Exosomes isolation and characterization in serum is feasible in non-small cell lung cancer patients: Critical analysis of evidence and potential role in clinical practice

Oncotarget

Volumn 7, Issue 19, 2016, Pages 28748-28760

  Taverna, Simona ^a,b   Giallombardo, Marco ^a,c   Gil Bazo, Ignacio ^d   Carreca, Anna Paola ^c   Castiglia, Marta ^c   Chacártegui, Jorge ^c   Araujo, Antonio ^e   Alessandro, Riccardo ^a,b   Pauwels, Patrick ^c   Peeters, Marc ^c   Rolfo, Christian ^c  

^a UNIVERSITY OF PALERMO   (Italy)

^b CNR Consiglio Nazionale delle Ricerche   (Italy)

^c ANTWERP UNIVERSITY HOSPITAL   (Belgium)

^d UNIVERSITY CLINIC OF NAVARRA   (Spain)

^e UNIVERSITY OF PORTO   (Portugal)

Author keywords

Biomarkers; Exosomes; Liquid biopsies; MicroRNAs; NSCLC

Indexed keywords

LIPID; MICRORNA; TUMOR MARKER;

ARTICLE; CANCER DIAGNOSIS; CANCER PATIENT; CANCER PROGNOSIS; CARCINOGENESIS; CLINICAL PRACTICE; EXOSOME; FEASIBILITY STUDY; GENE OVEREXPRESSION; HUMAN; MOLECULAR BIOLOGY; NON SMALL CELL LUNG CANCER; PREDICTION; TUMOR MICROENVIRONMENT; BLOOD; DISEASE EXACERBATION; GENE EXPRESSION REGULATION; GENETICS; IMMUNOLOGY; LUNG TUMOR; PROGNOSIS;

BIOMARKERS, TUMOR; CARCINOMA, NON-SMALL-CELL LUNG; DISEASE PROGRESSION; EXOSOMES; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; LUNG NEOPLASMS; MICRORNAS; PROGNOSIS; TUMOR MICROENVIRONMENT;

EID: 84968831957     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.7638     Document Type: Article

References (81)

