Skip to main content

Advertisement

Log in

Molecular mechanisms involved in gliomagenesis

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

Abstract

The application of molecular parameters in the World Health Organization classification of central nervous system tumors has advanced remarkably in this field. Large-scale genomic DNA analyses, including gene expression profiling, genome-wide association studies, and single-nucleotide polymorphism analysis, have revealed differences between tumors with the same pathological features. Because mutated genes and their signaling pathways can be targets for therapy, categorizing tumors by molecular parameters facilitates the selection of optimal therapeutic methods. Many genes are either oncogenes or tumor suppressor genes, and many of them are also involved in normal development, such as neural stem cell maintenance and neural differentiation. Moreover, genetic engineering has enabled the generation of tumors that phenocopy human tumors in mice. Here, I will discuss key molecular parameters, mechanisms of neural differentiation, isocitrate dehydrogenases, 1p36/19q13, and p53 in gliomagenesis. Because future therapeutic methods will be determined by the molecular mechanisms of tumors, identification of new parameters is still needed for further classification of glioma.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization Classification of Tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820

    Article  PubMed  Google Scholar 

  2. 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; Cancer Genome Atlas Research Network (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 

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

    Article  Google Scholar 

  4. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dimitrov L, Hong CS, Yang C, Zhuang Z, Heiss JD (2015) New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma. Int J Med Sci 12:201–213

    Article  PubMed  PubMed Central  Google Scholar 

  7. Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP (1994) Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145:1175–1190

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Ueki K (2005) Oligodendroglioma: impact of molecular biology on its definition, diagnosis and management. Neuropathology 25:247–253

    Article  PubMed  Google Scholar 

  9. Wesseling P, van den Bent M, Perry A (2015) Oligodendroglioma: pathology, molecular mechanisms and markers. Acta Neuropathol 129:809–827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gage F (2000) Mammalian neural stem cells. Science 287:1433–1438

    Article  CAS  PubMed  Google Scholar 

  11. Temple S (2001) The development of neural stem cells. Nature 414:112–117

    Article  CAS  PubMed  Google Scholar 

  12. Singh SK, Clarke ID, Hide T, Dirks PB (2004) Cancer stem cells in nervous system tumors. Oncogene 23:7267–7273

    Article  CAS  PubMed  Google Scholar 

  13. Kondo T (2006) Brain cancer stem-like cells. Eur J Cancer 42:1237–1242

    Article  CAS  PubMed  Google Scholar 

  14. Vescovi AL, Galli R, Reynolds BA (2006) Brain tumour stem cells. Nat Rev Cancer 6:425–436

    Article  CAS  PubMed  Google Scholar 

  15. Hide T, Takezaki T, Nakatani Y, Nakamura H, Kuratsu J, Kondo T (2009) Sox11 prevents tumorigenesis of glioma-initiating cells by inducing neuronal differentiation. Cancer Res 69:7953–7959

    Article  CAS  PubMed  Google Scholar 

  16. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710

    Article  CAS  PubMed  Google Scholar 

  17. Vescovi AL, Reynolds BA, Fraser DD, Weiss S (1993) bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron 11:951–966

    Article  CAS  PubMed  Google Scholar 

  18. Norton JD (2000) ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. J Cell Sci 113:3897–3905

    CAS  PubMed  Google Scholar 

  19. Graham V, Khudyakov J, Ellis P, Pevny L (2003) SOX2 functions to maintain neural progenitor identity. Neuron 39:749–765

    Article  CAS  PubMed  Google Scholar 

  20. Bruggeman SW, Valk-Lingbeek ME, van der Stoop PP, Jacobs JJ, Kieboom K, Tanger E, Hulsman D, Leung C, Arsenijevic Y, Marino S, van Lohuizen M (2005) Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev 19:1438–1443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 19:1432–1437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME (1997) Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278:477–483

    Article  CAS  PubMed  Google Scholar 

  23. Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T (1999) Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284:479–482

    Article  CAS  PubMed  Google Scholar 

  24. Lyden D, Young AZ, Zagzag D, Yan W, Gerald W, O’Reilly R, Bader BL, Hynes RO, Zhuang Y, Manova K, Benezra R (1999) Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401:670–677

