Proteomic Studies in Low-Grade Gliomas: What Have They Informed About Pathophysiology?

  • A. M. J. Gerth
  • R. F. Deighton
  • J. McCulloch
  • Ian R. WhittleEmail author


The study of normal, aberrant, and dysregulated proteins (proteomics) is now becoming an established technique in biological research. Proteomics has been widely applied in biological investigations of systemic cancers and also in high-grade gliomas (HGGs). However, relatively little work has been done on questions evaluating biological aspects of low-grade gliomas (LGGs). In this chapter, the proteomic literature on LGGs is critically and systematically reviewed. Protein lists from individual studies are summarized, and differences between “control” brain tissue and LGG, LGG and HGGs, LGGs with and without 1p/19q deletions, and the impact of IDH1 deletions are evaluated. Web-based bioinformatics tools, IPA and DAVID, are also used to assess protein-protein interactions between proteins differentially expressed in LGGs. Two highly significant and important functional protein networks are identified. One in silico network reveals underlying differences between LGG and control brain, and the other reveals underlying differences between HGGs and LGGs. The roles of cell proliferation, apoptosis, and aberrant subcellular processes are highlighted. In addition, the nascent literature on 1p/19q, and IDH1 deletions is reviewed. The findings from these studies show that systematic analysis of proteomic data in LGGs is much more informative than data derived from single studies. The lack of consistent proteomic differences identified between the various studies also highlights problems in proteomic methodologies and investigative study design. The results from this review provide novel insights into LGG biology and give some direction for focus of future studies.


Astrocytoma Oligodendroglioma Proteomics Protein-protein ­interactions Functional protein networks Oncogenesis 



Glioblastoma multiforme


High-grade glioma


Low-grade glioma


  1. 1.
    Persson O, Brynnel U, Levander F, Widegren B, Salford LG, Krogh M. Proteomic expression analysis and comparison of protein and mRNA expression profiles in human malignant gliomas. Proteomics Clin Appl. 2009;3:83–94.PubMedCrossRefGoogle Scholar
  2. 2.
    Dominguez DC, Lopes R, Torres ML. Proteomics: clinical applications. Clin Lab Sci. 2007;20:245–8.PubMedGoogle Scholar
  3. 3.
    Chakravarti A, Delaney MA, Noll E, Black PM, Loeffler JS, Muzikansky A, et al. Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas. Clin Cancer Res. 2001;7:2387–95.PubMedGoogle Scholar
  4. 4.
    Mischak H, Apweiler R, Banks RE, Conaway M, Coon J, Dominiczak A, et al. Clinical proteomics: a need to define the field and to begin to set adequate standards. Proteomics Clin Appl. 2007;1:148–56.PubMedCrossRefGoogle Scholar
  5. 5.
    Petrak J, Ivanek R, Toman O, Cmejla R, Cmejlova J, Vyoral D, et al. Déjà vu in proteomics. A hit parade of repeatedly identified differentially expressed proteins. Proteomics. 2008;8:1744–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Deighton RF, Short DM, McGregor RJ, Gow AJ, Whittle IR, McCulloch J. The utility of functional interaction and cluster analysis in CNS proteomics. J Neurosci Methods. 2009;180:321–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Whittle IR, Short DM, Deighton RF, Kerr LE, Smith C, McCulloch J. Proteomic analysis of glioma. Br J Neurosurg. 2007;21:576–82.PubMedCrossRefGoogle Scholar
  8. 8.
    Chumbalkar VC, Sawaya R, Bogler O. Proteomics: the new frontier also for brain tumor research. Curr Probl Cancer. 2008;32:143–54.PubMedCrossRefGoogle Scholar
  9. 9.
    Niclou SP, Fack F, Rajcevic U. Glioma proteomics: status and perspectives. J Proteomics. 2010;73:1823–38.PubMedCrossRefGoogle Scholar
  10. 10.
    Deighton RF, McGregor R, Kemp J, McCulloch J, Whittle IR. Glioma pathophysiology: insights emerging from proteomics. Brain Path. 2010;20:691–703.CrossRefGoogle Scholar
  11. 11.
