J Pathol Transl Med.  2018 Jan;52(1):1-8. 10.4132/jptm.2017.05.21.

Extracellular Vesicles and the Promise of Continuous Liquid Biopsies

Affiliations
  • 1Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA. wildmand@illinois.edu
  • 2Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Abstract

The rapid and accurate diagnosis of patients with minimally invasive procedures was once only found in science fiction. However, the discovery of extracellular vesicles (EVs) and their near ubiquity in body fluids, coupled with the advent of inexpensive next generation sequencing techniques and EV purification protocols, promises to make science fiction a reality. Purifying and sequencing the RNA content of EV from routine blood draws and urine samples are likely to enable pathologists and physicians to diagnose and track the progress of diseases in many inaccessible tissues in the near future. Here we present the evolutionary background of EV, summarize the biology of EV formation and cargo selection, and discuss the current barriers to making continuous liquid biopsies through the use of EV a science reality.

Keyword

Exosomes; Microvesicles; Extracellular vesicles; Cell-free RNA; Liquid biopsy

MeSH Terms

Biology
Biopsy*
Body Fluids
Diagnosis
Exosomes
Extracellular Vesicles*
Humans
RNA
RNA

Figure

  • Fig. 1. Extracellular vesicles are found in all domains of life, including Archaea [1,2], Bacteria [3-5], and Eukaryotes [3-15].

  • Fig. 2. Production of exosomes and microvesicles in cells. Microvesicles are generated from the budding of the plasma membrane (A). Exosomes are generated from the inward budding of multi-vesicular endosomes (MVEs) by the action of multiple proteins (B) and result in the release of exosomes (C) if the MVE is targeted to the plasma membrane instead of the late endosome.


Cited by  2 articles

Prognostic Role of S100A8 and S100A9 Protein Expressions in Non-small Cell Carcinoma of the Lung
Hyun Min Koh, Hyo Jung An, Gyung Hyuck Ko, Jeong Hee Lee, Jong Sil Lee, Dong Chul Kim, Jung Wook Yang, Min Hye Kim, Sung Hwan Kim, Kyung Nyeo Jeon, Gyeong-Won Lee, Se Min Jang, Dae Hyun Song
J Pathol Transl Med. 2019;53(1):13-22.    doi: 10.4132/jptm.2018.11.12.

Liquid biopsy using extracellular vesicle–derived DNA in lung adenocarcinoma
In Ae Kim, Jae Young Hur, Hee Joung Kim, Seung Eun Lee, Wan Seop Kim, Kye Young Lee
J Pathol Transl Med. 2020;54(6):453-461.    doi: 10.4132/jptm.2020.08.13.


