinetti,et al.  The potential of specific COX-2 inhibition. , 2000, Drug discovery today.

[33]  A. Chronopoulos,et al.  Exosomes as a platform for ‘liquid biopsy’ in pancreatic cancer , 2017 .

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

[35]  G. Kristiansen,et al.  Malignant ascites-derived exosomes of ovarian carcinoma patients contain CD24 and EpCAM. , 2007, Gynecologic oncology.

[36]  Jian-Kang Zhu,et al.  Phosphoproteins in extracellular vesicles as candidate markers for breast cancer , 2017, Proceedings of the National Academy of Sciences.

[37]  Muling Shi,et al.  Aptamer/AuNP Biosensor for Colorimetric Profiling of Exosomal Proteins. , 2017, Angewandte Chemie.

[38]  P. Fernández-Llama,et al.  Tamm-Horsfall protein and urinary exosome isolation. , 2010, Kidney international.

[39]  Graça Raposo,et al.  Exosomal-like vesicles are present in human blood plasma. , 2005, International immunology.

[40]  Lynne T. Bemis,et al.  Standardization of sample collection, isolation and analysis methods in extracellular vesicle research , 2013, Journal of extracellular vesicles.

[41]  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.

[42]  B. Goh,et al.  Exosomal protein FAM3C as a potential novel biomarker for non-small cell lung cancer. , 2014 .

[43]  L. Du,et al.  Exosomal long noncoding RNA CRNDE-h as a novel serum-based biomarker for diagnosis and prognosis of colorectal cancer , 2016, Oncotarget.

[44]  Yun Chen,et al.  Circular BANP, an upregulated circular RNA that modulates cell proliferation in colorectal cancer. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[45]  G. Capasso,et al.  Employing extracellular vesicles for non-invasive renal monitoring: A captivating prospect , 2014 .

[46]  Z. Lei,et al.  Screening circular RNA related to chemotherapeutic resistance in osteosarcoma by RNA sequencing. , 2018, Epigenomics.

[47]  In‐San Kim,et al.  Fibronectin on circulating extracellular vesicles as a liquid biopsy to detect breast cancer , 2016 .

[48]  F. Wang,et al.  Hsa_circ_0020397 regulates colorectal cancer cell viability, apoptosis and invasion by promoting the expression of the miR‐138 targets TERT and PD‐L1 , 2017, Cell biology international.

[49]  P. Laktionov,et al.  Isolation of Extracellular Vesicles: General Methodologies and Latest Trends , 2018, BioMed research international.

[50]  Hadi Shafiee,et al.  Microfluidic approaches for isolation, detection, and characterization of extracellular vesicles: Current status and future directions. , 2017, Biosensors & bioelectronics.

[51]  L. Kenny,et al.  Salivary exosomes as potential biomarkers in cancer. , 2018, Oral oncology.

[52]  Richard J Simpson,et al.  A protocol for exosome isolation and characterization: evaluation of ultracentrifugation, density-gradient separation, and immunoaffinity capture methods. , 2015, Methods in molecular biology.

[53]  P. Pauwels,et al.  Exosomes as diagnostic and predictive biomarkers in lung cancer. , 2017, Journal of thoracic disease.

[54]  T. Deguchi,et al.  Gamma-glutamyltransferase activity in exosomes as a potential marker for prostate cancer , 2017, BMC Cancer.

[55]  Y. Sadovsky,et al.  Review: placenta-specific microRNAs in exosomes - good things come in nano-packages. , 2014, Placenta.

[56]  D. Pisetsky,et al.  The role of microparticles in the pathogenesis of rheumatic diseases , 2010, Nature Reviews Rheumatology.

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

[58]  Lunhui Guan,et al.  A visible and colorimetric aptasensor based on DNA-capped single-walled carbon nanotubes for detection of exosomes. , 2017, Biosensors & bioelectronics.

