Skip to main content
SpringerLink
Log in

Circulating Extracellular Vesicles in Cancer Diagnosis and Monitoring

An Appraisal of Clinical Potential

  • Current Opinion
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Mammalian cells, including cancer cells, secrete extracellular vesicles. These vesicles are nanosized, bilayered proteolipids with diameters of 50–1,000 nm. It has been suggested that cancer cell-derived extracellular vesicles play diverse roles in cancer progression, which involve invasion, immune modulation, neovascularization, and metastasis. Moreover, their serum levels are significantly elevated in cancer patients compared with normal controls. Recent high-throughput proteomic and transcriptomic studies of these complex extracellular organelles have accelerated the discovery of cancer-specific biomarkers and the development of novel diagnostic tools based on extracellular vesicles. Although many vesicle-associated biomarker candidates have been reported for various types of cancer, few have been validated for clinical use due to preanalytical, technical, temporal, and financial problems. Here, we discuss the potential of extracellular vesicles as sources of biomarkers for cancer diagnosis and monitoring, as well as the limitations and obstacles to adoption of extracellular vesicle-based diagnosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  PubMed  Google Scholar 

  2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11–30.

    Article  PubMed  Google Scholar 

  3. Hu G, Drescher KM, Chen XM. Exosomal miRNAs: biological properties and therapeutic potential. Front Genet. 2012;3:56.

    PubMed  CAS  Google Scholar 

  4. D’Souza-Schorey C, Clancy JW. Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers. Genes Dev. 2012;26(12):1287–99.

    Article  PubMed  Google Scholar 

  5. Gyorgy B, Szabo TG, Pasztoi M, et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci. 2011;68(16):2667–88.

    Article  PubMed  CAS  Google Scholar 

  6. Choi DS, Kim DK, Kim YK, et al. Proteomics, transcriptomics, and lipidomics of exosomes and ectosomes. Proteomics (Epub 2013 Feb 11).

  7. 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.

    CAS  Google Scholar 

  8. Subra C, Laulagnier K, Perret B, et al. Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie. 2007;89(2):205–12.

    Article  PubMed  CAS  Google Scholar 

  9. Choi DS, Lee JM, Park GW, et al. Proteomic analysis of microvesicles derived from human colorectal cancer cells. J Proteome Res. 2007;6(12):4646–55.

    Article  PubMed  CAS  Google Scholar 

  10. Kim CW, Lee HM, Lee TH, et al. Extracellular membrane vesicles from tumor cells promote angiogenesis via sphingomyelin. Cancer Res. 2002;62(21):6312–7.

    PubMed  CAS  Google Scholar 

  11. Lee EY, Choi DS, Kim KP, et al. Proteomics in Gram-negative bacterial outer membrane vesicles. Mass Spectrom Rev. 2008;27(6):535–55.

    Article  PubMed  CAS  Google Scholar 

  12. Lee EY, Choi DY, Kim DK, et al. Gram-positive bacteria produce membrane vesicles: proteomics-based characterization of Staphylococcus aureus-derived membrane vesicles. Proteomics. 2009;9(24):5425–36.

    Article  PubMed  CAS  Google Scholar 

  13. Deatherage BL, Cookson BT. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect Immun. 2012;80(6):1948–57.

    Article  PubMed  CAS  Google Scholar 

  14. Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581–93.

    Article  PubMed  CAS  Google Scholar 

  15. Huber V, Fais S, Iero M, et al. Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. Gastroenterology. 2005;128(7):1796–804.

    Article  PubMed  CAS  Google Scholar 

  16. Valenti R, Huber V, Filipazzi P, et al. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res. 2006;66(18):9290–8.

    Article  PubMed  CAS  Google Scholar 

  17. Lee HM, Choi EJ, Kim JH, et al. A membranous form of ICAM-1 on exosomes efficiently blocks leukocyte adhesion to activated endothelial cells. Biochem Biophys Res Commun. 2010;397(2):251–6.

    Article  PubMed  CAS  Google Scholar 

  18. Hong BS, Cho JH, Kim H, et al. Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells. BMC Genomics. 2009;25(10):556.

    Article  Google Scholar 

  19. Smalley DM, Sheman NE, Nelson K, et al. Isolation and identification of potential urinary microparticle biomarkers of bladder cancer. J Proteome Res. 2008;7(5):2088–96.

    Article  PubMed  CAS  Google Scholar 

  20. Choi DS, Park JO, Jang SC, et al. Proteomic analysis of microvesicles derived from human colorectal cancer ascites. Proteomics. 2011;11(13):2745–51.

    Article  PubMed  CAS  Google Scholar 

  21. Jung T, Castellana D, Klingbeil P, et al. CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia. 2009;11(10):1093–105.