    Kalinina J, Peng J, Ritchie JC, Van Meir EG. Proteomics of gliomas: initial biomarker discovery and evolution of technology. Neuro Oncol. 2011;13:926–42.PubMedCrossRefGoogle Scholar
  12. 12.
    Deighton RF, Kerr LE, Short DM, Allerhand M, Whittle IR, McCulloch J. Network generation enhances interpretation of proteomic data from induced apoptosis. Proteomics. 2010;10:1307–15.PubMedCrossRefGoogle Scholar
  13. 13.
    Herrmann A, Ooi J, Launay S, Searcy JL, Deighton RF, McCulloch J, et al. Proteomic data in meningiomas: post-proteomic analysis can reveal novel pathophysiological pathways. J Neurooncol. 2011;104:401–10.PubMedCrossRefGoogle Scholar
  14. 14.
    Grzendowski M, Wolter M, Riemenschneider MJ, Knobbe CB, Schlegel U, Meyer HE, et al. Differential proteome analysis of human gliomas stratified for loss of heterozygosity on chromosomal arms 1p and 19q. Neuro Oncol. 2010;12:243–56.PubMedCrossRefGoogle Scholar
  15. 15.
    Anagnostopoulos AK, Dimas KS, Papathanassiou C, Braoudaki M, Anastasia E, Vougas K, et al. Proteomics studies of childhood pilocytic astrocytoma. J Proteome Res. 2011;10:2555–65.PubMedCrossRefGoogle Scholar
  16. 16.
    Huang DW, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.CrossRefGoogle Scholar
  17. 17.
    Hanash SM, Bobek MP, Rickman DS, Williams T, Rouillard JM, Kuick R, et al. Integrating cancer genomics and proteomics in the post-genome era. Proteomics. 2002;2:69–75.PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang R, Tremblay TL, McDermid A, Thibault P, Stanimirovic D. Identification of differentially expressed proteins in human glioblastoma cell lines and tumors. Glia. 2003;42:194–208.PubMedCrossRefGoogle Scholar
  19. 19.
    Hiratsuka M, Inoue T, Toda T, Kimura N, Shirayoshi Y, Kamitani H, et al. Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem Biophys Res Commun. 2003;309:558–66.PubMedCrossRefGoogle Scholar
  20. 20.
    Iwadate Y, Sakaida T, Hiwasa T, Nagai Y, Ishikura H, Takiguchi M, et al. Molecular classification and survival prediction in human gliomas based on proteome analysis. Cancer Res. 2004;64:2496–501.PubMedCrossRefGoogle Scholar
  21. 21.
    Odreman F, Vindigni M, Gonzales ML, Niccolini B, Candiano G, Zanotti B, et al. Proteomic studies on low- and high-grade human brain astrocytomas. J Proteome Res. 2005;4:698–708.PubMedCrossRefGoogle Scholar
  22. 22.
    Schwartz SA, Weil RJ, Johnson MD, Toms SA, Capriolo RM. Protein profiling in brain tumors using mass spectrometry: feasibility of a new technique for the analysis of protein expression. Clin Cancer Res. 2004;10:981–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Schwartz SA, Weil RJ, Thompson RC, Shyr Y, Moore JH, Toms SA, et al. Proteomic-based prognosis of brain tumor patients using direct-tissue matrix-­assisted laser desorption ionization mass spectrometry. Cancer Res. 2005;65:7674–81.PubMedGoogle Scholar
  24. 24.
    Fiore G, Di Cristo C, Monti G, Amoresano A, Columbano L, Pucci P, et al. Tubulin nitration in human gliomas. Neurosci Lett. 2006;394:57–62.PubMedCrossRefGoogle Scholar
  25. 25.
    Jiang R, Mircean C, Shmulevich I, Cogdell D, Jia Y, Tabus I, et al. Pathway alterations during glioma progression revealed by reverse phase protein lysate arrays. Proteomics. 2006;6:2964–71.PubMedCrossRefGoogle Scholar
  26. 26.