[59]  Jongmin Park,et al.  Integrated Magneto-Electrochemical Sensor for Exosome Analysis. , 2016, ACS nano.

[60]  P. Tassone,et al.  Circulating biomarkers in osteosarcoma: new translational tools for diagnosis and treatment , 2017, Oncotarget.

[61]  Lei Han,et al.  Long non-coding RNA HOTAIR promotes glioblastoma cell cycle progression in an EZH2 dependent manner , 2014, Oncotarget.

[62]  K. S. Park Nucleic acid aptamer-based methods for diagnosis of infections , 2017, Biosensors and Bioelectronics.

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

[64]  Hakho Lee,et al.  Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy , 2012, Nature Medicine.

[65]  R. Maizels,et al.  Exosomes and Other Extracellular Vesicles: The New Communicators in Parasite Infections , 2015, Trends in parasitology.

[66]  Michael S. Spilman,et al.  Structural heterogeneity and protein composition of exosome‐like vesicles (prostasomes) in human semen , 2009, The Prostate.

[67]  Jian-hui Jiang,et al.  Enhancement of the Intrinsic Peroxidase-Like Activity of Graphitic Carbon Nitride Nanosheets by ssDNAs and Its Application for Detection of Exosomes. , 2017, Analytical chemistry.

[68]  Hakho Lee,et al.  Multiparametric plasma EV profiling facilitates diagnosis of pancreatic malignancy , 2017, Science Translational Medicine.

[69]  R. Bernards,et al.  Enabling personalized cancer medicine through analysis of gene-expression patterns , 2008, Nature.

[70]  V. Govorun,et al.  Proteome–Metabolome Profiling of Ovarian Cancer Ascites Reveals Novel Components Involved in Intercellular Communication* , 2014, Molecular & Cellular Proteomics.

[71]  S. Hanash,et al.  High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

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

[73]  A. Möller,et al.  Exosomes derived from mesenchymal non‐small cell lung cancer cells promote chemoresistance , 2017, International journal of cancer.

[74]  Salma Khan,et al.  Early diagnostic value of survivin and its alternative splice variants in breast cancer , 2014, BMC Cancer.

[75]  Weian Zhao,et al.  Stem Cell Extracellular Vesicles: Extended Messages of Regeneration , 2016, Annual review of pharmacology and toxicology.

[76]  M. Hirashima,et al.  Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral Latent Membrane Protein 1 and the immunomodulatory protein galectin 9 , 2006, BMC Cancer.

[77]  She Chen,et al.  Characterization and proteomic analysis of ovarian cancer-derived exosomes. , 2013, Journal of proteomics.

[78]  S. Gabrielsson,et al.  Proinflammatory exosomes in bronchoalveolar lavage fluid of patients with sarcoidosis , 2010, Thorax.

[79]  Jameel Inal,et al.  A filtration-based protocol to isolate human plasma membrane-derived vesicles and exosomes from blood plasma. , 2011, Journal of immunological methods.

[80]  Yuanbo Chen,et al.  Effective isolation of exosomes with polyethylene glycol from cell culture supernatant for in-depth proteome profiling. , 2016, The Analyst.

[81]  W. Gong,et al.  TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1β/Derlin-1 pathway , 2017, Journal of Hematology & Oncology.

[82]  Yong Peng,et al.  The role of MicroRNAs in human cancer , 2016, Signal Transduction and Targeted Therapy.

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

[84]  Alissa M. Weaver,et al.  Circular RNAs are down-regulated in KRAS mutant colon cancer cells and can be transferred to exosomes , 2016, Scientific Reports.

[85]  U. Gezer,et al.  Exosomal lncRNA-p21 levels may help to distinguish prostate cancer from benign disease , 2015, Front. Genet..

[86]  S. Chieffi,et al.  Effects of an High-Fat Diet Enriched in Lard or in Fish Oil on the Hypothalamic Amp-Activated Protein Kinase and Inflammatory Mediators , 2016, Front. Cell. Neurosci..