    PubMed  CAS  Google Scholar 

  22. Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 2011;71(11):3792–801.

    Article  PubMed  CAS  Google Scholar 

  23. Lima LG, Chammas R, Monteiro RQ, et al. Tumor-derived microvesicles modulate the establishment of metastatic melanoma in a phosphatidylserine-dependent manner. Cancer Lett. 2009;283(2):168–75.

    Article  PubMed  CAS  Google Scholar 

  24. Choi DS, Choi DY, Hong BS, et al. Quantitative proteomics of extracellular vesicles derived from human primary and metastatic colorectal cancer cells. J Extracell Vesicles. 2012;1:18704.

    CAS  Google Scholar 

  25. Simpson RJ, Lim JW, Moritz RL, et al. Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics. 2009;6(3):267–83.

    Article  PubMed  CAS  Google Scholar 

  26. Raimondo F, Morosi L, Chinello C, et al. Advances in membranous vesicle and exosome proteomics improving biological understanding and biomarker discovery. Proteomics. 2011;11(4):709–20.

    Article  PubMed  CAS  Google Scholar 

  27. Colombo E, Borgiani B, Verderio C, et al. Microvesicles: novel biomarkers for neurological disorders. Front Physiol. 2012;3:63.

    Article  PubMed  CAS  Google Scholar 

  28. Muller G. Microvesicles/exosomes as potential novel biomarkers of metabolic diseases. Diabetes Metab Syndr Obes. 2012;5:247–82.

    Article  PubMed  Google Scholar 

  29. Simak J, Gelderman MP. Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers. Transfus Med Rev. 2006;20(1):1–26.

    Article  PubMed  Google Scholar 

  30. Kosaka N, Iguchi H, Ochiya T. Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci. 2010;101(10):2087–92.

    Article  PubMed  CAS  Google Scholar 

  31. Wittmann J, Jack HM. Serum microRNAs as powerful cancer biomarkers. Biochim Biophys Acta. 2010;1806(2):200–7.

    PubMed  CAS  Google Scholar 

  32. Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008;110(1):13–21.

    Article  PubMed  CAS  Google Scholar 

  33. Martinez MC, Andriantsitohaina R. Microparticles in angiogenesis: therapeutic potential. Circ Res. 2011;109(1):110–9.

    Article  PubMed  CAS  Google Scholar 

  34. Fleissner F, Goerzig Y, Haverich A, et al. Microvesicles as novel biomarkers and therapeutic targets in transplantation medicine. Am J Transplant. 2012;12(2):289–97.

    Article  PubMed  CAS  Google Scholar 

  35. Hosseini-Beheshti E, Pham S, Adomat H, et al. Exosomes as biomarker enriched microvesicles: characterization of exosomal proteins derived from a panel of prostate cell lines with distinct AR phenotypes. Mol Cell Proteomics. 2012;11(10):863–85.

    Article  PubMed  CAS  Google Scholar 

  36. Sandvig K, Llorente A. Proteomic analysis of microvesicles released by the human prostate cancer cell line PC-3. Mol Cell Proteomics. 2012;11(7):M111.012914.

    Article  PubMed  Google Scholar 

  37. Xiao D, Ohlendorf J, Chen Y, et al. Identifying mRNA, microRNA and protein profiles of melanoma exosomes. PLoS ONE. 2012;7(10):e46874.

    Article  PubMed  CAS  Google Scholar 

  38. Ohshima K, Inoue K, Fujiwara A, et al. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS ONE. 2010;5(10):e13247.

    Article  PubMed  Google Scholar 

  39. Roberson CD, Atay S, Gercel-Taylor C, et al. Tumor-derived exosomes as mediators of disease and potential diagnostic biomarkers. Cancer Biomark. 2010–2011;8(4–5):281–91.

    Google Scholar 

  40. Anderson NL, Anderson NG. The human plasma proteome: history, character, and diagnostic prospects. Mol Cell Proteomics. 2002;1(11):845–67.

    Article  PubMed  CAS  Google Scholar 

  41. Moon PG, Lee JE, You S, et al. Proteomic analysis of urinary exosomes from patients of early IgA nephropathy and thin basement membrane nephropathy. Proteomics. 2011;11(12):2459–75.

    Article  PubMed  CAS  Google Scholar 

  42. Keller S, Ridinger J, Rupp AK, et al. Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med. 2011;8(9):86.

    Article  Google Scholar 

  43. Mathivanan S, Lim JW, Tauro BJ, et al. Proteomics analysis of A33 immunoaffinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature. Mol Cell Proteomics. 2010;9(2):197–208.

    Article  PubMed  CAS  Google Scholar 

  44. Chen CL, Lai YF, Tang P, et al. Comparative and targeted proteomic analyses of urinary microparticles from bladder cancer and hernia patients. J Proteome Res. 2012;11(12):5611–29.

