Deciphering the Molecular and Cellular Basis for Dissemination of Diffuse Low-Grade Gliomas

  • Zahra Hassani
  • Jean-Philippe HugnotEmail author


Although initially silent, diffuse low-grade gliomas (DLGGs) always progress into a more aggressive pathology, eventually causing death of the patient. Their diffusive nature makes them difficult to fully remove by the surgical approach. Understanding the molecular pathways ruling DLGG dissemination would open up new lines of treatments aiming at limiting their spread throughout the brain. However, the rare occurrence of these tumors, the difficulties in growing them in culture, and the quasi-absence of DLGG-derived cell lines have definitely impeded the progress of knowledge on this topic. This explains the very few data available today on DLGG invasion and calls for more efforts from the scientific community to tackle this complex challenge. Here after reporting the main studies which have approached the problematic of DLGG dissemination, we propose some analogies with oligodendrocyte precursor migration and suggest some promising directions to take. We then raise central issues making DLGG dissemination difficult to study with our present state of knowledge and technical possibilities. Deciphering the migratory strategies adopted by DLGG to invade the brain would be a major advance for the development of therapies aiming at maintaining DLGG in a confined and resectable nutshell.


Oligodendroglioma Oligodendrocyte progenitors Migration Diffuse low-grade glioma Molecular basis 


  1. 1.
    Virchow R. Die krankhaften Geschwülste. Dreissig Vorlesungen, gehalten während des Wintersemesters 1862–1863 an Der Universität Zu Berlin. Berlin: A Hirschwald; 1863.Google Scholar
  2. 2.
    Giese A, Bjerkvig R, Berens ME, Westphal M. Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol. 2003;21(8):1624–36.PubMedCrossRefGoogle Scholar
  3. 3.
    Berens ME, Giese A. “…those left behind.” Biology and oncology of invasive glioma cells. Neoplasia. 1999;1(3):208–19.PubMedCrossRefGoogle Scholar
  4. 4.
    Teodorczyk M, Martin-Villalba A. Sensing invasion: cell surface receptors driving spreading of glioblastoma. J Cell Physiol. 2010;222(1):1–10.PubMedCrossRefGoogle Scholar
  5. 5.
    Tate MC, Aghi MK. Biology of angiogenesis and invasion in glioma. Neurotherapeutics. 2009;6(3):447–57.PubMedCrossRefGoogle Scholar
  6. 6.
    Sontheimer H. An unexpected role for ion channels in brain tumor metastasis. Exp Biol Med (Maywood). 2008;233(7):779–91.CrossRefGoogle Scholar
  7. 7.
    Sontheimer H. A role for glutamate in growth and invasion of primary brain tumors. J Neurochem. 2008;105(2):287–95.PubMedCrossRefGoogle Scholar
  8. 8.
    Hoelzinger DB, Demuth T, Berens ME. Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. J Natl Cancer Inst. 2007;99(21):1583–93.PubMedCrossRefGoogle Scholar
  9. 9.
    Salhia B, Tran NL, Symons M, Winkles JA, Rutka JT, Berens ME. Molecular pathways triggering glioma cell invasion. Expert Rev Mol Diagn. 2006;6(4):613–26.PubMedCrossRefGoogle Scholar
  10. 10.
    Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB, Berens ME. Molecular targets of glioma invasion. Cell Mol Life Sci. 2007;64(4):458–78.PubMedCrossRefGoogle Scholar
  11. 11.
    Demuth T, Berens ME. Molecular mechanisms of glioma cell migration and invasion. J Neurooncol. 2004;70(2):217–28.PubMedCrossRefGoogle Scholar
  12. 12.
    Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG. Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol. 2004;36(6):1046–69.PubMedCrossRefGoogle Scholar
  13. 13.
    Gunther W, Skaftnesmo KO, Arnold H, Terzis AJ. Molecular approaches to brain tumour invasion. Acta Neurochir (Wien). 2003;145(12):1029–36.CrossRefGoogle Scholar
  14. 14.