    Article  CAS  PubMed  Google Scholar 

  25. Kondo T, Raff M (2000) The Id4 HLH protein and the timing of oligodendrocyte differentiation. EMBO J 19:1998–2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fukuda S, Kondo T, Takebayashi H, Taga T (2004) Negative regulatory effect of an oligodendrocytic bHLH factor OLIG2 on the astrocytic differentiation pathway. Cell Death Differ 11:196–202

    Article  CAS  PubMed  Google Scholar 

  27. Noble M, Murray K, Stroobant P, Waterfield MD, Riddle P (1988) Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. Nature 333:560–562

    Article  CAS  PubMed  Google Scholar 

  28. Raff MC, Lillien LE, Richardson WD, Burne JF, Noble MD (1988) Platelet-derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture. Nature 333:562–565

    Article  CAS  PubMed  Google Scholar 

  29. Richardson WD, Pringle N, Mosley MJ, Westermark B, Dubois-Dalcq M (1988) A role for platelet-derived growth factor in normal gliogenesis in the central nervous system. Cell 53:309–319

    Article  CAS  PubMed  Google Scholar 

  30. Rodriguez-Pena A (1999) Oligodendrocyte development and thyroid hormone. J Neurobiol 40:497–512

    Article  CAS  PubMed  Google Scholar 

  31. Rowitch DH, S-Jacques B, Lee SM, Flax JD, Snyder EY, McMahon AP (1999) Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J Neurosci 19:8954–8965

    CAS  PubMed  Google Scholar 

  32. Mekki-Dauriac S, Agius E, Kan P, Cochard P (2002) Bone morphogenetic proteins negatively control oligodendrocyte precursor specification in the chick spinal cord. Development 129:5117–5130

    CAS  PubMed  Google Scholar 

  33. Lai K, Kaspar BK, Gage FH, Schaffer DV (2003) Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 6:21–27

    Article  CAS  PubMed  Google Scholar 

  34. Shimizu T, Kagawa T, Wada T, Muroyama Y, Takada S, Ikenaka K (2005) Wnt signaling controls the timing of oligodendrocyte development in the spinal cord. Dev Biol 282:397–410

    Article  CAS  PubMed  Google Scholar 

  35. Krämer-Albers EM, White R (2011) From axon-glial signaling to myelination: the integrating role of oligodendroglial Fyn kinase. Cell Mol Life Sci 68:2003–2012

    Article  PubMed  Google Scholar 

  36. Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, Yu W, Li Z, Gong L, Peng Y, Ding J, Lei Q, Guan KL, Xiong Y (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324:261–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE, O’Rourke DM, Berger SL, Chan TA, Levine RL, Mellinghoff IK, Thompson CB (2012) IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483:474–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang G, Sai K, Gong F, Yang Q, Chen F, Lin J (2014) Mutation of isocitrate dehydrogenase 1 induces glioma cell proliferation via NK-κB activation in a hypoxia-inducible factor 1-α dependent manner. Mol Med Rep 9:1799–1805

    CAS  PubMed  Google Scholar 

  39. Sasaki M, Knobbe CB, Itsumi M, Elia AJ, Harris IS, Chio II, Cairns RA, McCracken S, Wakeham A, Haight J, Ten AY, Snow B, Ueda T, Inoue S, Yamamoto K, Ko M, Rao A, Yen KE, Su SM, Mak TW (2012) D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev 26:2038–2049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bonner MY, Arbiser JL (2012) Targeting NADPH oxidases for the treatment of cancer and inflammation. Cell Mol Life Sci 69:2435–2442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Billon N, Terrinoni A, Jolicoeur C, McCarthy A, Richardson WD, Melino G, Raff M (2004) Roles for p53 and p73 during oligodendrocyte development. Development 131:1211–1220

    Article  CAS  PubMed  Google Scholar 

  42. Wolf RM, Wilkes JJ, Chao MV, Resh MD (2001) Tyrosine phosphorylation of p190 RhoGAP by Fyn regulates oligodendrocyte differentiation. J Neurobiol 49:62–78