[87]  G R Burmester,et al.  Association of citrullinated proteins with synovial exosomes. , 2006, Arthritis and rheumatism.

[88]  Charlotte Lawson,et al.  Microvesicles and exosomes: new players in metabolic and cardiovascular disease. , 2016, The Journal of endocrinology.

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

[90]  Yang Yang,et al.  A microfluidic ExoSearch chip for multiplexed exosome detection towards blood-based ovarian cancer diagnosis. , 2016, Lab on a chip.

[91]  P. Chang,et al.  Comparative and targeted proteomic analyses of urinary microparticles from bladder cancer and hernia patients. , 2012, Journal of proteome research.

[92]  S. Mathivanan,et al.  Exosomes in bodily fluids are a highly stable resource of disease biomarkers , 2015, Proteomics. Clinical applications.

[93]  A. Molinari,et al.  Microenvironmental pH Is a Key Factor for Exosome Traffic in Tumor Cells* , 2009, The Journal of Biological Chemistry.

[94]  J. Szostak,et al.  In vitro selection of functional nucleic acids. , 1999, Annual review of biochemistry.

[95]  V. Zhdanov,et al.  Determination of exosome concentration in solution using surface plasmon resonance spectroscopy. , 2014, Analytical chemistry.

[96]  Johan Skog,et al.  Glioblastoma microvesicles transport RNA and protein that promote tumor growth and provide diagnostic biomarkers , 2008, Nature Cell Biology.

[97]  A. Hölscher,et al.  Exosomal onco-miRs from serum of patients with adenocarcinoma of the esophagus: comparison of miRNA profiles of exosomes and matching tumor , 2015, Tumor Biology.

[98]  A. Llorente,et al.  Molecular lipid species in urinary exosomes as potential prostate cancer biomarkers. , 2017, European journal of cancer.

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

[100]  Wang Lq,et al.  Exosomes mediated transfer of lncRNA UCA1 results in increased tamoxifen resistance in breast cancer cells. , 2016 .

[101]  Hakho Lee,et al.  Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor , 2014, Nature Biotechnology.

[102]  K. Mimori,et al.  Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer , 2015, British Journal of Cancer.

[103]  Alessandro Sciarra,et al.  Increased PSA expression on prostate cancer exosomes in in vitro condition and in cancer patients. , 2017, Cancer letters.

[104]  L. Buée,et al.  Potential Contribution of Exosomes to the Prion-Like Propagation of Lesions in Alzheimer’s Disease , 2012, Front. Physio..

[105]  E. Trams,et al.  Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. , 1981, Biochimica et biophysica acta.

[106]  Xiuhui Li,et al.  Role of exosomal proteins in cancer diagnosis , 2017, Molecular Cancer.

[107]  Rong-Fong Shen,et al.  Identification and proteomic profiling of exosomes in human urine. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[108]  Y. Akimoto,et al.  Exosome-like vesicles with dipeptidyl peptidase IV in human saliva. , 2008, Biological & pharmaceutical bulletin.

[109]  Liquid Profiling in Lung Cancer - Quantification of Extracellular miRNAs in Bronchial Lavage. , 2016, Advances in experimental medicine and biology.

[110]  Gregory E. Rice,et al.  Tumor-derived exosomes in ovarian cancer – liquid biopsies for early detection and real-time monitoring of cancer progression , 2017, Oncotarget.

[111]  Claudia Berrondo,et al.  Expression of the Long Non-Coding RNA HOTAIR Correlates with Disease Progression in Bladder Cancer and Is Contained in Bladder Cancer Patient Urinary Exosomes , 2016, PloS one.

[112]  Wei Liang,et al.  Exosomes-mediated transfer of long noncoding RNA ZFAS1 promotes gastric cancer progression , 2017, Journal of Cancer Research and Clinical Oncology.

[113]  M. Ratajczak,et al.  Exosomes: an overview of biogenesis, composition and role in ovarian cancer , 2014, Journal of Ovarian Research.