    Li J, Zhuang Z, Okamoto H, Vortmeyer AO, Park DM, Furuta M, et al. Proteomic profiling distinguishes astrocytomas and identifies differential tumor markers. Neurology. 2006;66:733–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Khalil AA. Biomarker discovery: a proteomic approach for brain cancer profiling. Cancer Sci. 2007;98:201–13.PubMedCrossRefGoogle Scholar
  28. 28.
    Okamoto H, Li J, Glasker S, Vortmeyer AO, Jaffe H, Robison RA, et al. Proteomic comparison of oligodendrogliomas with and without 1pLOH. Cancer Biol Ther. 2007;6:391–6.PubMedGoogle Scholar
  29. 29.
    Park CK, Kim JH, Moon MJ, Jung JH, Lim SY, Park SH, et al. Investigation of molecular factors associated with malignant transformation of oligodendroglioma by proteomic study of a single case of rapid tumor progression. J Cancer Res Clin Oncol. 2008;134:255–62.PubMedCrossRefGoogle Scholar
  30. 30.
    Park CK, Jung JH, Park SH, Jung HW, Cho BK. Multifarious proteomic signatures and regional heterogeneity in glioblastomas. J Neurooncol. 2009;94:31–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Grzendowski M, Riemenschneider MJ, Hawranke E, Stefanski A, Meyer HE, Reifenberger G, et al. Simultaneous extraction of nucleic acids and proteins from tissue specimens by ultracentrifugation: a protocol using the high-salt protein fraction for quantitative proteome analysis. Proteomics. 2009;9:4985–90.PubMedCrossRefGoogle Scholar
  32. 32.
    Gimenez M, Souza VC, Izumi C, Barbieri MR, Chammas R, Oba-Shinjo SM, et al. Proteomic analysis of low- to high-grade astrocytomas reveals an alteration of the expression level of raf kinase inhibitor protein and nucleophosmin. Proteomics. 2010;10:2812–21.PubMedCrossRefGoogle Scholar
  33. 33.
    Xiong GZ, Xiao HS, Lu JX, Zhang DS, Bi CL, Peng L, et al. Differential protein expression in low-grade astrocytomas and peritumoral human brain tissues. Neural Regen Res. 2010;5:1915–20.Google Scholar
  34. 34.
    Rostomily RC, Born DE, Beyer RP, Jin J, Alvord Jr EC, Mikheev AM, et al. Quantitative proteomic analysis of oligodendrogliomas with and without 1p/19q deletion. J Proteome Res. 2010;9:2610–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Zhuang Z, Qi M, Li J, Okamoto H, Xu DS, Iyer RR, et al. Proteomic identification of glutamine synthase as a differential marker for oligodendrogliomas and astrocytomas. J Neurosurg. 2011;115:789–95.PubMedCrossRefGoogle Scholar
  36. 36.
    Thirant C, Varlet P, Lipecka J, Le Gall M, Broussard C, Chafey P, et al. Proteomic analysis of oligodendrogliomas expressing a mutant isocitrate dehydrogenase-1. Proteomics. 2011;11:4139–54.PubMedCrossRefGoogle Scholar
  37. 37.
    Bourne TD, Schiff D. Update on molecular findings, management and outcome in low-grade gliomas. Nat Rev Neurol. 2010;6:695–701.PubMedCrossRefGoogle Scholar
  38. 38.
    Chumbalkar VC, Subhashini C, Dhople VM, Sundaram CS, Jagannadham MV, Kumar KN, et al. Differential protein expression in human gliomas and molecular insights. Proteomics. 2005;5:1167–77.PubMedCrossRefGoogle Scholar
  39. 39.
    Fontaine D, Vandenbos F, Lebrun C, Paquis V, Frenay M. Diagnostic and prognostic values of 1p and 19q deletions in adult gliomas: critical review of the literature and implications in daily clinical practice. Rev Neurol (Paris). 2008;164:595–604.CrossRefGoogle Scholar
  40. 40.
    Kim YH, Nobusawa S, Mittelbronn M, Paulus W, Brokinkel B, Keyvani K, et al. Molecular classification of low-grade diffuse gliomas. Am J Pathol. 2010;177:2708–14.PubMedCrossRefGoogle Scholar
  41. 41.
    Smith JS, Perry A, Borell TJ, Lee HK, O’Fallon J, Hosek SM, et al. Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol. 2000;18:636–45.PubMedGoogle Scholar
  42. 42.
