Skip to main content

Advertisement

SpringerLink
Log in

ExRNA in Biofluids as Biomarkers for Brain Tumors

  • Review Paper
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Patients with high-grade gliomas and glioblastomas (GBMs) have poor survival despite optimal surgical and drug therapy. Minimally invasive diagnostic biomarkers would enable early diagnosis and tumor-specific treatments for ‘personalized targeted’ therapy, and would create the basis for response tracking in patients with GBM. Extracellular vesicles (EVs) isolated from cerebrospinal fluid and blood contain glioma-specific molecules, including tumor-derived EV RNAs that are detectable in small copy numbers in these biofluids. EV RNA mutations or expression changes are also detectable, the analysis of which gives rise to ‘liquid biopsy’ tumor profiling.

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

Similar content being viewed by others

References

  • Akers JC, Ramakrishnan V, Kim R, Skog J, Nakano I, Pingle S, Kalinina J, Hua W, Kesari S, Mao Y, Breakefield XO, Hochberg FH, Van Meir EG, Carter BS, Chen CC (2013) MiR-21 in the extracellular vesicles (EVs) of cerebrospinal fluid (CSF): a platform for glioblastoma biomarker development. PLoS One 8:e78115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U, Beier CP (2007) CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67:4010–4015

    Article  CAS  PubMed  Google Scholar 

  • Beier CP, Kumar P, Meyer K, Leukel P, Bruttel V, Aschenbrenner I, Riemenschneider MJ, Fragoulis A, Rummele P, Lamszus K, Schulz JB, Weis J, Bogdahn U, Wischhusen J, Hau P, Spang R, Beier D (2012) The cancer stem cell subtype determines immune infiltration of glioblastoma. Stem Cells Dev 21:2753–2761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bleeker FE, Atai NA, Lamba S, Jonker A, Rijkeboer D, Bosch KS, Tigchelaar W, Troost D, Vandertop WP, Bardelli A, Van Noorden CJ (2010) The prognostic IDH1(R132) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol 119:487–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonavia R, Inda MM, Cavenee WK, Furnari FB (2011) Heterogeneity maintenance in glioblastoma: a social network. Cancer Res 71:4055–4060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bronisz A, Wang Y, Nowicki MO, Peruzzi P, Ansari KI, Ogawa D, Balaj L, De Rienzo G, Mineo M, Nakano I, Ostrowski MC, Hochberg F, Weissleder R, Lawler SE, Chiocca EA, Godlewski J (2014) Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1. Cancer Res 74:738–750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butler WE, Atai N, Carter B, Hochberg F (2014) Informatic system for a global tissue-fluid biorepository with a graph theory-oriented graphical user interface. J Extracell Vesicles. doi:10.3402/jev.v3.24247

    PubMed  PubMed Central  Google Scholar 

  • Chen WW, Balaj L, Liau LM, Samuels ML, Kotsopoulos SK, Maguire CA, Loguidice L, Soto H, Garrett M, Zhu LD, Sivaraman S, Chen C, Wong ET, Carter BS, Hochberg FH, Breakefield XO, Skog J (2013) BEAMing and droplet digital PCR analysis of mutant IDH1 mRNA in glioma patient serum and cerebrospinal fluid extracellular vesicles. Mol Ther Nucleic Acids. 2:e109

    Article  PubMed  PubMed Central  Google Scholar 

  • Chittiboina P, Connor DE Jr, Caldito G, Quillin JW, Wilson JD, Nanda A (2012) Occult tumors presenting with negative imaging: analysis of the literature. J Neurosurg 116:1195–1203

    Article  PubMed  Google Scholar 

  • Darefsky AS, King JT Jr, Dubrow R (2012) Adult glioblastoma multiforme survival in the temozolomide era: a population-based analysis of Surveillance, Epidemiology, and End Results registries. Cancer 118:2163–2172

    Article  PubMed  PubMed Central  Google Scholar 

  • de Vrij J, Maas SL, Kwappenberg KM, Schnoor R, Kleijn A, Dekker L, Luider TM, de Witte LD, Litjens M, van Strien ME, Hol EM, Kroonen J, Robe PA, Lamfers ML, Schilham MW, Broekman ML (2015) Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells. Int J Cancer. 137:1630–1642