1. Atkinson AJ J, Colburn WA, DeGruttola VG, DeMets DL, Downing GJ, Hoth DF, Oates J A, Peck CC, Schooley, RT, Spilker BA, Woodcock J, and Zeger SL. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69: 89-95. doi:10.1067/mcp.2001.113989.
2. Boukouris S, and Mathivanan S. Exosomes in bodily fluids are a highly stable resource of disease biomarkers. Proteomics Clin Appl. 2015; 9: 358-67. doi:10.1002/prca.201400114.
3. Johnstone RM, Adam M, Hammond JR, Orr L, and Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987; 262: 9412-20.
4. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding C V, Melief CJ, and Geuze HJ. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996; 183: 1161-72. doi:10.1084/jem.183.3.1161.
5. Demory Beckler M, Higginbotham JN, Franklin JL, Ham A-J, Halvey PJ, Imasuen IE, Whitwell C, Li M, Liebler DC, and Coffey RJ. Proteomic Analysis of Exosomes from Mutant KRAS Colon Cancer Cells Identifies Intercellular Transfer of Mutant KRAS. Mol Cell Proteomics. 2012; 12: 343-55. doi:10.1074/mcp.M112.022806.
6. Jemal A, Siegel R, Ward E, Hao Y, Xu J, and Thun MJ. Cancer Statistics. CA Cancer J Clin. 2009; 59: 225-49. doi:10.3322/caac.20006.
7. Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, Simms L, and Frances A. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist. 2009; 14: 253-63. doi:10.1634/theoncologist.2008-0232.
8. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K. Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non -small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011; 29: 2866-74. doi:10.1200/JCO.2010.33.4235.
9. Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T and Mitsudomi T. Mutations of the epidermal growth factor receptor gene in lung cancer: Biological and clinical implications. Cancer Res. 2004; 64: 8919-23. doi:10.1158/0008-5472.CAN-04-2818.
10. Sequist LV, Yang JC-H, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31: 3327-34. doi:10.1200/JCO.2012.44.2806.
11. Rosell R, Carcereny E, Gervais R, Vergnenegre A, and Massuti B. Erlotinib versus standard chemotherapy as firstline treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46.
12. Rolfo C, Giovannetti E, Hong DS, Bivona T, Raez LE, Bronte G, Buffoni L, Reguart NS, Edgardo S, Germonpre P, Taron M, Passiglia F, Van Meerbeeck JP, et al. Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors. Cancer Treat Rev. 2014; 40: 990-1004. doi:10.1016/j.ctrv.2014.05.009.
13. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, and Varmus H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005; 2: 0225-35. doi:10.1371/journal. pmed.0020073.
14. Shih JY, Gow CH, and Yang PC. EGFR mutation conferring primary resistance to gefitinib in non-small-cell lung cancer. N Engl J Med. 2005; 353: 207-8. doi:10.1056/NEJM200507143530217.
15. Kobayashi S, Boggon TJ, Dayaram T, Jänne P a, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, and Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005; 352: 786-92. doi:10.1056/NEJMoa044238.
16. Pao W, and Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and nonsmall-cell lung cancer: current knowledge and future directions. J Clin Oncol. 2005; 23: 2556-68. doi:10.1200/JCO.2005.07.799.
17. Hammerman PS, Jänne PA, and Johnson BE. Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase. Clin Cancer Res. 2009; 15: 7502-9. doi:10.1158/1078-0432. CCR-09-0189.
18. Solomon BJ, Mok T, Kim D-W, Wu Y-L, Nakagawa K, Mekhail T, Felip E, Cappuzzo F, Paolini J, Usari T, Iyer S, Reisman A, Wilner KD, et al. First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. N Engl J Med. 2014; 371: 2167-77. doi:10.1056/NEJMoa1408440.
19. Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, Michellys PY, Awad MM, Yanagitani N, Kim S, Pferdekamper AMC, Li Jie, Kasibhatla S, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in nonsmall cell lung cancer. Cancer Discov. 2014; 4: 662-73. doi:10.1158/2159-8290.CD-13-0846.
20. Gadgeel L, Riely GJ, Chiappori AA, West HL, Azada MC, Morcos PN, Lee RM, Garcia L, Yu Li, Boisserie F, Laurenzio L, Di Golding S, Sato J, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged nonsmall-cell lung cancer (AF-002JG): results from the dosefinding portion of a phase 1/2 study. Lancet Oncol. 2015;15: 1119-28.