    Hartmann C, Hentschel B, Tatagiba M, Schramm J, Schnell O, Seigel C, et al. Molecular markers in low-grade gliomas: predictive or prognostic? Clin Cancer Res. 2011;17:4588–99.PubMedCrossRefGoogle Scholar
  43. 43.
    Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807–12.PubMedCrossRefGoogle Scholar
  44. 44.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed A, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–73.PubMedCrossRefGoogle Scholar
  45. 45.
    Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, et al. J Clin Oncol. 2009;27:4150–4.PubMedCrossRefGoogle Scholar
  46. 46.
    Ichimura K, Pearson DM, Kocialkowski S, Backlund LM, Chan R, Jones DT, et al. IDH1 mutations are present in the majority of adult gliomas but rare in gliioblastoma. Neuro Oncol. 2009;11:341–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Capper D, Reuss D, Schittenhelm J, Hartmann C, Bremer J, Sahm F, et al. Mutation-specific IDH1 ­antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology. Acta Neuropathol. 2010;121:241–52.PubMedCrossRefGoogle Scholar
  48. 48.
    Van Den Bent MJ, Dubbink HJ, Marie Y, Brandes AA, Taphoorn MJ, Wesseling P, et al. IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin Cancer Res. 2010;16:1597–604.PubMedCrossRefGoogle Scholar
  49. 49.
    Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2011;75:1560–6.CrossRefGoogle Scholar
  50. 50.
    Bello L, Fava E, Carrabba G, Papagno C, Gaini SM. Present day’s standards in microsurgery of low-grade gliomas. Adv Tech Stand Neurosurg. 2010;35:113–57.PubMedCrossRefGoogle Scholar
  51. 51.
    Lote K, Egeland T, Hager B, Stenwig B, Skullerud K, Berg-Johnsen J, et al. Survival, prognostic factors, and therapeutic efficacy in low-grade glioma: a retrospective study in 379 patients. J Clin Oncol. 1997;15:3129–40.PubMedGoogle Scholar
  52. 52.
    Stieber VW. Low-grade gliomas. Curr Treat Options Oncol. 2001;2:495–506.PubMedCrossRefGoogle Scholar
  53. 53.
    Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005;64:479–89.PubMedGoogle Scholar
  54. 54.
    Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, et al. Genetic pathways to glioblastoma: a population based study. Cancer Res. 2004;64:6892–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Sanai N, Chang S, Berger MS. Low-grade gliomas in adults. J Neurosurg. 2011;115:948–65.PubMedCrossRefGoogle Scholar
  56. 56.
    Rutka JT, Murakami M, Dirks PB, Hubbard SL, Becker LE, Fukuyama K, et al. Role of glial filaments in cells and tumors of glial origin: a review. J Neurosurg. 1997;87:420–30.PubMedCrossRefGoogle Scholar
  57. 57.
    Chin D, Boyle GM, Williams RM, Ferguson K, Pandeya N, Campbell CM, et al. Alpha B-crystallin, a new independent marker for poor prognosis in head and neck cancer. Laryngoscope. 2005;115:1239–42.PubMedCrossRefGoogle Scholar
  58. 58.
    Holcakova J, Hernychova L, Bouchal P, Brozkova K, Zaloudik J, Valik D, et al. Identification of alpha B-crystallin, a biomarker of renal cell carcinoma by SELDI-TOF MS. Int J Biol Markers. 2008;23:48–53.PubMedGoogle Scholar
  59. 59.
    Ou K, Yu K, Kesuma D, Hooi M, Huang N, Chen W, et al. Novel breast cancer biomarkers identified by integrative proteomic and gene expression mapping. J Proteome Res. 2008;7:1518–28.PubMedCrossRefGoogle Scholar
  60. 60.
    Parcellier A, Schmitt E, Brunet M, Hammann A, Solary E, Garrido C. Small heat shock proteins HSP27 and alphaB-crystallin: cytoprotective and oncogenic functions. Antioxid Redox Signal. 2005;7:404–13.PubMedCrossRefGoogle Scholar
  61. 61.
