Skip to main content

Advertisement

SpringerLink
Log in

MicroRNA and extracellular vesicles in glioblastoma: small but powerful

  • Review Article
  • Published:
Brain Tumor Pathology Aims and scope Submit manuscript

Abstract

To promote the tumor growth, angiogenesis, metabolism, and invasion, glioblastoma (GBM) cells subvert the surrounding microenvironment by influencing the endogenous activity of other brain cells including endothelial cells, macrophages, astrocytes, and microglia. Large number of studies indicates that the intra-cellular communication between the different cell types of the GBM microenvironment occurs through the functional transfer of oncogenic components such as proteins, non-coding RNAs, DNA and lipids via the release and uptake of extracellular vesicles (EVs). Unlike the communication through the secretion of chemokines and cytokines, the transfer and gene silencing activity of microRNAs through EVs is more complex as the biogenesis and proper packaging of microRNAs is crucial for their uptake by recipient cells. Although the specific mechanism of EV-derived microRNA uptake and processing in recipient cells is largely unknown, the screening, identifying and finally targeting of the EV-associated pro-tumorigenic microRNAs are emerging as new therapeutic strategy to combat the GBM.

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

Similar content being viewed by others

References

  1. Stupp R et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466

    Article  CAS  PubMed  Google Scholar 

  2. Ostrom QT et al (2014) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro Oncol 16(Suppl 4):iv1–iv63

    Article  PubMed  PubMed Central  Google Scholar 

  3. Huntzinger E, Izaurralde E (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12(2):99–110

    Article  CAS  PubMed  Google Scholar 

  4. Piwecka M et al (2015) Comprehensive analysis of microRNA expression profile in malignant glioma tissues. Mol Oncol 9(7):1324–1340

    Article  CAS  PubMed  Google Scholar 

  5. Lee Y et al (2004) MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23(20):4051–4060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Denli AM et al (2004) Processing of primary microRNAs by the microprocessor complex. Nature 432(7014):231–235

    Article  CAS  PubMed  Google Scholar 

  7. Gregory RI et al (2004) The microprocessor complex mediates the genesis of microRNAs. Nature 432(7014):235–240

    Article  CAS  PubMed  Google Scholar 

  8. Bohnsack MT, Czaplinski K, Gorlich D (2004) Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 10(2):185–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chendrimada TP et al (2005) TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436(7051):740–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chan JA, Krichevsky AM, Kosik KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65(14):6029–6033

    Article  CAS  PubMed  Google Scholar 

  11. Ciafre SA et al (2005) Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun 334(4):1351–1358

    Article  CAS  PubMed  Google Scholar 

  12. Furnari FB et al (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21(21):2683–2710

    Article  CAS  PubMed  Google Scholar 

  13. Sumazin P et al (2011) An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma. Cell 147(2):370–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Brennan CW et al (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Phillips HS et al (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9(3):157–173

    Article  CAS  PubMed  Google Scholar 

  16. Verhaak RG et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim TM et al (2011) A developmental taxonomy of glioblastoma defined and maintained by MicroRNAs. Cancer Res 71(9):3387–3399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tang W et al (2013) Subtyping glioblastoma by combining miRNA and mRNA expression data using compressed sensing-based approach. EURASIP J Bioinf Syst Biol 2013(1):2

    Article  CAS  Google Scholar 

  19. Genovese G et al (2012) microRNA regulatory network inference identifies miR-34a as a novel regulator of TGF-beta signaling in glioblastoma. Cancer Discov 2(8):736–749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mathew LK et al (2014) miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma. Proc Natl Acad Sci USA 111(1):291–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang H et al (2015) Upregulation of miR-181s reverses mesenchymal transition by targeting KPNA4 in glioblastoma. Sci Rep 5:13072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hayes J et al (2015) Prediction of clinical outcome in glioblastoma using a biologically relevant nine-microRNA signature. Mol Oncol 9(3):704–714

    Article  CAS  PubMed  Google Scholar 

  23. Papagiannakopoulos T et al (2012) Pro-neural miR-128 is a glioma tumor suppressor that targets mitogenic kinases. Oncogene 31(15):1884–1895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cancer Genome Atlas Research N (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068