Reference

1. Ellen AF, Rohulya OV, Fusetti F, Wagner M, Albers SV, Driessen AJ. The sulfolobicin genes of Sulfolobus acidocaldarius encode novel antimicrobial proteins. J Bacteriol. 2011; 193:4380–7.
2. Ellen AF, Zolghadr B, Driessen AM, Albers SV. Shaping the archaeal cell envelope. Archaea. 2010; 2010:608243.
Article
3. Avila-Calderon ED, Araiza-Villanueva MG, Cancino-Diaz JC, et al. Roles of bacterial membrane vesicles. Arch Microbiol. 2015; 197:1–10.
Article
4. Haurat MF, Elhenawy W, Feldman MF. Prokaryotic membrane vesicles: new insights on biogenesis and biological roles. Biol Chem. 2015; 396:95–109.
Article
5. Lai FW, Lichty BD, Bowdish DM. Microvesicles: ubiquitous contributors to infection and immunity. J Leukoc Biol. 2015; 97:237–45.
Article
6. Lopez-Verrilli MA, Court FA. Exosomes: mediators of communication in eukaryotes. Biol Res. 2013; 46:5–11.
Article
7. Lykke-Andersen S, Brodersen DE, Jensen TH. Origins and activities of the eukaryotic exosome. J Cell Sci. 2009; 122(Pt 10):1487–94.
Article
8. Deatherage BL, Cookson BT. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect Immun. 2012; 80:1948–57.
Article
9. Kriebel PW, Barr VA, Rericha EC, Zhang G, Parent CA. Collective cell migration requires vesicular trafficking for chemoattractant delivery at the trailing edge. J Cell Biol. 2008; 183:949–61.
Article
10. Lavialle F, Deshayes S, Gonnet F, et al. Nanovesicles released by Dictyostelium cells: a potential carrier for drug delivery. Int J Pharm. 2009; 380:206–15.
11. Regente M, Corti-Monzón G, Maldonado AM, Pinedo M, Jorrín J, de la Canal L. Vesicular fractions of sunflower apoplastic fluids are associated with potential exosome marker proteins. FEBS Lett. 2009; 583:3363–6.
Article
12. An Q, van Bel AJ, Huckelhoven R. Do plant cells secrete exosomes derived from multivesicular bodies? Plant Signal Behav. 2007; 2:4–7.
Article
13. Albuquerque PC, Nakayasu ES, Rodrigues ML, et al. Vesicular transport in Histoplasma capsulatum: an effective mechanism for trans-cell wall transfer of proteins and lipids in ascomycetes. Cell Microbiol. 2008; 10:1695–710.
14. Raposo G, Nijman HW, Stoorvogel W, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996; 183:1161–72.
Article
15. Lo Cicero A, Stahl PD, Raposo G. Extracellular vesicles shuffling intercellular messages: for good or for bad. Curr Opin Cell Biol. 2015; 35:69–77.
Article
16. Choi DS, Kim DK, Kim YK, Gho YS. Proteomics of extracellular vesicles: exosomes and ectosomes. Mass Spectrom Rev. 2015; 34:474–90.
Article
17. Kim DK, Kang B, Kim OY, et al. EVpedia: an integrated database of high-throughput data for systemic analyses of extracellular vesicles. J Extracell Vesicles. 2013; 2:20384.
Article
18. Morelli AE, Larregina AT, Shufesky WJ, et al. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood. 2004; 104:3257–66.
Article
19. Coakley G, Maizels RM, Buck AH. Exosomes and other extracellular vesicles: the new communicators in parasite infections. Trends Parasitol. 2015; 31:477–89.
Article
20. Ogawa Y, Kanai-Azuma M, Akimoto Y, Kawakami H, Yanoshita R. Exosome-like vesicles with dipeptidyl peptidase IV in human saliva. Biol Pharm Bull. 2008; 31:1059–62.
Article
21. Cheng L, Sun X, Scicluna BJ, Coleman BM, Hill AF. Characterization and deep sequencing analysis of exosomal and non-exosomal miRNA in human urine. Kidney Int. 2014; 86:433–44.
Article
22. Huang X, Yuan T, Tschannen M, et al. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics. 2013; 14:319.
Article
23. Knight M, Redman CW, Linton EA, Sargent IL. Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br J Obstet Gynaecol. 1998; 105:632–40.
Article
24. Mitchell MD, Peiris HN, Kobayashi M, et al. Placental exosomes in normal and complicated pregnancy. Am J Obstet Gynecol. 2015; 213(4 Suppl):S173–81.
Article
25. Gerlach JQ, Kruger A, Gallogly S, et al. Surface glycosylation profiles of urine extracellular vesicles. PLoS One. 2013; 8:e74801.
Article
26. Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol. 1967; 13:269–88.
Article
27. Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol. 1983; 97:329–39.
Article
28. Urbanelli L, Buratta S, Sagini K, Ferrara G, Lanni M, Emiliani C. Exosome-based strategies for diagnosis and therapy. Recent Pat CNS Drug Discov. 2015; 10:10–27.
Article
29. Li M, Zeringer E, Barta T, Schageman J, Cheng A, Vlassov AV. Analysis of the RNA content of the exosomes derived from blood serum and urine and its potential as biomarkers. Philos Trans R Soc Lond B Biol Sci. 2014; 369:20130502.
Article
30. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation: association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987; 262:9412–20.
Article
31. Michael A, Bajracharya SD, Yuen PS, et al. Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis. 2010; 16:34–8.
Article
32. Vella LJ, Greenwood DL, Cappai R, Scheerlinck JP, Hill AF. Enrichment of prion protein in exosomes derived from ovine cerebral spinal fluid. Vet Immunol Immunopathol. 2008; 124:385–93.