    Asamoto M, Cohen SM. Prohibitin gene is overexpressed but not mutated in rat bladder carcinomas and cell lines. Cancer Lett. 1994;83:201–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Frazoni A, Dima M, D’Agnostino M, Puppin C, Fabbro D, Loreto CD, et al. Prohibitin is overexpressed in papillary thyroid carcinomas bearing the BRAF (V600E) mutation. Thyroid. 2009;19:247–55.CrossRefGoogle Scholar
  63. 63.
    Ummanni R, Junker H, Zimmermann U, Venz S, Teller S, Giebel J, et al. Prohibitin identified by proteomic analysis of prostate biopsies distinguishes hyperplasia and cancer. Cancer Lett. 2008;266:171–85.PubMedCrossRefGoogle Scholar
  64. 64.
    Rajalingham K, Rudel T. Ras-Raf signalling needs prohibitin. Cell Cycle. 2005;4:1503–5.CrossRefGoogle Scholar
  65. 65.
    Rajalingham K, Wunder C, Brinkmann V, Churin Y, Hekman M, Sievers C, et al. Prohibitin is requires for Ras-induced Raf-MEK-ERK activation and epithelial cell migration. Nat Cell Biol. 2005;7:837–43.CrossRefGoogle Scholar
  66. 66.
    Li HZ, Gao Y, Zhao XL, Liu YX, Sun BC, Yang J, et al. Effects of raf kinase inhibitor protein expression on metastasis and progression of human breast cancer. Mol Cancer Res. 2009;7:832–40.PubMedCrossRefGoogle Scholar
  67. 67.
    Kim HS, Kim GY, Lim SJ, Kim YW. Raf-1 kinase inhibitory protein expression in thyroid carcinomas. Endocr Pathol. 2010;21:253–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Al-Mulla F, Bitar MS, Feng J, Park S, Yeung KC. A new model for raf kinase inhibitory protein induced chemotherapeutic resistance. PLoS One. 2012;7:e29532.PubMedCrossRefGoogle Scholar
  69. 69.
    McKenzie AJ, Campbell SL, Howe AK. Protein kinase A activity and anchoring are required for ovarian cancer cell migration and invasion. PLoS One. 2011;6:e26552.PubMedCrossRefGoogle Scholar
  70. 70.
    Riveros S, Cardenas J, Bornens M, Rios RM. Microtubule nucleation at the cis-side of the Golgi apparatus requires AKAP450 and GM130. EMBO J. 2009;28:1016–28.CrossRefGoogle Scholar
  71. 71.
    Wang X, Ren JH, Lin F, Wei JX, Long M, Yan L, et al. Stathmin is involved in arsenic trioxide-induced apoptosis in human cervical cancer cell lines via PI3K linked signal pathway. Cancer Biol Ther. 2010;10:632–43.PubMedCrossRefGoogle Scholar
  72. 72.
    Zhang X, Cao H, Gao D. The expression Stathmin gene in laryngeal squamous cell carcinoma. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2009;23:872–3. 877.PubMedGoogle Scholar
  73. 73.
    Service RF. Proteomics ponders prime time. Science. 2008;321:1758–61.PubMedCrossRefGoogle Scholar
  74. 74.
    Reitman ZJ, Jin G, Karoly ED, Spasojevic I, Yang J, Kinzler KW, et al. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc Natl Acad Sci. 2011;108:3270–5.PubMedCrossRefGoogle Scholar
  75. 75.
    Bonetta L. Protein-protein interactions: Interactome under construction. Nature. 2010;468:851–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  • A. M. J. Gerth
    • 1
    • 2
  • R. F. Deighton
    • 2
    • 3
  • J. McCulloch
    • 2
  • Ian R. Whittle
    • 3
    • 4
    Email author
  1. 1.Centre for Clinical Brain Science, Western General HospitalUniversity of EdinburghEdinburghUK
  2. 2.Centre for Cognitive and Neural SystemsUniversity of EdinburghEdinburghUK
  3. 3.Division of Clinical NeurosciencesUniversity of Edinburgh, Western General HospitalEdinburghUK
  4. 4.Department of Clinical NeurosciencesWestern General HospitalEdinburghScotland, UK

Personalised recommendations