    Visted T, Enger PO, Lund-Johansen M, Bjerkvig R. Mechanisms of tumor cell invasion and angiogenesis in the central nervous system. Front Biosci. 2003;8:e289–304.PubMedCrossRefGoogle Scholar
  15. 15.
    Weiss WA, Burns MJ, Hackett C, Aldape K, Hill JR, Kuriyama H, et al. Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Res. 2003;63(7):1589–95.PubMedGoogle Scholar
  16. 16.
    Farin A, Suzuki SO, Weiker M, Goldman JE, Bruce JN, Canoll P. Transplanted glioma cells migrate and proliferate on host brain vasculature: a dynamic analysis. Glia. 2006;53(8):799–808.PubMedCrossRefGoogle Scholar
  17. 17.
    Oellers P, Schallenberg M, Stupp T, Charalambous P, Senner V, Paulus W, et al. A coculture assay to visualize and monitor interactions between migrating glioma cells and nerve fibers. Nat Protoc. 2009;4(6):923–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Giese A, Laube B, Zapf S, Mangold U, Westphal M. Glioma cell adhesion and migration on human brain sections. Anticancer Res. 1998;18(4A):2435–47.PubMedGoogle Scholar
  19. 19.
    Giese A, Kluwe L, Laube B, Meissner H, Berens ME, Westphal M. Migration of human glioma cells on myelin. Neurosurgery. 1996;38(4):755–64.PubMedCrossRefGoogle Scholar
  20. 20.
    Palfi S, Swanson KR, De Bouard S, Chretien F, Oliveira R, Gherardi RK, et al. Correlation of in vitro infiltration with glioma histological type in organotypic brain slices. Br J Cancer. 2004;91(4):745–52.PubMedGoogle Scholar
  21. 21.
    de Bouard S, Christov C, Guillamo JS, Kassar-Duchossoy L, Palfi S, Leguerinel C, et al. Invasion of human glioma biopsy specimens in cultures of rodent brain slices: a quantitative analysis. J Neurosurg. 2002;97(1):169–76.PubMedCrossRefGoogle Scholar
  22. 22.
    Colin C, Baeza N, Tong S, Bouvier C, Quilichini B, Durbec P, et al. In vitro identification and functional characterization of glial precursor cells in human gliomas. Neuropathol Appl Neurobiol. 2006;32(2):189–202.PubMedCrossRefGoogle Scholar
  23. 23.
    Bernstein JJ, Goldberg WJ, Laws Jr ER. Migration of fresh human malignant astrocytoma cells into hydrated gel wafers in vitro. J Neurooncol. 1994;18(2):151–61.PubMedCrossRefGoogle Scholar
  24. 24.
    Ducray F, Idbaih A, de Reynies A, Bieche I, Thillet J, Mokhtari K, et al. Anaplastic oligodendrogliomas with 1p19q codeletion have a proneural gene expression profile. Mol Cancer. 2008;7:41.PubMedCrossRefGoogle Scholar
  25. 25.
    Patt S, Labrakakis C, Bernstein M, Weydt P, Cervos-Navarro J, Nisch G, et al. Neuron-like physiological properties of cells from human oligodendroglial tumors. Neuroscience. 1996;71(2):601–11.PubMedCrossRefGoogle Scholar
  26. 26.
    Liu XY, Gerges N, Korshunov A, Sabha N, Khuong-Quang DA, Fontebasso AM, et al. Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumors carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol. 2012;124(5):615–25.PubMedCrossRefGoogle Scholar
  27. 27.
    Sahm F, Koelsche C, Meyer J, Pusch S, Lindenberg K, Mueller W, et al. CIC and FUBP1 mutations in ­oligodendrogliomas, oligoastrocytomas and astrocytomas. Acta Neuropathol. 2012;123(6):853–60.PubMedCrossRefGoogle Scholar
  28. 28.
    Persson AI, Petritsch C, Swartling FJ, Itsara M, Sim FJ, Auvergne R, et al. Non-stem cell origin for oligodendroglioma. Cancer Cell. 2010;18(6):669–82.PubMedCrossRefGoogle Scholar
  29. 29.