Article
33. Skriner K, Adolph K, Jungblut PR, Burmester GR. Association of citrullinated proteins with synovial exosomes. Arthritis Rheum. 2006; 54:3809–14.
Article
34. Sullivan R, Saez F, Girouard J, Frenette G. Role of exosomes in sperm maturation during the transit along the male reproductive tract. Blood Cells Mol Dis. 2005; 35:1–10.
Article
35. Admyre C, Johansson SM, Qazi KR, et al. Exosomes with immune modulatory features are present in human breast milk. J Immunol. 2007; 179:1969–78.
Article
36. Keller S, Rupp C, Stoeck A, et al. CD24 is a marker of exosomes secreted into urine and amniotic fluid. Kidney Int. 2007; 72:1095–102.
Article
37. Stamer WD, Hoffman EA, Luther JM, Hachey DL, Schey KL. Protein profile of exosomes from trabecular meshwork cells. J Proteomics. 2011; 74:796–804.
Article
38. Hood JL. The association of exosomes with lymph nodes. Semin Cell Dev Biol. 2017; 67:29–38.
Article
39. Admyre C, Grunewald J, Thyberg J, et al. Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid. Eur Respir J. 2003; 22:578–83.
Article
40. Mangeot PE, Dollet S, Girard M, et al. Protein transfer into human cells by VSV-G-induced nanovesicles. Mol Ther. 2011; 19:1656–66.
Article
41. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013; 200:373–83.
Article
42. Ostrowski EA, Shen Y, Tian X, et al. Genomic signatures of cooperation and conflict in the social amoeba. Curr Biol. 2015; 25:1661–5.
Article
43. Leung KF, Dacks JB, Field MC. Evolution of the multivesicular body ESCRT machinery: retention across the eukaryotic lineage. Traffic. 2008; 9:1698–716.
Article
44. Tu H, Liu Y, Marjanovic M, et al. Concurrence of extracellular vesicle enrichment and metabolic switch visualized label-free in the tumor microenvironment. Sci Adv. 2017; 3:e1600675.
Article
45. Batagov AO, Kurochkin IV. Exosomes secreted by human cells transport largely mRNA fragments that are enriched in the 3’-untranslated regions. Biol Direct. 2013; 8:12.
Article
46. Greening DW, Xu R, Ji H, Tauro BJ, Simpson RJ. A protocol for exosome isolation and characterization: evaluation of ultracentrifugation, density-gradient separation, and immunoaffinity capture methods. Methods Mol Biol. 2015; 1295:179–209.
Article
47. Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol. 2009; 11:1143–9.
Article
48. Aldick T, Bielaszewska M, Uhlin BE, Humpf HU, Wai SN, Karch H. Vesicular stabilization and activity augmentation of enterohaemorrhagic Escherichia coli haemolysin. Mol Microbiol. 2009; 71:1496–508.
49. Dutta S, Iida K, Takade A, Meno Y, Nair GB, Yoshida S. Release of Shiga toxin by membrane vesicles in Shigella dysenteriae serotype 1 strains and in vitro effects of antimicrobials on toxin production and release. Microbiol Immunol. 2004; 48:965–9.
50. Wai SN, Lindmark B, Söderblom T, et al. Vesicle-mediated export and assembly of pore-forming oligomers of the enterobacterial ClyA cytotoxin. Cell. 2003; 115:25–35.
Article
51. Buck AH, Coakley G, Simbari F, et al. Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity. Nat Commun. 2014; 5:5488.
Article
52. Greening DW, Gopal SK, Xu R, Simpson RJ, Chen W. Exosomes and their roles in immune regulation and cancer. Semin Cell Dev Biol. 2015; 40:72–81.
Article
53. Mincheva-Nilsson L, Baranov V. Placenta-derived exosomes and syncytiotrophoblast microparticles and their role in human reproduction: immune modulation for pregnancy success. Am J Reprod Immunol. 2014; 72:440–57.
Article
54. Stenqvist AC, Nagaeva O, Baranov V, Mincheva-Nilsson L. Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus. J Immunol. 2013; 191:5515–23.
Article
55. Andre F, Schartz NE, Movassagh M, et al. Malignant effusions and immunogenic tumour-derived exosomes. Lancet. 2002; 360:295–305.
Article
56. Mallat Z, Hugel B, Ohan J, Lesèche G, Freyssinet JM, Tedgui A. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation. 1999; 99:348–53.
57. Miguet L, Pacaud K, Felden C, et al. Proteomic analysis of malignant lymphocyte membrane microparticles using double ionization coverage optimization. Proteomics. 2006; 6:153–71.
Article
58. Yuan A, Farber EL, Rapoport AL, et al. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One. 2009; 4:e4722.
Article
59. Deregibus MC, Cantaluppi V, Calogero R, et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood. 2007; 110:2440–8.
60. Thimon V, Frenette G, Saez F, Thabet M, Sullivan R. Protein composition of human epididymosomes collected during surgical vasectomy reversal: a proteomic and genomic approach. Hum Reprod. 2008; 23:1698–707.
Article
61. Skog J, Wurdinger T, van Rijn S, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008; 10:1470–6.
Article
62. Fourcade O, Simon MF, Viodé C, et al. Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell. 1995; 80:919–27.
Article