    Article  CAS  PubMed  Google Scholar 

  43. Wolf RM, Draghi N, Liang X, Dai C, Uhrbom L, Eklöf C, Westermark B, Holland EC, Resh MD (2003) p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human chromosome 19q13.3. Genes Dev 17:476–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bartolomé RA, Wright N, Molina-Ortiz I, Sánchez-Luque FJ, Teixidó J (2008) Activated G(alpha)13 impairs cell invasiveness through p190RhoGAP-mediated inhibition of RhoA activity. Cancer Res 68:8221–8230

    Article  PubMed  Google Scholar 

  45. Bagchi A, Papazoglu C, Wu Y, Capurso D, Brodt M, Francis D, Bredel M, Vogel H, Mills AA (2007) CHD5 is a tumor suppressor at human 1p36. Cell 128:459–475

    Article  CAS  PubMed  Google Scholar 

  46. Chautard E, Ouédraogo ZG, Biau J, Verrelle P (2014) Role of Akt in human malignant glioma: from oncogenesis to tumor aggressiveness. J Neurooncol 117:205–215

    Article  CAS  PubMed  Google Scholar 

  47. Li X, Wu C, Chen N, Gu H, Yen A, Cao L, Wang E, Wang L (2016) PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget 7:33440–33450

    Google Scholar 

  48. Kaneko S, Nakatani Y, Takezaki T, Hide T, Yamashita D, Ohtsu N, Ohnishi T, Terasaka S, Houkin K, Kondo T (2015) Ceacam1L Modulates STAT3 signaling to control the proliferation of glioblastoma-initiating cells. Cancer Res 75:4224–4234

    Article  CAS  PubMed  Google Scholar 

  49. Yamashita D, Kondo T, Ohue S, Takahashi H, Ishikawa M, Matoba R, Suehiro S, Kohno S, Harada H, Tanaka J, Ohnishi T (2015) miR340 suppresses the stem-like cell function of glioma-initiating cells by targeting tissue plasminogen activator. Cancer Res 75:1123–1133

    Article  CAS  PubMed  Google Scholar 

  50. Ohtsu N, Nakatani Y, Yamashita D, Ohue S, Ohnishi T, Kondo T (2016) Eva1 maintains the stem-like character of glioblastoma-initiating cells by activating the noncanonical NF-κB signaling pathway. Cancer Res 76:171–181

    Article  CAS  PubMed  Google Scholar 

  51. Kruiswijk F, Labuschagne CF, Vousden KH (2015) p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol 16:393–405

    Article  CAS  PubMed  Google Scholar 

  52. Hollstein M, Hainaut P (2010) Massibely regulated genes: the example of TP53. J Pathol 220:164–173

    CAS  PubMed  Google Scholar 

  53. Meek DW, Anderson CW (2009) Posttranslational modification of p53: cooperative integrators of function. Cold Spring Harb Perspect Biol 1:a000950

    Article  PubMed  PubMed Central  Google Scholar 

  54. Salama R, Sadaie M, Hoare M, Narita M (2014) Cellular senescence and its effector programs. Genes Dev 28:99–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Reed SM, Quelle DE (2014) p53 acetylation: regulation and consequences. Cancer 7:30–69

    Article  Google Scholar 

  56. Tang J, Jiehui D, Cao H, Bai J, Zheng J (2015) p53-mediated autophagic regulation: A prospective strategy for cancer therapy. Cancer Lett 363:101–107

    Article  CAS  PubMed  Google Scholar 

  57. Nilsson MB, Zage PE, Zeng L, Xu L, Cascone T, Wu HK, Saigal B, Zweidler-McKay PA, Heymach JV (2010) Multiple receptor tyrosine kinases regulate HIF-1alpha and HIF-2alpha in normoxia and hypoxia in neuroblastoma: implications for antiangiogenic mechanisms of multikinase inhibitors. Oncogene 29:2938–2949

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

T.K. was supported, in part, by a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-DIRECT), Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Toru Kondo.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kondo, T. Molecular mechanisms involved in gliomagenesis. Brain Tumor Pathol 34, 1–7 (2017). https://doi.org/10.1007/s10014-017-0278-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10014-017-0278-8

Keywords

Navigation