    Bouvier-Labit C, Liprandi A, Monti G, Pellissier JF, Figarella-Branger D. CD44H is expressed by cells of the oligodendrocyte lineage and by oligodendrogliomas in humans. J Neurooncol. 2002;60(2):127–34.PubMedCrossRefGoogle Scholar
  30. 30.
    Jothy S. CD44 and its partners in metastasis. Clin Exp Metastasis. 2003;20(3):195–201.PubMedCrossRefGoogle Scholar
  31. 31.
    Radotra B, McCormick D. Glioma invasion in vitro is mediated by CD44-hyaluronan interactions. J Pathol. 1997;181(4):434–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Radotra B, McCormick D. CD44 is involved in migration but not spreading of astrocytoma cells in vitro. Anticancer Res. 1997;17(2A):945–9.PubMedGoogle Scholar
  33. 33.
    Back SA, Tuohy TM, Chen H, Wallingford N, Craig A, Struve J, et al. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med. 2005;11(9):966–72.PubMedGoogle Scholar
  34. 34.
    McDonald JM, Dunlap S, Cogdell D, Dunmire V, Wei Q, Starzinski-Powitz A, et al. The SHREW1 gene, frequently deleted in oligodendrogliomas, functions to inhibit cell adhesion and migration. Cancer Biol Ther. 2006;5(3):300–4.PubMedCrossRefGoogle Scholar
  35. 35.
    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(5):2610–8.PubMedCrossRefGoogle Scholar
  36. 36.
    de Castro F, Bribian A. The molecular orchestra of the migration of oligodendrocyte precursors during development. Brain Res. 2005;49(2):227–41.CrossRefGoogle Scholar
  37. 37.
    Miyamoto Y, Yamauchi J, Tanoue A. Cdk5 phosphorylation of WAVE2 regulates oligodendrocyte precursor cell migration through nonreceptor tyrosine kinase Fyn. J Neurosci. 2008;28(33):8326–37.PubMedCrossRefGoogle Scholar
  38. 38.
    Yamazaki D, Kurisu S, Takenawa T. Involvement of Rac and Rho signaling in cancer cell motility in 3D substrates. Oncogene. 2009;28(13):1570–83.PubMedCrossRefGoogle Scholar
  39. 39.
    Liu J, Zhao Y, Sun Y, He B, Yang C, Svitkina T, et al. Exo70 stimulates the Arp2/3 complex for lamellipodia formation and directional cell migration. Curr Biol. 2012;22(16):1510–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Kurisu S, Suetsugu S, Yamazaki D, Yamaguchi H, Takenawa T. Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells. Oncogene. 2005;24(8):1309–19.PubMedCrossRefGoogle Scholar
  41. 41.
    Iwaya K, Norio K, Mukai K. Coexpression of Arp2 and WAVE2 predicts poor outcome in invasive breast carcinoma. Mod Pathol. 2007;20(3):339–43.PubMedCrossRefGoogle Scholar
  42. 42.
    Spassky N, de Castro F, Le Bras B, Heydon K, Queraud-LeSaux F, Bloch-Gallego E, et al. Directional guidance of oligodendroglial migration by class 3 semaphorins and netrin-1. J Neurosci. 2002;22(14):5992–6004.PubMedGoogle Scholar
  43. 43.
    Karayan-Tapon L, Wager M, Guilhot J, Levillain P, Marquant C, Clarhaut J, et al. Semaphorin, neuropilin and VEGF expression in glial tumours: SEMA3G, a prognostic marker? Br J Cancer. 2008;99(7):1153–60.PubMedCrossRefGoogle Scholar
  44. 44.
    Bagci T, Wu JK, Pfannl R, Ilag LL, Jay DG. Autocrine semaphorin 3A signaling promotes glioblastoma dispersal. Oncogene. 2009;28(40):3537–50.PubMedCrossRefGoogle Scholar
  45. 45.