    PubMed  CAS  Google Scholar 

  45. Yates JR, Ruse CI, Nakorchevsky A. Proteomics by mass spectrometry: approaches, advances, and applications. Annu Rev Biomed Eng. 2009;11:49–79.

    Article  PubMed  CAS  Google Scholar 

  46. Kuzyk MA, Smith D, Yang J, et al. Multiple reaction monitoring-based, multiplexed, absolute quantitation of 45 proteins in human plasma. Mol Cell Proteomics. 2009;8(8):1860–77.

    Article  PubMed  CAS  Google Scholar 

  47. Anderson L, Hunter CL. Quantitative mass spectrometric multiple reaction monitoring assays for major plasma proteins. Mol Cell Proteomics. 2006;5(4):573–88.

    PubMed  CAS  Google Scholar 

  48. Addona TA, Abbatiello SE, Schilling B, et al. Multi-site assessment of the precision and reproducibility of multiple reaction monitoring-based measurements of proteins in plasma. Nat Biotechnol. 2009;27(7):633–41.

    Article  PubMed  CAS  Google Scholar 

  49. Linnet K, Bossuyt PM, Moons KG, et al. Quantifying the accuracy of a diagnostic test or marker. Clin Chem. 2012;58(9):1292–301.

    Article  PubMed  CAS  Google Scholar 

  50. Khan S, Jutzy JM, Valenzuela MM, et al. Plasma-derived exosomal survivin, a plausible biomarker for early detection of prostate cancer. PLoS ONE. 2012;7(10):e46737.

    Article  PubMed  CAS  Google Scholar 

  51. Mitchell PJ, Welton J, Staffurth J, et al. Can urinary exosomes act as treatment response markers in prostate cancer? J Transl Med. 2009;12(7):4.

    Article  Google Scholar 

  52. Baran J, Baj-Krzyworzeka M, Weglarczyk K, et al. Circulating tumour-derived microvesicles in plasma of gastric cancer patients. Cancer Immunol Immunother. 2010;59(6):841–50.

    Article  PubMed  CAS  Google Scholar 

  53. Huttner HB, Janich P, Kohrmann M, et al. The stem cell marker prominin-1/CD133 on membrane particles in human cerebrospinal fluid offers novel approaches for studying central nervous system disease. Stem Cells. 2008;26(3):698–705.

    Article  PubMed  CAS  Google Scholar 

  54. Li Y, Zhang Y, Qiu F, et al. Proteomic identification of exosomal LRG1: a potential urinary biomarker for detecting NSCLC. Electrophoresis. 2011;32(15):1976–83.

    Article  PubMed  CAS  Google Scholar 

  55. Nilsson J, Skog J, Nordstrand A, et al. Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer. 2009;100(10):1603–7.

    Article  PubMed  CAS  Google Scholar 

  56. 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(12):1470–6.

    Article  PubMed  CAS  Google Scholar 

  57. Tanaka Y, Kamohara H, Kinoshita K, et al. Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer. 2013;119(6):1159–67.

    Article  PubMed  CAS  Google Scholar 

  58. Davies RT, Kim J, Jang SC, et al. Microfluidic filtration system to isolate extracellular vesicles from blood. Lab Chip. 2012;12(24):5202–10.

    Article  PubMed  CAS  Google Scholar 

  59. Shao H, Chung J, Balaj L, et al. Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nat Med. 2012;18(12):1835–40.

    Article  PubMed  CAS  Google Scholar 

  60. Rubin O, Crettaz D, Tissot JD, et al. Pre-analytical and methodological challenges in red blood cell microparticle proteomics. Talanta. 2010;82(1):1–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Dong-Sic Choi and Jaewook Lee equally contributed to this manuscript. This study was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government (MEST) (No. 20120005634 and No. 2012R1A1A2042534), the Ministry of Health and Welfare grant funded by the Korea Government (MEST) (No. A120273), and a grant from the KRIBB Research Initiative Program. The authors have no conflicts of interest that are directly relevant to the content of this article.

Author information

Authors and Affiliations

  1. Department of Life Sciences, Pohang University of Science and Technology, Pohang, 790-784, Republic of Korea

    Dong-Sic Choi, Jaewook Lee, Gyeongyun Go, Yoon-Keun Kim & Yong Song Gho

Authors
  1. Dong-Sic Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaewook Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gyeongyun Go
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoon-Keun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong Song Gho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong Song Gho.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Choi, DS., Lee, J., Go, G. et al. Circulating Extracellular Vesicles in Cancer Diagnosis and Monitoring. Mol Diagn Ther 17, 265–271 (2013). https://doi.org/10.1007/s40291-013-0042-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-013-0042-7

Keywords

Search

Navigation