[114]  Shuzhen Wei,et al.  hsa_circ_0013958: a circular RNA and potential novel biomarker for lung adenocarcinoma , 2017, The FEBS journal.

[115]  Hui Chen,et al.  An ultrasensitive polydopamine bi-functionalized SERS immunoassay for exosome-based diagnosis and classification of pancreatic cancer† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8sc01611a , 2018, Chemical science.

[116]  Zhiqiang Gao,et al.  Progress in Exosome Isolation Techniques , 2017, Theranostics.

[117]  Yuan Zhang,et al.  Proteomic identification of exosomal LRG1: A potential urinary biomarker for detecting NSCLC , 2011, Electrophoresis.

[118]  Kim Ekroos,et al.  Molecular lipidomics of exosomes released by PC-3 prostate cancer cells. , 2013, Biochimica et biophysica acta.

[119]  W. Guo,et al.  Exosomes: New players in cancer , 2017, Oncology reports.

[120]  Xiaowu Li,et al.  Circular RNA IARS (circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis , 2018, Journal of Experimental & Clinical Cancer Research.

[121]  N. Nguyen,et al.  Circulating tumor DNA and liquid biopsy: opportunities, challenges, and recent advances in detection technologies. , 2018, Lab on a chip.

[122]  Michael A. Hollingsworth,et al.  Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver , 2015, Nature Cell Biology.

[123]  Hongwei Pan,et al.  Identification of a serum circulating lncRNA panel for the diagnosis and recurrence prediction of bladder cancer , 2016, Oncotarget.

[124]  Mutsa P. Seremwe,et al.  A Comparative Study of Serum Exosome Isolation Using Differential Ultracentrifugation and Three Commercial Reagents , 2017, PloS one.

[125]  Hui Liu,et al.  Tumor-derived exosomal lnc-Sox2ot promotes EMT and stemness by acting as a ceRNA in pancreatic ductal adenocarcinoma , 2018, Oncogene.

[126]  A. Welm,et al.  Plasma exosome microRNAs are indicative of breast cancer , 2016, Breast Cancer Research.

[127]  Cesar M. Castro,et al.  Integrated Kidney Exosome Analysis for the Detection of Kidney Transplant Rejection. , 2017, ACS nano.

[128]  Shuhong Zhao,et al.  Over-expression of CircRNA_100876 in non-small cell lung cancer and its prognostic value. , 2017, Pathology, research and practice.

[129]  Trairak Pisitkun,et al.  Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator. , 2007, American journal of physiology. Renal physiology.

[130]  B. Kalionis,et al.  Role of Exosomal Noncoding RNAs in Lung Carcinogenesis , 2015, BioMed research international.

[131]  H. Baba,et al.  Clinical impact of serum exosomal microRNA‐21 as a clinical biomarker in human esophageal squamous cell carcinoma , 2013, Cancer.

[132]  Bow J. Tauro The isolation and characterization of exosomes , 2013 .

[133]  T. V. van Leeuwen,et al.  Reproducible extracellular vesicle size and concentration determination with tunable resistive pulse sensing , 2014, Journal of extracellular vesicles.

[134]  D. Skupski,et al.  Heat shock protein-containing exosomes in mid-trimester amniotic fluids. , 2008, Journal of reproductive immunology.

[135]  L. Zitvogel,et al.  Malignant effusions and immunogenic tumour-derived exosomes , 2002, The Lancet.

[136]  H. Yamaue,et al.  Clinical implications of carcinoembryonic antigen distribution in serum exosomal fraction—Measurement by ELISA , 2017, PloS one.

[137]  John R Yates,et al.  Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). , 2009, Journal of proteome research.

[138]  S. Fan,et al.  Exosomes containing differential expression of microRNA and mRNA in osteosarcoma that can predict response to chemotherapy , 2017, Oncotarget.

