Clinical and Translational Oncology

, Volume 19, Issue 6, pp 651–657 | Cite as

Exosomal microRNAs in liquid biopsies: future biomarkers for prostate cancer

  • A. Valentino
  • P. Reclusa
  • R. Sirera
  • M. Giallombardo
  • C. Camps
  • P. Pauwels
  • S. Crispi
  • C. Rolfo
Review Article

Abstract

Prostate cancer is the second most diagnosed cancer in males in the world. Plasma quantification of prostate-specific antigen substantially improved the early detection of prostate cancer, but still lacks the required specificity. Clinical management of prostate cancer needs advances in the development of new non-invasive biomarkers, ameliorating current diagnosis and prognosis and guiding therapeutic decisions. microRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level. These miRNAs are expressed in the cells and are also present in cell-derived extracellular vesicles such as exosomes. Exosomes have been shown to act as mediators for cell to cell communication because of the regulatory functions of their content. High levels of exosomes are found in several body fluids from cancer patients and could be a potential source of non-invasive biomarkers. In this review, we summarize the diagnostic and prognostic utility of exosomal miRNAs in prostate cancer.

Keywords

Prostate cancer MiRNAs Exosome Biomarker Liquid biopsies 

Notes

Acknowledgements

The authors would like to thank Dr. Rodolfo Mauceri for the artwork of the figures illustrating this review.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Damber JE, Aus G. Prostate cancer. Lancet. 2008;371(9625):1710–21.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Wright ME, Chang SC, Schatzkin A, Albanes D, Kipnis V, Mouw T, et al. Prospective study of adiposity and weight change in relation to prostate cancer incidence and mortality. Cancer. 2007;109(4):675–84.CrossRefPubMedGoogle Scholar
  4. 4.
    Mellado B, Codony J, Ribal MJ, Visa L, Gascón P. Molecular biology of androgen-independent prostate cancer: the role of the androgen receptor pathway. Clin Transl Oncol. 2009;11(1):5–10.CrossRefPubMedGoogle Scholar
  5. 5.
    Ruijter E, van de Kaa C, Miller G, Ruiter D, Debruyne F, Schalken J. Molecular genetics and epidemiology of prostate carcinoma. Endocr Rev. 1999;20(1):22–45.CrossRefPubMedGoogle Scholar
  6. 6.
    Kopper L, Tímár J. Genomics of prostate cancer: is there anything to “translate”? Pathol Oncol Res. 2005;11(4):197–203.CrossRefPubMedGoogle Scholar
  7. 7.
    Brinkmann AO, Kuiper GG, Ris-Stalpers C, van Rooij HC, Romalo G, Trifiro M, et al. Androgen receptor abnormalities. J Steroid Biochem Mol Biol. 1991;40(1–3):349–52.CrossRefPubMedGoogle Scholar
  8. 8.
    Cansino Alcaide JR, Martínez-Piñeiro L. Molecular biology in prostate cancer. Clin Transl Oncol. 2006;8(3):148–52.CrossRefPubMedGoogle Scholar
  9. 9.
    Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995;332(21):1393–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Heise M, Haus O. Hereditary prostate cancer. Postepy Hig Med Dosw (Online). 2014;68:653–65.CrossRefPubMedGoogle Scholar
  11. 11.
    Hosseini-Beheshti E, Pham S, Adomat H, Li N, Tomlinson Guns ES. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014;65(1):124–37.CrossRefPubMedGoogle Scholar
  13. 13.
    Watahiki A, Macfarlane RJ, Gleave ME, Crea F, Wang Y, Helgason CD, et al. Plasma miRNAs as biomarkers to identify patients with castration-resistant metastatic prostate cancer. Int J Mol Sci. 2013;14(4):7757–70.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ruiz-Martín I, Rodríguez-Sánchez CA, Ocaña-Fernández A, del Valle-Zapico J, Soto de Prado-Otero D, Cruz-Hernández JJ. Metastatic prostate cancer with a normal prostate-specific antigen level. Clin Transl Oncol. 2005;7(9):412–3.Google Scholar
  15. 15.
    Tarhan F, Orçun A, Küçükercan I, Camursoy N, Kuyumcuoğlu U. Effect of prostatic massage on serum complexed prostate-specific antigen levels. Urology. 2005;66(6):1234–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597–610.PubMedGoogle Scholar
  17. 17.
    Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov. 2010;9(10):775–89.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Dykxhoorn DM. MicroRNAs and metastasis: little RNAs go a long way. Cancer Res. 2010;70(16):6401–6.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ. Processing of primary microRNAs by the Microprocessor complex. Nature. 2004;432(7014):231–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Heneghan HM, Miller N, Kerin MJ. MiRNAs as biomarkers and therapeutic targets in cancer. Curr Opin Pharmacol. 2010;10(5):543–50.CrossRefPubMedGoogle Scholar
  21. 21.
    Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103(7):2257–61.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435(7043):834–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Budd WT, Seashols-Williams SJ, Clark GC, Weaver D, Calvert V, Petricoin E, et al. Dual action of miR-125b as a tumor suppressor and OncomiR-22 promotes prostate cancer tumorigenesis. PLoS ONE. 2015;10(11):e0142373.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Chiosea S, Jelezcova E, Chandran U, Acquafondata M, McHale T, Sobol RW, et al. Up-regulation of dicer, a component of the MicroRNA machinery, in prostate adenocarcinoma. Am J Pathol. 2006;169(5):1812–20.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK, Calin GA. MicroRNAs in body fluids–the mix of hormones and biomarkers. Nat Rev Clin Oncol. 2011;8(8):467–77.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Metias SM, Lianidou E, Yousef GM. MicroRNAs in clinical oncology: at the crossroads between promises and problems. J Clin Pathol. 2009;62(9):771–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373–83.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Théry C, Boussac M, Véron P, Ricciardi-Castagnoli P, Raposo G, Garin J, et al. Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol. 2001;166(12):7309–18.CrossRefPubMedGoogle Scholar
  29. 29.
    Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P, et al. Malignant effusions and immunogenic tumour-derived exosomes. Lancet. 2002;360(9329):295–305.CrossRefPubMedGoogle Scholar
  30. 30.
    Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008;110(1):13–21.CrossRefPubMedGoogle Scholar
  31. 31.
    Gonzales PA, Zhou H, Pisitkun T, Wang NS, Star RA, Knepper MA, et al. Isolation and purification of exosomes in urine. Methods Mol Biol. 2010;641:89–99.CrossRefPubMedGoogle Scholar
  32. 32.
    Simons M, Raposo G. Exosomes–vesicular carriers for intercellular communication. Curr Opin Cell Biol. 2009;21(4):575–81.CrossRefPubMedGoogle Scholar
  33. 33.
    Keller S, Sanderson MP, Stoeck A, Altevogt P. Exosomes: from biogenesis and secretion to biological function. Immunol Lett. 2006;107(2):102–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Schmidt O, Teis D. The ESCRT machinery. Curr Biol. 2012;22(4):R116–20.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kowal J, Tkach M, Théry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol. 2014;29:116–25.CrossRefPubMedGoogle Scholar
  36. 36.
    Lakkaraju A, Rodriguez-Boulan E. Itinerant exosomes: emerging roles in cell and tissue polarity. Trends Cell Biol. 2008;18(5):199–209.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 2009;10(8):513–25.CrossRefPubMedGoogle Scholar
  38. 38.
    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.CrossRefPubMedGoogle Scholar
  39. 39.
    Gould SJ, Raposo G. As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles. 2013;2:20389. doi: 10.3402/jev.v2i0.20389.CrossRefGoogle Scholar
  40. 40.
    Kanchi Ravi R, Khosroheidari M, DiStefano JK. A modified precipitation method to isolate urinary exosomes. J Vis Exp. 2015;95:51158. doi: 10.3791/51158 PubMed PMID: 25651044.Google Scholar
  41. 41.
    Ronquist G, Brody I, Gottfries A, Stegmayr B. An Mg2+ and Ca2+-stimulated adenosine triphosphatase in human prostatic fluid: part I. Andrologia. 1978;10:261–72.CrossRefPubMedGoogle Scholar
  42. 42.
    Burden HP, Holmes CH, Persad R, Whittington K. Prostasomes—their effects on human male reproduction and fertility. Hum Reprod Update. 2006;12(3):283–92.CrossRefPubMedGoogle Scholar