    Article  PubMed  Google Scholar 

  • Fischer I, Cunliffe CH, Bollo RJ, Raza S, Monoky D, Chiriboga L, Parker EC, Golfinos JG, Kelly PJ, Knopp EA, Gruber ML, Zagzag D, Narayana A (2008) High-grade glioma before and after treatment with radiation and Avastin: initial observations. Neuro Oncol. 10:700–708

    Article  PubMed  PubMed Central  Google Scholar 

  • Gonda DD, Akers JC, Kim R, Kalkanis SN, Hochberg FH, Chen CC, Carter BS (2013) Neuro-oncologic applications of exosomes, microvesicles, and other nano-sized extracellular particles. Neurosurgery. 72:501–510

    Article  PubMed  Google Scholar 

  • Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003

    Article  CAS  PubMed  Google Scholar 

  • Heimberger AB, Hlatky R, Suki D, Yang D, Weinberg J, Gilbert M, Sawaya R, Aldape K (2005) Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res 11:1462–1466

    Article  CAS  PubMed  Google Scholar 

  • Hochberg FH, Atai NA, Gonda D, Hughes MS, Mawejje B, Balaj L, Carter RS (2014) Glioma diagnostics and biomarkers: an ongoing challenge in the field of medicine and science. Expert Rev Mol Diagn. 14:439–452

    Article  CAS  PubMed  Google Scholar 

  • Jackson RJ, Fuller GN, Abi-Said D, Lang FF, Gokaslan ZL, Shi WM, Wildrick DM, Sawaya R (2001) Limitations of stereotactic biopsy in the initial management of gliomas. Neuro Oncol 3:193–200

    CAS  PubMed  PubMed Central  Google Scholar 

  • Joshi P, Benussi L, Furlan R, Ghidoni R, Verderio C (2015) Extracellular vesicles in Alzheimer’s disease: friends or foes? Focus on abeta-vesicle interaction. Int J Mol Sci 16:4800–4813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kunadt M, Eckermann K, Stuendl A, Gong J, Russo B, Strauss K, Rai S, Kugler S, Falomir Lockhart L, Schwalbe M, Krumova P, Oliveira LM, Bahr M, Mobius W, Levin J, Giese A, Kruse N, Mollenhauer B, Geiss-Friedlander R, Ludolph AC, Freischmidt A, Feiler MS, Danzer KM, Zweckstetter M, Jovin TM, Simons M, Weishaupt JH, Schneider A (2015) Extracellular vesicle sorting of alpha-Synuclein is regulated by sumoylation. Acta Neuropathol. 129:695–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kushwaha D, Ramakrishnan V, Ng K, Steed T, Nguyen T, Futalan D, Akers JC, Sarkaria J, Jiang T, Chowdhury D, Carter BS, Chen CC (2014) A genome-wide miRNA screen revealed miR-603 as a MGMT-regulating miRNA in glioblastomas. Oncotarget. 5:4026–4039

    Article  PubMed  PubMed Central  Google Scholar 

  • Kutikova L, Bowman L, Chang S, Long SR, Thornton DE, Crown WH (2007) Utilization and cost of health care services associated with primary malignant brain tumors in the United States. J Neurooncol 81:61–65

    Article  PubMed  Google Scholar 

  • Laterra J, Keep R, Betz LA, Goldstein GW (1999) Basic neurochemistry: molecular, cellular and medical aspects, vol 6., Blood-cerebrospinal fluid barrier Lippincott-Raven, Philadelphia

    Google Scholar 

  • Lechapt-Zalcman E, Levallet G, Dugue AE, Vital A, Diebold MD, Menei P, Colin P, Peruzzy P, Emery E, Bernaudin M, Chapon F, Guillamo JS (2012) O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation and low MGMT-encoded protein expression as prognostic markers in glioblastoma patients treated with biodegradable carmustine wafer implants after initial surgery followed by radiotherapy with concomitant and adjuvant temozolomide. Cancer 118:4545–4554

    Article  CAS  PubMed  Google Scholar 

  • Lottaz C, Beier D, Meyer K, Kumar P, Hermann A, Schwarz J, Junker M, Oefner PJ, Bogdahn U, Wischhusen J, Spang R, Storch A, Beier CP (2010) Transcriptional profiles of CD133+ and CD133− glioblastoma-derived cancer stem cell lines suggest different cells of origin. Cancer Res 70:2030–2040