    Nasarre C, Koncina E, Labourdette G, Cremel G, Roussel G, Aunis D, et al. Neuropilin-2 acts as a modulator of Sema3A-dependent glioma cell migration. Cell Adh Migr. 2009;3(4):383–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Olivier C, Cobos I, Perez Villegas EM, Spassky N, Zalc B, Martinez S. Monofocal origin of telencephalic oligodendrocytes in the anterior entopeduncular area of the chick embryo. Development. 2001;128(10):1757–69.PubMedGoogle Scholar
  47. 47.
    Tchoghandjian A, Baeza-Kallee N, Beclin C, Metellus P, Colin C, Ducray F, et al. Cortical and subventricular zone glioblastoma-derived stem-like cells display different molecular profiles and differential in vitro and in vivo properties. Ann Surg Oncol. 2012;19 Suppl 3:608–19.CrossRefGoogle Scholar
  48. 48.
    Pallud J, Varlet P, Devaux B, Geha S, Badoual M, Deroulers C, et al. Diffuse low-grade oligodendrogliomas extend beyond MRI-defined abnormalities. Neurology. 2010;74(21):1724–31.PubMedCrossRefGoogle Scholar
  49. 49.
    Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A. Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol. 2009;118(5):599–601.PubMedCrossRefGoogle Scholar
  50. 50.
    Sahm F, Capper D, Jeibmann A, Habel A, Paulus W, Troost D, et al. Addressing diffuse glioma as a systemic brain disease with single-cell analysis. Arch Neurol. 2012;69(4):523–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Mariani L, McDonough WS, Hoelzinger DB, Beaudry C, Kaczmarek E, Coons SW, et al. Identification and validation of P311 as a glioblastoma invasion gene using laser capture microdissection. Cancer Res. 2001;61(10):4190–6.PubMedGoogle Scholar
  52. 52.
    Daumas-Duport C, Varlet P, Tucker ML, Beuvon F, Cervera P, Chodkiewicz JP. Oligodendrogliomas. Part I: patterns of growth, histological diagnosis, clinical and imaging correlations: a study of 153 cases. J Neurooncol. 1997;34(1):37–59.PubMedCrossRefGoogle Scholar
  53. 53.
    Kelly PJ, Daumas-Duport C, Scheithauer BW, Kall BA, Kispert DB. Stereotactic histologic correlations of computed tomography- and magnetic resonance imaging-defined abnormalities in patients with glial neoplasms. Mayo Clin Proc. 1987;62(6):450–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Amberger VR, Hensel T, Ogata N, Schwab ME. Spreading and migration of human glioma and rat C6 cells on central nervous system myelin in vitro is ­correlated with tumor malignancy and involves a ­metalloproteolytic activity. Cancer Res. 1998;58(1):149–58.PubMedGoogle Scholar
  55. 55.
    Pernet V, Schwab ME. The role of Nogo-A in axonal plasticity, regrowth and repair. Cell Tissue Res. 2011;349(1):97–104.CrossRefGoogle Scholar
  56. 56.
    Belien AT, Paganetti PA, Schwab ME. Membrane-type 1 matrix metalloprotease (MT1-MMP) enables invasive migration of glioma cells in central nervous system white matter. J Cell Biol. 1999;144(2):373–84.PubMedCrossRefGoogle Scholar
  57. 57.
    Giese A, Loo MA, Tran N, Haskett D, Coons SW, Berens ME. Dichotomy of astrocytoma migration and proliferation. Int J Cancer. 1996;67(2):275–82.PubMedCrossRefGoogle Scholar
  58. 58.
    Mariani L, Beaudry C, McDonough WS, Hoelzinger DB, Demuth T, Ross KR, et al. Glioma cell motility is associated with reduced transcription of proapoptotic and proliferation genes: a cDNA microarray analysis. J Neurooncol. 2001;53(2):161–76.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  1. 1.INSERM U1051, Université Montpellier 2, Institute for Neurosciences of Montpellier, Hôpital Saint EloiMontpellierFrance
  2. 2.Team “Brain Plasticity, Stem Cells and Glial Tumor”UM2-UM1-INSERM U1051, Institute of Neurosciences of MontpellierMontpellierFrance

Personalised recommendations