  43. 43.
    Aalberts M, Stout TA, Stoorvogel W. Prostasomes: extracellular vesicles from the prostate. Reproduction. 2013;147(1):R1–14. doi: 10.1530/REP-13-0358 Review. PubMed PMID: 24149515.CrossRefPubMedGoogle Scholar
  44. 44.
    Carlsson L, Påhlson C, Bergquist M, Ronquist G, Stridsberg M. Antibacterial activity of human prostasomes. Prostate. 2000;44(4):279–86.CrossRefPubMedGoogle Scholar
  45. 45.
    Bjartell A, Montironi R, Berney DM, Egevad L. Tumour markers in prostate cancer II: diagnostic and prognostic cellular biomarkers. Acta Oncol. 2011;50(Suppl 1):76–84.CrossRefPubMedGoogle Scholar
  46. 46.
    Brouwers JF, Aalberts M, Jansen JW, van Niel G, Wauben MH, Stout TA, et al. Distinct lipid compositions of two types of human prostasomes. Proteomics. 2013;13(10–11):1660–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Li H, Huang S, Guo C, Guan H, Xiong C. Cell-free seminal mRNA and microRNA exist in different forms. PLoS ONE. 2012;7(4):e34566.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Babiker AA, Nilsson B, Ronquist G, Carlsson L, Ekdahl KN. Transfer of functional prostasomal CD59 of metastatic prostatic cancer cell origin protects cells against complement attack. Prostate. 2005;62(2):105–14.CrossRefPubMedGoogle Scholar
  49. 49.
    Sahlén G, Ahlander A, Frost A, Ronquist G, Norlén BJ, Nilsson BO. Prostasomes are secreted from poorly differentiated cells of prostate cancer metastases. Prostate. 2004;61(3):291–7.CrossRefPubMedGoogle Scholar
  50. 50.
    Tavoosidana G, Ronquist G, Darmanis S, Yan J, Carlsson L, Wu D, et al. Multiple recognition assay reveals prostasomes as promising plasma biomarkers for prostate cancer. Proc Natl Acad Sci USA. 2011;108(21):8809–14.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Ahadi A, Brennan S, Kennedy PJ, Hutvagner G, Tran N. Long non-coding RNAs harboring miRNA seed regions are enriched in prostate cancer exosomes. Sci Rep. 2016;6:24922.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Huang X, Yuan T, Tschannen M, Sun Z, Jacob H, Du M, et al. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genom. 2013;14:319.CrossRefGoogle Scholar
  53. 53.
    Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10(12):1470–6.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Brase JC, Johannes M, Schlomm T, Fälth M, Haese A, Steuber T, et al. Circulating miRNAs are correlated with tumor progression in prostate cancer. Int J Cancer. 2011;128(3):608–16.CrossRefPubMedGoogle Scholar
  55. 55.
    Casanova-Salas I, Rubio-Briones J, Fernández-Serra A, López-Guerrero JA. miRNAs as biomarkers in prostate cancer. Clin Transl Oncol. 2012;14(11):803–11.CrossRefPubMedGoogle Scholar
  56. 56.
    Endzeliņš E, Melne V, Kalniņa Z, Lietuvietis V, Riekstiņa U, Llorente A, et al. Diagnostic, prognostic and predictive value of cell-free miRNAs in prostate cancer: a systematic review. Mol Cancer. 2016;15(1):41.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Shariat SF, Semjonow A, Lilja H, Savage C, Vickers AJ, Bjartell A. Tumor markers in prostate cancer I: blood-based markers. Acta Oncol. 2011;50(Suppl 1):61–75.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Hizir MS, Balcioglu M, Rana M, Robertson NM, Yigit MV. Simultaneous detection of circulating oncomiRs from body fluids for prostate cancer staging using nanographene oxide. ACS Appl Mater Interfaces. 2014;6(17):14772–8.PubMedGoogle Scholar
  59. 59.
    Bonci D, Coppola V, Musumeci M, Addario A, Giuffrida R, Memeo L, et al. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med. 2008;14(11):1271–7.CrossRefPubMedGoogle Scholar
  60. 60.
    Li Z, Ma YY, Wang J, Zeng XF, Li R, Kang W, et al. Exosomal microRNA-141 is upregulated in the serum of prostate cancer patients. Onco Targets Ther. 2016;9:139–48.PubMedGoogle Scholar
  61. 61.
    Hessvik NP, Sandvig K, Llorente A. Exosomal miRNAs as Biomarkers for prostate cancer. Front Genet. 2013;4:36.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Gallo A, Tandon M, Alevizos I, Illei GG. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS ONE. 2012;7(3):e30679.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Bonci D, Coppola V, Patrizii M, Addario A, Cannistraci A, Francescangeli F, et al. A microRNA code for prostate cancer metastasis. Oncogene. 2016;35(9):1180–92.CrossRefPubMedGoogle Scholar
  64. 64.
    Bryant RJ, Pawlowski T, Catto JW, Marsden G, Vessella RL, Rhees B, et al. Changes in circulating microRNA levels associated with prostate cancer. Br J Cancer. 2012;106(4):768–74.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Lodes MJ, Caraballo M, Suciu D, Munro S, Kumar A, Anderson B. Detection of cancer with serum miRNAs on an oligonucleotide microarray. PLoS One. 2009; 4(7):e6229.Google Scholar
  66. 66.
    Circulating microRNAs (miRNA) in serum of patients with prostate cancer. Mahn R, Heukamp LC, Rogenhofer S, von Ruecker A, Müller SC, Ellinger J. Urology. 2011; 77(5):1265.e9-16.Google Scholar
  67. 67.
    Motamedinia P, Scott AN, Bate KL, Sadeghi N, Salazar G, Shapiro E, et al. Urine exosomes for non-invasive assessment of gene expression and mutations of prostate cancer. PLoS ONE. 2016;11(5):e0154507.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Øverbye A, Skotland T, Koehler CJ, Thiede B, Seierstad T, Berge V, et al. Identification of prostate cancer biomarkers in urinary exosomes. Oncotarget. 2015;6(30):30357–76.PubMedPubMedCentralGoogle Scholar
  69. 69.
    McKiernan J, Donovan MJ, O’Neill V, Bentink S, Noerholm M, Belzer S, et al. A novel urine exosome gene expression assay to predict high-grade prostate cancer at initial biopsy. JAMA Oncol. 2016;2(7):882–9.CrossRefPubMedGoogle Scholar
  70. 70.
    Nilsson J, Skog J, Nordstrand A, Baranov V, Mincheva-Nilsson L, Breakefield XO, et al. Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer. 2009;100(10):1603–7.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Samsonov R, Shtam T, Burdakov V, Glotov A, Tsyrlina E, Berstein L, et al. Lectin-induced agglutination method of urinary exosomes isolation followed by mi-RNA analysis: application for prostate cancer diagnostic. Prostate. 2016;76(1):68–79.CrossRefPubMedGoogle Scholar
  72. 72.
    Moltzahn F, Olshen AB, Baehner L, Peek A, Fong L, Stöppler H, et al. Microfluidic-based multiplex qRT-PCR identifies diagnostic and prognostic microRNA signatures in the sera of prostate cancer patients. Cancer Res. 2011;71(2):550–60.CrossRefPubMedGoogle Scholar
  73. 73.
    Lodes MJ, Caraballo M, Suciu D, Munro S, Kumar A, Anderson B. Detection of cancer with serum miRNAs on an oligonucleotide microarray. PLoS ONE. 2009;4(7):e6229.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 2010;24(18):1967–2000.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    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(11–12):1154–63.CrossRefPubMedGoogle Scholar
  76. 76.
    Corcoran C, Rani S, O’Driscoll L. miR-34a is an intracellular and exosomal predictive biomarker for response to docetaxel with clinical relevance to prostate cancer progression. Prostate. 2014;74(13):1320–34.CrossRefPubMedGoogle Scholar
  77. 77.
    Fujita Y, Kojima K, Hamada N, Ohhashi R, Akao Y, Nozawa Y, et al. Effects of miR-34a on cell growth and chemoresistance in prostate cancer PC3 cells. Biochem Biophys Res Commun. 2008;377(1):114–9.CrossRefPubMedGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2016

Authors and Affiliations

  1. 1.Phase I-Early Clinical Trials Unit, Oncology DepartmentAntwerp University HospitalEdegemBelgium
  2. 2.Center for Oncological Research (CORE)Antwerp UniversityAntwerpBelgium
  3. 3.Gene Expression and Molecular Genetics Laboratory, Institute of Biosciences and BioResourcesNational Center for Research, CNRNaplesItaly
  4. 4.Department of BiotechnologyUniversitat Politecnica de ValenciaValenciaSpain
  5. 5.Medical Oncology DepartmentHospital General Universitario de ValenciaValenciaSpain
  6. 6.Department of MedicineUniversitat de ValènciaValenciaSpain
  7. 7.Molecular Pathology UnitAntwerp University HospitalAntwerpBelgium

Personalised recommendations