    Article  CAS  PubMed  Google Scholar 

  • Masui K, Cloughesy TF, Mischel PS (2012) Review: molecular pathology in adult high-grade gliomas: from molecular diagnostics to target therapies. Neuropathol Appl Neurobiol 38:271–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McNamara MG, Sahebjam S, Mason WP (2013) Emerging biomarkers in glioblastoma. Cancers. 5:1103–1119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mellai M, Monzeglio O, Piazzi A, Caldera V, Annovazzi L, Cassoni P, Valente G, Cordera S, Mocellini C, Schiffer D (2012) MGMT promoter hypermethylation and its associations with genetic alterations in a series of 350 brain tumors. J Neurooncol 107:617–631

    Article  CAS  PubMed  Google Scholar 

  • Messali A, Hay JW, Villacorta R (2013) The cost-effectiveness of temozolomide in the adjuvant treatment of newly diagnosed glioblastoma in the United States. Neuro Oncol. 15:1532–1542

    Article  PubMed  PubMed Central  Google Scholar 

  • Nakano I, Garnier D, Minata M, Rak J (2015) Extracellular vesicles in the biology of brain tumour stem cells—implications for inter-cellular communication, therapy and biomarker development. Semin Cell Dev Biol. 40:17–26

    Article  CAS  PubMed  Google Scholar 

  • Nickel GC, Barnholtz-Sloan J, Gould MP, McMahon S, Cohen A, Adams MD, Guda K, Cohen M, Sloan AE, LaFramboise T (2012) Characterizing mutational heterogeneity in a glioblastoma patient with double recurrence. PLoS One 7:e35262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, Verhaak RG, Hoadley KA, Hayes DN, Perou CM, Schmidt HK, Ding L, Wilson RK, Van Den Berg D, Shen H, Bengtsson H, Neuvial P, Cope LM, Buckley J, Herman JG, Baylin SB, Laird PW, Aldape K (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, Louis DN, Rozenblatt-Rosen O, Suva ML, Regev A, Bernstein BE (2014) Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344:1396–1401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patz S, Trattnig C, Grunbacher G, Ebner B, Gully C, Novak A, Rinner B, Leitinger G, Absenger M, Tomescu OA, Thallinger GG, Fasching U, Wissa S, Archelos-Garcia J, Schafer U (2013) More than cell dust: microparticles isolated from cerebrospinal fluid of brain injured patients are messengers carrying mRNAs, miRNAs, and proteins. J Neurotrauma 30:1232–1242

    Article  PubMed  Google Scholar 

  • Pelloski CE, Ballman KV, Furth AF, Zhang L, Lin E, Sulman EP, Bhat K, McDonald JM, Yung WK, Colman H, Woo SY, Heimberger AB, Suki D, Prados MD, Chang SM, Barker FG 2nd, Buckner JC, James CD, Aldape K (2007) Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J Clin Oncol 25:2288–2294

    Article  CAS  PubMed  Google Scholar 

  • Ramakrishnan V, Kushwaha D, Koay DC, Reddy H, Mao Y, Zhou L, Ng K, Zinn P, Carter B, Chen CC (2011) Post-transcriptional regulation of O(6)-methylguanine-DNA methyltransferase MGMT in glioblastomas. Cancer Biomark. 10:185–193

    CAS  PubMed  Google Scholar 

  • Reddy SP, Britto R, Vinnakota K, Aparna H, Sreepathi HK, Thota B, Kumari A, Shilpa BM, Vrinda M, Umesh S, Samuel C, Shetty M, Tandon A, Pandey P, Hegde S, Hegde AS, Balasubramaniam A, Chandramouli BA, Santosh V, Kondaiah P, Somasundaram K, Rao MR (2008) Novel glioblastoma markers with diagnostic and prognostic value identified through transcriptome analysis. Clin Cancer Res 14:2978–2987

    Article  CAS  PubMed  Google Scholar 

  • Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, De Maria R (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468:824–828

    Article  CAS  PubMed  Google Scholar 

  • Rock JP, Hearshen D, Scarpace L, Croteau D, Gutierrez J, Fisher JL, Rosenblum ML, Mikkelsen T (2002) Correlations between magnetic resonance spectroscopy and image-guided histopathology, with special attention to radiation necrosis. Neurosurgery. 51:912–919 (discussion 919–920)

    PubMed  Google Scholar 

  • Ruano Y, Mollejo M, Camacho FI, Rodriguez de Lope A, Fiano C, Ribalta T, Martinez P, Hernandez-Moneo JL, Melendez B (2008) Identification of survival-related genes of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma multiforme. Cancer 112:1575–1584