21. Rolfo C, Castiglia M, Hong D, Alessandro R, Mertens I, Baggerman G, Zwaenepoel K, Gil-Bazo I, Passiglia F, Carreca AP, Taverna S, Vento R, Peeters M, et al. Liquid biopsies in lung cancer: The new ambrosia of researchers. Biochim Biophys Acta. 2014; 1846: 539-46. doi:10.1016/j. bbcan.2014.10.001.
22. Toss A, Mu Z, Fernandez S, and Cristofanilli M. CTC enumeration and characterization: moving toward personalized medicine. Ann Transl Med. 2014; 2: 108. doi:10.3978/j.issn.2305-5839.2014.09.06.
23. Diaz LA Jr, and Bardelli A. Liquid biopsies: Genotyping circulating tumor DNA. J Clin Oncol. 2014; 32: 579-86. doi:10.1200/JCO.2012.45.2011.
24. Schwarzenbach H, Hoon DSB, and Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011; 11: 426-37. doi:10.1038/nrc3066.
25. Alix-Panabierès C, and Pantel K. Circulating tumor cells: Liquid biopsy of cancer. Clin Chem. 2013; 59: 110-8. doi:10.1373/clinchem.2012.194258.
26. Yoneda K, Tanaka F, Kondo N, Hashimoto M, Takuwa T, Matsumoto S, Okumura Y, Tsubota N, Sato A, Tsujimura T, Kuribayashi K, Fukuoka K, Tabata C, et al. Circulating Tumor Cells (CTCs) in Malignant Pleural Mesothelioma (MPM). Ann Surg Oncol. 2013; 4: S472-80. doi:10.1245/s10434-013-3399-2.
27. Krebs MG, Sloane R, Priest L, Lancashire L, Hou J-M, Greystoke A, Ward TH, Ferraldeschi R, Hughes A, Clack G, Ranson M, Dive C, and Blackhall FH. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol. 2011; 29: 1556-63. doi:10.1200/JCO.2010.28.7045.
28. Cristofanilli M, and Braun S. Circulating tumor cells revisited. JAMA. 2010; 303: 1092-3. doi:10.1146/annurevmed-062310-094219.
29. Tanaka F, Yoneda K, Kondo N, Hashimoto M, Takuwa T, Matsumoto S, Okumura Y, Rahman S, Tsubota N, Tsujimura T, Kuribayashi K, Fukuoka K, Nakano T, et al. Circulating tumor cell as a diagnostic marker in primary lung cancer. Clin Cancer Res. 2009; 15: 6980-6. doi:10.1158/1078-0432.CCR-09-1095.
30. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, and Hayes DF. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004; 351: 781-91. doi:10.1056/NEJMoa040766.
31. Garofalo M, Quintavalle C, Di Leva G, Zanca C, Romano G, Taccioli C, Liu CG, Croce CM and Condorelli G. MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer. Oncogene. 2008; 27: 3845-55. doi:10.1038/onc.2008.6.
32. Théry C, Zitvogel L, and Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002; 2: 569-79.
33. Kowal J, Tkach M, and Théry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014; 29: 116-25. doi:10.1016/j.ceb.2014.05.004.
34. Fontana S, Saieva L, Taverna S, and Alessandro R. Contribution of proteomics to understanding the role of tumor-derived exosomes in cancer progression: State of the art and new perspectives. Proteomics. 2013; 13: 1581-94. doi:10.1002/pmic.201200398.
35. Benito-Martin A, Di Giannatale A, Ceder S, and Peinado H. The New Deal: A Potential Role for Secreted Vesicles in Innate Immunity and Tumor Progression. Front Immunol. 2015; 6:66. doi:10.3389/fimmu.2015.00066.
36. Carroll-Portillo A, Surviladze Z, Cambi A, Lidke DS, and Wilson BS. Mast cell synapses and exosomes: Membrane contacts for information exchange. Front Immunol. 2012; 3:1-9. doi:10.3389/fimmu.2012.00046.
37. Skokos D, Le Panse S, Villa I, Rousselle J-C, Peronet R, David B, Namane A, and Mécheri S. Mast Cell-Dependent B and T Lymphocyte Activation Is Mediated by the Secretion of Immunologically Active Exosomes. J Immunol. 2001; 166: 868-76. doi:10.4049/jimmunol.166.2.868.
38. Vincent-Schneider H, Stumptner-Cuvelette P, Lankar D, Pain S, Raposo G, Benaroch P, and Bonnerot C. Exosomes bearing HLA-DR1 molecules need dendritic cells to efficiently stimulate specific T cells. Int Immunol. 2002; 14: 713-22. doi:10.1093/intimm/dxf048.
39. Taverna S, Flugy A, Saieva L, Kohn EC, Santoro A, Meraviglia S, De Leo G, and Alessandro R. Role of exosomes released by chronic myelogenous leukemia cells in angiogenesis. Int J Cancer. 2012;130: 2033-43. doi:10.1002/ijc.26217.
40. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Santos GG, Nitadori-Hoshino A, Hoffman C, Badal K, Garci BA, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2013; 18: 883-91. doi:10.1038/nm.2753.
41. Vlassov AV, Magdaleno S, Setterquist R, and Conrad R. Exosomes: Current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta -Gen Subj. 2012; 1820:940-8. doi:10.1016/j.bbagen.2012.03.017.
42. Mathivanan S, Fahner CJ, Reid GE, and Simpson RJ. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 2012; 40: D1241-4. doi:10.1093/nar/gkr828.
43. Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, Zheng Y, Hoshino A, Brazier H, Xiang J, Williams C, Rodriguez-Barrueco R, Silva JM, et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 2014; 24: 766-9. doi:10.1038/cr.2014.44.
44. Mathivanan S, Ji H, Tauro BJ, Chen YS, and Simpson RJ. Identifying mutated proteins secreted by colon cancer cell lines using mass spectrometry. J Proteomics. 2012; 5; 76 Spec No.:141-9. doi:10.1016/j.jprot.2012.06.031.
45. Zakharova L, Svetlova M, and Fomina AF. T cell exosomes induce cholesterol accumulation in human monocytes via phosphatidylserine receptor. J Cell Physiol. 2007; 212: 174-81. doi:10.1002/jcp.21013.
46. Subra C, Grand D, Laulagnier K, Stella A, Lambeau G, Paillasse M, De Medina P, Monsarrat B, Perret B, Silvente-Poirot S, Poirot M, and Record M. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J Lipid Res. 2010; 51: 2105-20. doi:10.1194/jlr.M003657.
47. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, and Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007; 9: 654-9. doi:10.1038/ncb1596.
48. Taylor DD and Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008; 110: 13-21. doi:10.1016/j.ygyno.2008.04.033.
49. Taverna S, Giallombardo M, Pucci M, Flugy A, Manno M, Raccosta S, Rolfo C, De Leo G, and Alessandro R. Curcumin inhibits in vitro and in vivo chronic myelogenous leukemia cells growth: a possible role for exosomal disposal of miR-21. Oncotarget. 2015; 6(26): 21918-33. doi: 10.18632/oncotarget.4204.
50. Pigati L, Yaddanapudi SCS, Iyengar R, Kim DJ, Hearn SA, Danforth D, Hastings ML, and Duelli DM. Selective release of MicroRNA species from normal and malignant mammary epithelial cells. PLoS One. 2010; 5(10): e13515. doi:10.1371/journal.pone.0013515.
51. Jaiswal R, Gong J, Sambasivam S, Combes V, Mathys J-M, Davey R, Grau GER, and Bebawy M. Microparticleassociated nucleic acids mediate trait dominance in cancer. FASEB J. 2012; 26:420-9. doi:10.1096/fj.11-186817.
52. Wang W, and Lotze MT. Good things come in small packages: exosomes, immunity and cancer. Cancer Gene. Ther 2014; 21: 139-41. doi:10.1038/cgt.2014.14.
53. Zhao X, Parpart S, Takai A, Roessler S, Budhu A, Yu Z, Blank M, Zhang Ye, Jia HL, Ye QH, Qin LX, Tang ZY, Thorgeirsson SS, et al. Integrative genomics identifies YY1AP1 as an oncogenic driver in EpCAM+ AFP+ hepatocellular carcinoma. Oncogene. 2015; 34(39): 5095-104. doi:10.1038/onc.2014.438.
54. Logozzi M, De Milito A, Lugini L, Borghi M, Calabrò L, Spada M, Perdicchio M, Marino ML, Federici C, Iessi E, Brambilla D, Venturi G, Lozupone F, et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One. 2009; 4:e5219. doi:10.1371/journal.pone.0005219.
55. D'Asti E, Garnier D, Lee TH, Montermini L, Meehan B, and Rak J. Oncogenic extracellular vesicles in brain tumor progression. Front Physiol. 2012; 3: 1-15. doi:10.3389/fphys.2012.00294.
56. Que R, Ding G, Chen J, and Cao L. Analysis of serum exosomal microRNAs and clinicopathologic features of patients with pancreatic adenocarcinoma. World J Surg Oncol. 2013; 11:219. doi:10.1186/1477-7819-11-219.
57. Brase JC, Johannes M, Schlomm T, Haese A, Steuber T, Beissbarth T, Kuner R, and Sültmann H. Circulating miRNAs are correlated with tumor progression in prostate cancer. Int J Cancer. 2011; 128:608-16. doi:10.1002/ijc.25376.
58. Tanaka Y, Kamohara H, Kinoshita K, Kurashige J, Ishimoto T, Iwatsuki M, Watanabe M, and Baba H. Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer. 2013; 119:1159-67. doi:10.1002/cncr.27895.
59. Chiba M, Kimura M, and Asari S. Exosomes secreted from human colorectal cancer cell lines contain mRNAs, microRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines. Oncol Rep. 2012; 28:1551-8. doi:10.3892/or.2012.1967.
60. Al-Nedawi K, Meehan B, Kerbel RS, Allison AC, and Rak J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc Natl Acad Sci U S A. 2009; 106: 3794-9. doi:10.1073/pnas.0804543106.
61. Huang S-H, Li Y, Zhang J, Rong J, and Ye S. Epidermal growth factor receptor-containing exosomes induce tumorspecific regulatory T cells. Cancer Invest. 2013; 31:330-5. doi:10.3109/07357907.2013.789905.
62. Jakobsen KR, Paulsen BS, Baek R, Varming K, Sorensen BS, and Jørgensen MM. Exosomal proteins as potential diagnostic markers in advanced non-small cell lung carcinoma. J Extracell Vesicles. 2015; 4:26659.