[139]  S. Kassis,et al.  Exfoliation of the beta-adrenergic receptor and the regulatory components of adenylate cyclase by cultured rat glioma C6 cells. , 1986, Biochimica et biophysica acta.

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

[141]  Jiang-xia Zhao,et al.  Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis , 2015, Cell Research.

[142]  Naoto Tsuchiya,et al.  Circulating Exosomal microRNAs as Biomarkers of Colon Cancer , 2014, PloS one.

[143]  Xiaojie Li,et al.  Clinical application of a microfluidic chip for immunocapture and quantification of circulating exosomes to assist breast cancer diagnosis and molecular classification , 2017, PloS one.

[144]  W. Weimar,et al.  Effects of Hypoxia on the Immunomodulatory Properties of Adipose Tissue-Derived Mesenchymal Stem cells , 2013, Front. Immunol..

[145]  F. Borràs,et al.  Urinary Extracellular Vesicles as Source of Biomarkers in Kidney Diseases , 2015, Front. Immunol..

[146]  Riitta Lahesmaa,et al.  Exosomes with Immune Modulatory Features Are Present in Human Breast Milk1 , 2007, The Journal of Immunology.

[147]  X. Niu,et al.  Exosomes secreted by human urine-derived stem cells could prevent kidney complications from type I diabetes in rats , 2016, Stem Cell Research & Therapy.

[148]  Manal M. Hassan,et al.  Serum exosomal miR-4772-3p is a predictor of tumor recurrence in stage II and III colon cancer , 2016, Oncotarget.

[149]  R. Johnstone,et al.  Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). , 1987, The Journal of biological chemistry.

[150]  S. Aliño,et al.  Cell-Free Circulating Plasma hTERT mRNA Is a Useful Marker for Prostate Cancer Diagnosis and Is Associated with Poor Prognosis Tumor Characteristics , 2012, PloS one.

[151]  G. Yousef,et al.  Liquid biopsy: a step forward towards precision medicine in urologic malignancies , 2017, Molecular Cancer.

[152]  J. Thyberg,et al.  Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid , 2003, European Respiratory Journal.

[153]  Richard J Simpson,et al.  Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. , 2012, Methods.

[154]  G. Raposo,et al.  Intestinal epithelial cells secrete exosome-like vesicles. , 2001, Gastroenterology.

[155]  Johan Skog,et al.  Liquid biopsy for cancer screening, patient stratification and monitoring , 2018 .

[156]  I. Kurochkin,et al.  Characterization of RNA in exosomes secreted by human breast cancer cell lines using next-generation sequencing , 2013, PeerJ.

[157]  Laurence Zitvogel,et al.  Molecular Characterization of Dendritic Cell-Derived Exosomes , 1999, The Journal of cell biology.

[158]  P. Workman,et al.  Can molecular biomarker-based patient selection in Phase I trials accelerate anticancer drug development? , 2010, Drug discovery today.

[159]  I. Brody,et al.  The prostasome: its secretion and function in man. , 1985, Biochimica et biophysica acta.

[160]  R. Nieuwland,et al.  Single-step isolation of extracellular vesicles by size-exclusion chromatography , 2014, Journal of extracellular vesicles.

[161]  Hai Wu,et al.  Androgen-responsive circular RNA circSMARCA5 is up-regulated and promotes cell proliferation in prostate cancer. , 2017, Biochemical and biophysical research communications.

[162]  M. Zembala,et al.  Circulating tumour-derived microvesicles in plasma of gastric cancer patients , 2010, Cancer Immunology, Immunotherapy.

[163]  B. Bao,et al.  Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review , 2013, Cancer and Metastasis Reviews.

[164]  J. Bloem,et al.  Magnetic resonance imaging of the bladder and prostate , 1985, World Journal of Urology.

[165]  Allan Stensballe,et al.  Diagnostic and prognostic potential of extracellular vesicles in peripheral blood. , 2014, Clinical therapeutics.