    Article  CAS  Google Scholar 

  25. Wang F et al (2014) MiRNA-181c inhibits EGFR-signaling-dependent MMP9 activation via suppressing Akt phosphorylation in glioblastoma. Tumour Biol 35(9):8653–8658

    Article  CAS  PubMed  Google Scholar 

  26. Kefas B et al (2008) microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer Res 68(10):3566–3572

    Article  CAS  PubMed  Google Scholar 

  27. Silber J et al (2008) miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 6(1):1–17

    Article  CAS  Google Scholar 

  28. Yin D et al (2013) miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme. Oncogene 32(9):1155–1163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kim J et al (2014) microRNA-148a is a prognostic oncomiR that targets MIG6 and BIM to regulate EGFR and apoptosis in glioblastoma. Cancer Res 74(5):1541–1553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lu J et al (2005) MicroRNA expression profiles classify human cancers. Nature 435(7043):834–838

    Article  CAS  PubMed  Google Scholar 

  31. Chen Y et al (2008) MicroRNA-21 down-regulates the expression of tumor suppressor PDCD4 in human glioblastoma cell T98G. Cancer Lett 272(2):197–205

    Article  CAS  PubMed  Google Scholar 

  32. Gabriely G et al (2008) MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol 28(17):5369–5380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Corsten MF et al (2007) MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell-delivered S-TRAIL in human gliomas. Cancer Res 67(19):8994–9000

    Article  CAS  PubMed  Google Scholar 

  34. Kwak HJ et al (2011) Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. Oncogene 30(21):2433–2442

    Article  CAS  PubMed  Google Scholar 

  35. Sasayama T et al (2009) MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC. Int J Cancer 125(6):1407–1413

    Article  CAS  PubMed  Google Scholar 

  36. Gabriely G et al (2011) Human glioma growth is controlled by microRNA-10b. Cancer Res 71(10):3563–3572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lavon I et al (2010) Gliomas display a microRNA expression profile reminiscent of neural precursor cells. Neuro Oncol 12(5):422–433

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ernst A et al (2010) De-repression of CTGF via the miR-17-92 cluster upon differentiation of human glioblastoma spheroid cultures. Oncogene 29(23):3411–3422

    Article  CAS  PubMed  Google Scholar 

  39. Dews M et al (2010) The myc-miR-17~92 axis blunts TGF{beta} signaling and production of multiple TGF{beta}-dependent antiangiogenic factors. Cancer Res 70(20):8233–8246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kim H et al (2010) Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship. Proc Natl Acad Sci 107(5):2183–2188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Galli R et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64(19):7011–7021

    Article  CAS  PubMed  Google Scholar 

  42. Singh SK et al (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401

    Article  CAS  PubMed  Google Scholar 

  43. Yuan X et al (2004) Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23(58):9392–9400

    Article  CAS  PubMed  Google Scholar 

  44. Bao S et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760

    Article  CAS  PubMed  Google Scholar 

  45. Bier A et al (2013) MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting RTVP-1. Oncotarget 4(5):665–676

    Article  PubMed  PubMed Central  Google Scholar 

  46. Sathyan P et al (2015) Mir-21–Sox2 axis delineates glioblastoma subtypes with prognostic impact. J Neurosci 35(45):15097–15112

    Article  CAS  PubMed  Google Scholar 

  47. Lopez-Bertoni H et al (2015) DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2. Oncogene 34(30):3994–4004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li Y et al (2009) MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res 69(19):7569–7576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kefas B et al (2009) The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors. J Neurosci 29(48):15161–15168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Floyd DH et al (2014) Novel anti-apoptotic microRNAs 582-5p and 363 promote human glioblastoma stem cell survival via direct inhibition of caspase 3, caspase 9, and Bim. PLoS One 9(5):e96239

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Godlewski J et al (2008) Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res 68(22):9125–9130

    Article  CAS  PubMed  Google Scholar 

  52. Peruzzi P et al (2013) MicroRNA-128 coordinately targets polycomb repressor complexes in glioma stem cells. Neuro Oncol 15(9):1212–1224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wong HK et al (2015) The cancer genome atlas analysis predicts MicroRNA for targeting cancer growth and vascularization in glioblastoma. Mol Ther 23(7):1234–1247

    Article  CAS  PubMed  Google Scholar 

  54. Alvarado AG et al (2015) Coordination of self-renewal in glioblastoma by integration of adhesion and microRNA signaling. Neuro Oncol. doi:10.1093/neuonc/nov196

    PubMed  Google Scholar 

  55. Zhang Y et al (2014) Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma. Cell Death Differ 21(5):720–734

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Gilbertson RJ, Rich JN (2007) Making a tumour’ bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 7(10):733–736

    Article  CAS  PubMed  Google Scholar 

  57. Babae N et al (2014) Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma. Oncotarget 5(16):6687–6700

    Article  PubMed  PubMed Central  Google Scholar 

  58. Sun J et al (2015) MiR-137 inhibits proliferation and angiogenesis of human glioblastoma cells by targeting EZH2. J Neurooncol 122(3):481–489

    Article  CAS  PubMed  Google Scholar 

  59. Ostergaard L et al (2013) The relationship between tumor blood flow, angiogenesis, tumor hypoxia, and aerobic glycolysis. Cancer Res 73(18):5618–5624

    Article  CAS  PubMed  Google Scholar 

  60. Fang L et al (2011) MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-beta8. Oncogene 30(7):806–821

    Article  CAS  PubMed  Google Scholar 

  61. Smits M et al (2012) Myc-associated zinc finger protein (MAZ) is regulated by miR-125b and mediates VEGF-induced angiogenesis in glioblastoma. FASEB J 26(6):2639–2647

    Article  CAS  PubMed  Google Scholar 

  62. Bronisz A et al (2014) Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1. Cancer Res 74(3):738–750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314

    Article  CAS  PubMed  Google Scholar 

  64. Godlewski J et al (2010) MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. Mol Cell 37(5):620–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Godlewski J et al (2010) microRNA-451: a conditional switch controlling glioma cell proliferation and migration. Cell Cycle 9(14):2742–2748

    Article  CAS  PubMed  Google Scholar 

  66. Ansari KI et al (2015) Glucose-based regulation of miR-451/AMPK signaling depends on the OCT1 transcription factor. Cell Rep 11(6):902–909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Bronisz A, Chiocca EA, Godlewski J (2015) Response to energy depletion: miR-451/AMPK loop. Oncotarget 6(20):17851–17852

    Article  PubMed  PubMed Central  Google Scholar 

  68. Hardie DG (2015) AMPK: positive and negative regulation, and its role in whole-body energy homeostasis. Curr Opin Cell Biol 33:1–7

    Article  CAS  PubMed  Google Scholar 

  69. Kefas B et al (2010) Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. Neuro Oncol 12(11):1102–1112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Masui K et al (2013) mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell Metab 18(5):726–739

    Article  CAS  PubMed  Google Scholar 

  71. Charles NA et al (2011) The brain tumor microenvironment. Glia 59(8):1169–1180

    Article  PubMed  Google Scholar 

  72. Nduom EK, Weller M, Heimberger AB (2015) Immunosuppressive mechanisms in glioblastoma. Neuro Oncol 17(Suppl 7):vii9–vii14

    Article  PubMed  Google Scholar 

  73. Codo P et al (2014) MicroRNA-mediated down-regulation of NKG2D ligands contributes to glioma immune escape. Oncotarget 5(17):7651–7662

    Article  PubMed  PubMed Central  Google Scholar 

  74. Wei J et al (2013) miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res 73(13):3913–3926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ueda R et al (2009) Dicer-regulated microRNAs 222 and 339 promote resistance of cancer cells to cytotoxic T-lymphocytes by down-regulation of ICAM-1. Proc Natl Acad Sci 106(26):10746–10751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hussain SF et al (2006) The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol 8(3):261–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Xu S et al (2014) Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma. J Natl Cancer Inst 106(8):dju162. doi:10.1093/jnci/dju162

  78. Wei J et al (2015) MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints. Neuro Oncol. doi:10.1093/neuonc/nov292

    Google Scholar 

  79. Ohno M et al (2013) Expression of miR-17-92 enhances anti-tumor activity of T-cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts. J Immunother Cancer 1:21

    Article  PubMed  PubMed Central  Google Scholar 

  80. Kosaka A et al (2015) Transgene-derived overexpression of miR-17-92 in CD8 + T-cells confers enhanced cytotoxic activity. Biochem Biophys Res Commun 458(3):549–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Heijnen HF et al (1999) Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 94(11):3791–3799

    CAS  PubMed  Google Scholar 

  82. Kowal J, Tkach M, Thery C (2014) Biogenesis and secretion of exosomes. Curr Opin Cell Biol 29:116–125

    Article  CAS  PubMed  Google Scholar 

  83. Dainiak N (1991) Surface membrane-associated regulation of cell assembly, differentiation, and growth. Blood 78(2):264–276

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  85. Ostrowski M et al. (2010) Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 12(1):19–30; sup pp 1–13

  86. Dolo V et al (1998) Selective localization of matrix metalloproteinase 9, beta1 integrins, and human lymphocyte antigen class I molecules on membrane vesicles shed by 8701-BC breast carcinoma cells. Cancer Res 58(19):4468–4474

    CAS  PubMed  Google Scholar 

  87. Schiera G et al (2007) Neurons produce FGF2 and VEGF and secrete them at least in part by shedding extracellular vesicles. J Cell Mol Med 11(6):1384–1394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Proia P et al (2008) Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor. Int J Mol Med 21(1):63–67

    CAS  PubMed  Google Scholar 

  89. Li CC et al (2013) Glioma microvesicles carry selectively packaged coding and non-coding RNAs which alter gene expression in recipient cells. RNA Biol 10(8):1333–1344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hessvik NP et al (2012) Profiling of microRNAs in exosomes released from PC-3 prostate cancer cells. Biochim Biophys Acta 1819(11–12):1154–1163

    Article  CAS  PubMed  Google Scholar 

  91. Armstrong DA et al (2015) MicroRNA molecular profiling from matched tumor and bio-fluids in bladder cancer. Mol Cancer 14(1):194

    Article  PubMed  PubMed Central  Google Scholar 

  92. Villarroya-Beltri C et al (2013) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 4:2980

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Koppers-Lalic D et al (2014) Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep 8(6):1649–1658

    Article  CAS  PubMed  Google Scholar 

  94. van der Vos KE et al (2016) Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain. Neuro Oncol 18(1):58–69

    Article  PubMed  Google Scholar 

  95. Skog J et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10(12):1470–1476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ridder K et al (2015) Extracellular vesicle-mediated transfer of functional RNA in the tumor microenvironment. Oncoimmunology 4(6):e1008371

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Gasser O et al (2003) Characterisation and properties of ectosomes released by human polymorphonuclear neutrophils. Exp Cell Res 285(2):243–257

    Article  CAS  PubMed  Google Scholar 

  98. Eken C et al (2008) Polymorphonuclear neutrophil-derived ectosomes interfere with the maturation of monocyte-derived dendritic cells. J Immunol 180(2):817–824

    Article  CAS  PubMed  Google Scholar 

  99. Pluskota E et al (2008) Expression, activation, and function of integrin alphaMbeta2 (Mac-1) on neutrophil-derived microparticles. Blood 112(6):2327–2335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hoshino A et al (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527(7578):329–335

    Article  CAS  PubMed  Google Scholar 

  101. Gasser O, Schifferli JA (2004) Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood 104(8):2543–2548

    Article  CAS  PubMed  Google Scholar 

  102. Al-Nedawi K et al (2008) Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 10(5):619–624

    Article  CAS  PubMed  Google Scholar 

  103. Nakase I et al (2015) Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes. Sci Rep 5:10300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Svensson KJ et al (2013) Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft-mediated endocytosis negatively regulated by caveolin-1. J Biol Chem 288(24):17713–17724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Christianson HC et al (2013) Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci USA 110(43):17380–17385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Atai NA et al (2013) Heparin blocks transfer of extracellular vesicles between donor and recipient cells. J Neurooncol 115(3):343–351

    Article  CAS  PubMed  Google Scholar 

  107. Montecalvo A et al (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119(3):756–766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Parolini I et al (2009) Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 284(49):34211–34222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mineo M et al (2012) Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a Src-dependent fashion. Angiogenesis 15(1):33–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kucharzewska P et al (2013) Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci USA 110(18):7312–7317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Agrawal R et al (2014) Hypoxic signature of microRNAs in glioblastoma: insights from small RNA deep sequencing. BMC Genom 15:686

    Article  Google Scholar 

  112. Tadokoro H et al (2013) Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem 288(48):34343–34351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Li R et al (2014) Identification of intrinsic subtype-specific prognostic microRNAs in primary glioblastoma. J Exp Clin Cancer Res 33:9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Yan W et al (2014) MicroRNA expression patterns in the malignant progression of gliomas and a 5-microRNA signature for prognosis. Oncotarget 5(24):12908–12915

    Article  PubMed  PubMed Central  Google Scholar 

  115. Hu J et al (2016) MiR-215 is induced post-transcriptionally via HIF-Drosha complex and mediates glioma-initiating cell adaptation to hypoxia by targeting KDM1B. Cancer Cell 29(1):49–60

    Article  CAS  PubMed  Google Scholar 

  116. Chen CC et al (2009) Stereotactic brain biopsy: single center retrospective analysis of complications. Clin Neurol Neurosurg 111(10):835–839

    Article  PubMed  Google Scholar 

  117. Westphal M, Lamszus K (2015) Circulating biomarkers for gliomas. Nat Rev Neurol 11(10):556–566

    Article  CAS  PubMed  Google Scholar 

  118. Pisitkun T, Shen RF, Knepper MA (2004) Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci USA 101(36):13368–13373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gallo A et al (2012) The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One 7(3):e30679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Akers JC et al (2013) MiR-21 in the extracellular vesicles (EVs) of cerebrospinal fluid (CSF): a platform for glioblastoma biomarker development. PLoS One 8(10):e78115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Qu S, Guan J, Liu Y (2015) Identification of microRNAs as novel biomarkers for glioma detection: a meta-analysis based on 11 articles. J Neurol Sci 348(1–2):181–187

    Article  CAS  PubMed  Google Scholar 

  122. Shi L et al (2010) MiR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 activity. Brain Res 1352:255–264

    Article  CAS  PubMed  Google Scholar 

  123. Teplyuk NM et al (2012) MicroRNAs in cerebrospinal fluid identify glioblastoma and metastatic brain cancers and reflect disease activity. Neuro Oncol 14(6):689–700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Roth P et al (2011) A specific miRNA signature in the peripheral blood of glioblastoma patients. J Neurochem 118(3):449–457

    Article  CAS  PubMed  Google Scholar 

  125. Manterola L et al (2014) A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro Oncol 16(4):520–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Bronisz A et al (2012) Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat Cell Biol 14(2):159–167

    Article  CAS  PubMed Central  Google Scholar 

  127. Sun JY et al (2015) MicroRNA-320 inhibits cell proliferation in glioma by targeting E2F1. Mol Med Rep 12(2):2355–2359

    CAS  PubMed  Google Scholar 

Download references

Financial support

NCI 1R01 CA176203-01A1 (JG).

Author information

Author notes

    Authors and Affiliations

    1. Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, 4 Blackfan Circle, Boston, MA, 02115, USA

      Arun K. Rooj, Marco Mineo & Jakub Godlewski

    Authors
    1. Arun K. Rooj
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Marco Mineo
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jakub Godlewski
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Jakub Godlewski.

    Ethics declarations

    Conflict of interest

    Authors declare no conflict of interest.

    Additional information

    A. K. Rooj and M. Mineo contributed equally to the manuscript.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Rooj, A.K., Mineo, M. & Godlewski, J. MicroRNA and extracellular vesicles in glioblastoma: small but powerful. Brain Tumor Pathol 33, 77–88 (2016). https://doi.org/10.1007/s10014-016-0259-3

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10014-016-0259-3

    Keywords

    Search

    Navigation