63. Park JO, Choi D-Y, Choi D-S, Kim HJ, Kang JW, Jung JH, Lee JH, Kim J, Freeman MR, Lee, KY, Gho YS, and Kim KP. Identification and characterization of proteins isolated from microvesicles derived from human lung cancer pleural effusions. Proteomics. 2013; 13: 2125-34. doi:10.1002/pmic.201200323.
64. Li Y, Zhang Y, Qiu F, and Qiu Z. Proteomic identification of exosomal LRG1: A potential urinary biomarker for detecting NSCLC. Electrophoresis. 2011; 32: 1976-83. doi:10.1002/elps.201000598.
65. Xiao X, Yu S, Li S, Wu J, Ma R, Cao H, Zhu Y, and Feng J. Exosomes: decreased sensitivity of lung cancer A549 cells to cisplatin. PLoS One. 2014; 9: 1-6. doi:10.1371/journal. pone.0089534.
66. Nana-Sinkam SP and Croce CM. Clinical applications for microRNAs in cancer. Clin Pharmacol Ther. 2013; 93: 98-104. doi:10.1038/clpt.2012.192.
67. Crawford M, Brawner E, Batte K, Yu L, Hunter MG, Otterson GA, Nuovo G, Marsh CB and Nana-Sinkam SP. MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines. Biochem Biophys Res Commun. 2008; 373:607-12. doi:10.1016/j.bbrc.2008.06.090.
68. Ma ZL, Hou P, Li Y, Wang D, Yuan T, Wei JL, Zhao BT, Lou JT, Zhao XT, Jin Y, and Jin YX. MicroRNA-34a inhibits the proliferation and promotes the apoptosis of non-small cell lung cancer H1299 cell line by targeting TGFβR2. Tumor Biol. 2015; 36: 2481-90. doi:10.1007/s13277-014-2861-5.
69. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu CG, Croce CM, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006; 9: 189-98. doi:10.1016/j. ccr.2006.01.025.
70. Rodríguez M, Silva J, López-Alfonso A, López-Muñiz M, Peña C, Domínguez G, García JM, López-Gónzalez A, Méndez M, Provencio M, García V, and Bonilla F. Different exosome cargo from plasma/bronchoalveolar lavage in non-small-cell lung cancer. Genes Chromosom Cancer. 2014; 53: 713-24.
71. Sun Y, Bai Y, Zhang F, Wang Y, Guo Y, and Guo L. miR-126 inhibits non-small cell lung cancer cells proliferation by targeting EGFL7. Biochem Biophys Res Commun. 2010; 391: 1483-9. doi:10.1016/j.bbrc.2009.12.098.
72. Silva J, García V, Zaballos á, Provencio M, Lombardía L, Almonacid L, García JM, Domínguez G, Peña C, Diaz R, Herrera M, Varela A, and Bonilla F. Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival. Eur Respir J. 2011; 37: 617-23. doi:10.1183/09031936.00029610.
73. Zhang H, Su Y, Xu F, Kong J, Yu H, and Qian B. Circulating microRNAs in relation to EGFR status and survival of lung adenocarcinoma in female nonsmokers. PLoS One. 2013; 8: 1-10. doi:10.1371/journal. pone.0081408.
74. Lin J, Li J, Huang B, Liu J, Chen X, Chen XM, Xu YM, Huang LF, and Wang XZ. Exosomes: Novel Biomarkers for Clinical Diagnosis. Sci World J. 2015; 2015:657086. doi:10.1155/2015/657086.
75. Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, and Bonnerot C. Exosomal-like vesicles are present in human blood plasma. Int Immunol. 2005; 17: 879-87. doi:10.1093/intimm/dxh267.
76. Nilsson J, Skog J, Nordstrand A, Baranov V, Mincheva-Nilsson L, Breakefield XO, and Widmark A. Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer. 2009; 100: 1603-7. doi:10.1038/sj.bjc.6605058.
77. An T, Qin S, Xu Y, Tang Y, Huang Y, Situ B, Inal JM, and Zheng L. Exosomes serve as tumour markers for personalized diagnostics owing to their important role in cancer metastasis. J Extracell Vesicles. 2015; 4: 27522. doi:10.3402/jev.v4.27522.
78. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, and Wood MJA. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011; 29: 341-5. doi:10.1038/nbt.1807.
79. Tran T-H, Mattheolabakis G, Aldawsari H, and Amiji M. Exosomes as nanocarriers for immunotherapy of cancer and inflammatory diseases. Clin Immunol. 2015; 160: 46-58. doi:10.1016/j.clim.2015.03.021.
80. Morse M a, Garst J, Osada T, Khan S, Hobeika A, Clay TM, Valente N, Shreeniwas R, Sutton MA, Delcayre A, Hsu DH, Le Pecq JB, and Lyerly HK. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med. 2005; 3:9. doi:10.1186/1479-5876-3-9.
81. Viaud S, Ploix S, Lapierre V, Théry C, Commere P-H, Tramalloni D, Gorrichon K, Virault-Rocroy P, Tursz T, Lantz O, Zitvogel L, and Chaput N. Updated technology to produce highly immunogenic dendritic cell-derived exosomes of clinical grade: a critical role of interferon-γ. J Immunother. 2011; 34: 65-75. doi:10.1097/CJI.0b013e3181fe535b.