    Article  CAS  PubMed  Google Scholar 

  • Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE 2nd, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD (2010) Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 28:4722–4729

    Article  PubMed  PubMed Central  Google Scholar 

  • Sarkaria JN, Kitange GJ, James CD, Plummer R, Calvert H, Weller M, Wick W (2008) Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clin Cancer Res 14:2900–2908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shao H, Chung J, Balaj L, Charest A, Bigner DD, Carter BS, Hochberg FH, Breakefield XO, Weissleder R, Lee H (2012) Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nat Med 18:1835–1840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shao H, Chung J, Lee K, Balaj L, Min C, Carter BS, Hochberg FH, Breakefield XO, Lee H, Weissleder R (2015) Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma. Nat Commun. 6:6999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC, Curtis C, Watts C, Tavare S (2013) Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci USA 110:4009–4014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sreekanthreddy P, Srinivasan H, Kumar DM, Nijaguna MB, Sridevi S, Vrinda M, Arivazhagan A, Balasubramaniam A, Hegde AS, Chandramouli BA, Santosh V, Rao MR, Kondaiah P, Somasundaram K (2010) Identification of potential serum biomarkers of glioblastoma: serum osteopontin levels correlate with poor prognosis. Cancer Epidemiol Biomarkers Prev. 19:1409–1422

    Article  CAS  PubMed  Google Scholar 

  • Thon N, Kreth S, Kreth FW (2013) Personalized treatment strategies in glioblastoma: MGMT promoter methylation status. Onco Targets Ther. 6:1363–1372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Towner RA, Jensen RL, Colman H, Vaillant B, Smith N, Casteel R, Saunders D, Gillespie DL, Silasi-Mansat R, Lupu F, Giles CB, Wren JD (2013) ELTD1, a potential new biomarker for gliomas. Neurosurgery. 72:77–90 (discussion 91)

    Article  PubMed  PubMed Central  Google Scholar 

  • Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D, Parsons R (1997) Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res 57:4183–4186

    CAS  PubMed  Google Scholar 

  • Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C, Tabar V (2010) Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468:829–833

    Article  CAS  PubMed  Google Scholar 

  • Weber MA, Zoubaa S, Schlieter M, Juttler E, Huttner HB, Geletneky K, Ittrich C, Lichy MP, Kroll A, Debus J, Giesel FL, Hartmann M, Essig M (2006) Diagnostic performance of spectroscopic and perfusion MRI for distinction of brain tumors. Neurology 66:1899–1906

    Article  CAS  PubMed  Google Scholar 

  • Witwer KW, Buzas EI, Bemis LT, Bora A, Lasser C, Lotvall J, Nolte-’t Hoen EN, Piper MG, Sivaraman S, Skog J, Thery C, Wauben MH, Hochberg F (2013) Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. doi:10.3402/jev.v2i0.20360

    PubMed  PubMed Central  Google Scholar 

  • Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 89:2965–2969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yip S, Miao J, Cahill DP, Iafrate AJ, Aldape K, Nutt CL, Louis DN (2009) MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res 15:4622–4629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhi F, Chen X, Wang S, Xia X, Shi Y, Guan W, Shao N, Qu H, Yang C, Zhang Y, Wang Q, Wang R, Zen K, Zhang CY, Zhang J, Yang Y (2010) The use of hsa-miR-21, hsa-miR-181b and hsa-miR-106a as prognostic indicators of astrocytoma. Eur J Cancer 46:1640–1649

    Article  CAS  PubMed  Google Scholar 

  • Zhou X, Ren Y, Moore L, Mei M, You Y, Xu P, Wang B, Wang G, Jia Z, Pu P, Zhang W, Kang C (2010) Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Invest 90:144–155

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University of California – San Diego, 3855 Health Science Drive #0987, La Jolla, San Diego, CA, 92093-0987, USA

    Robert C. Rennert, Fred H. Hochberg & Bob S. Carter

Authors
  1. Robert C. Rennert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fred H. Hochberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bob S. Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert C. Rennert.

Ethics declarations

Conflict of interest

This manuscript was prepared without external funding. R.C.R., F.H.H., and B.S.C. have no conflicts of interest to report.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rennert, R.C., Hochberg, F.H. & Carter, B.S. ExRNA in Biofluids as Biomarkers for Brain Tumors. Cell Mol Neurobiol 36, 353–360 (2016). https://doi.org/10.1007/s10571-015-0284-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-015-0284-5

Keywords

Search

Navigation