63. Chavez-Muñoz C, Morse J, Kilani R, Ghahary A. Primary human keratinocytes externalize stratifin protein via exosomes. J Cell Biochem. 2008; 104:2165–73.
Article
64. Collino F, Deregibus MC, Bruno S, et al. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One. 2010; 5:e11803.
Article
65. Del Tatto M, Ng T, Aliotta JM, et al. Marrow cell genetic phenotype change induced by human lung cancer cells. Exp Hematol. 2011; 39:1072–80.
Article
66. Yang M, Chen J, Su F, et al. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer. 2011; 10:117.
Article
67. Bard MP, Hegmans JP, Hemmes A, et al. Proteomic analysis of exosomes isolated from human malignant pleural effusions. Am J Respir Cell Mol Biol. 2004; 31:114–21.
Article
68. Del Conde I, Shrimpton CN, Thiagarajan P, López JA. Tissue-factorbearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood. 2005; 106:1604–11.
Article
69. Mack M, Kleinschmidt A, Brühl H, et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nat Med. 2000; 6:769–75.
Article
70. Gardiner C, Tannetta DS, Simms CA, Harrison P, Redman CW, Sargent IL. Syncytiotrophoblast microvesicles released from preeclampsia placentae exhibit increased tissue factor activity. PLoS One. 2011; 6:e26313.
Article
71. Sabapatha A, Gercel-Taylor C, Taylor DD. Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences. Am J Reprod Immunol. 2006; 56:345–55.
Article
72. Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood. 1999; 94:3791–9.
73. Utleg AG, Yi EC, Xie T, et al. Proteomic analysis of human prostasomes. Prostate. 2003; 56:150–61.
Article
74. Martínez-Lorenzo MJ, Anel A, Gamen S, et al. Activated human T cells release bioactive Fas ligand and APO2 ligand in microvesicles. J Immunol. 1999; 163:1274–81.
75. Kesimer M, Scull M, Brighton B, et al. Characterization of exosomelike vesicles released from human tracheobronchial ciliated epithelium: a possible role in innate defense. FASEB J. 2009; 23:1858–68.
Article
76. Kalra H, Simpson RJ, Ji H, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 2012; 10:e1001450.
Article
77. Matsumura T, Sugimachi K, Iinuma H, et al. Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br J Cancer. 2015; 113:275–81.
Article
78. Hessvik NP, Phuyal S, Brech A, Sandvig K, Llorente A. Profiling of microRNAs in exosomes released from PC-3 prostate cancer cells. Biochim Biophys Acta. 2012; 1819:1154–63.
Article
79. Bryant RJ, Pawlowski T, Catto JW, et al. Changes in circulating microRNA levels associated with prostate cancer. Br J Cancer. 2012; 106:768–74.
Article
80. Saadatpour L, Fadaee E, Fadaei S, et al. Glioblastoma: exosome and microRNA as novel diagnosis biomarkers. Cancer Gene Ther. 2016; 23:415–8.
Article
81. Asaga S, Kuo C, Nguyen T, Terpenning M, Giuliano AE, Hoon DS. Direct serum assay for microRNA-21 concentrations in early and advanced breast cancer. Clin Chem. 2011; 57:84–91.
Article
82. Maas SL, Breakefield XO, Weaver AM. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 2017; 27:172–88.
Article
83. Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015; 523:177–82.
Article
84. Salomon C, Yee S, Scholz-Romero K, et al. Extravillous trophoblast cells-derived exosomes promote vascular smooth muscle cell migration. Front Pharmacol. 2014; 5:175.
Article
85. Coleman BM, Hill AF. Extracellular vesicles: their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases. Semin Cell Dev Biol. 2015; 40:89–96.
86. Lener T, Gimona M, Aigner L, et al. Applying extracellular vesicles based therapeutics in clinical trials: an ISEV position paper. J Extracell Vesicles. 2015; 4:30087.
87. Whitford W, Ludlow JW, Cadwell JJ. Continuous production of exosomes: utilizing the technical advantages of hollow-fiber bioreactor technology. Gen Eng Biotechnol News. 2015; 35:34.
88. Tauro BJ, Greening DW, Mathias RA, et al. Comparison of ultracentrifugation, density gradient separation, and immunoaffinity capture methods for isolating human colon cancer cell line LIM1863-derived exosomes. Methods. 2012; 56:293–304.
Article
89. Witwer KW, Buzás EI, Bemis LT, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. 2013; 2:20360.
Article
90. Fesler A, Jiang J, Zhai H, Ju J. Circulating microRNA testing for the early diagnosis and follow-up of colorectal cancer patients. Mol Diagn Ther. 2014; 18:303–8.
Article
91. Chikina M, Zaslavsky E, Sealfon SC. CellCODE: a robust latent variable approach to differential expression analysis for heterogeneous cell populations. Bioinformatics. 2015; 31:1584–91.
Article
92. Smith ZJ, Lee C, Rojalin T, et al. Single exosome study reveals subpopulations distributed among cell lines with variability related to membrane content. J Extracell Vesicles. 2015; 4:28533.
Article
93. Kibria G, Ramos EK, Lee KE, et al. A rapid, automated surface protein profiling of single circulating exosomes in human blood. Sci Rep. 2016; 6:36502.
Article
Full Text Links
  • JPTM
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr