Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

The molecular and cell biology of pediatric low-grade gliomas

Oncogene volume 33, pages 2019–2026 (2014)Cite this article

Subjects

Abstract

Pilocytic astrocytoma (PA) is the most common glial cell tumor arising in children. Sporadic cases are associated with KIAA1549:BRAF fusion rearrangements, while 15–20% of children develop PA in the context of the neurofibromatosis 1 (NF1) inherited tumor predisposition syndrome. The unique predilection of these tumors to form within the optic pathway and brainstem (NF1-PA) and cerebellum (sporadic PA) raises the possibility that gliomagenesis requires more than biallelic inactivation of the NF1 tumor suppressor gene or expression of the KIAA1549:BRAF transcript. Several etiologic explanations include differential susceptibilities of preneoplastic neuroglial cell types in different brain regions to these glioma-causing genetic changes, contributions from non-neoplastic cells and signals in the tumor microenvironment, and genomic modifiers that confer glioma risk. As clinically-faithful rodent models of sporadic PA are currently under development, Nf1 genetically-engineered mouse (GEM) models have served as tractable systems to study the role of the cell of origin, deregulated intracellular signaling, non-neoplastic cells in the tumor microenvironment and genomic modifiers in gliomagenesis. In this report, we highlight advances in Nf1-GEM modeling and review new experimental evidence that supports the emerging concept that Nf1- and KIAA1549:BRAF-induced gliomas arise from specific cell types in particular brain locations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Dolecek TA, Propp JM, Stroup NE, Kruchko C . CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol 2012; 14 (Suppl 5): v1–v49.

    PubMed  PubMed Central  Google Scholar 

  2. Pfister S, Witt O . Pediatric gliomas. Recent Results Cancer Res 2009; 171: 67–81.

    PubMed  Google Scholar 

  3. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007; 114: 97–109.

    PubMed  PubMed Central  Google Scholar 

  4. Gutmann DH, Donahoe J, Brown T, James CD, Perry A . Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas. Neuropathol Appl Neurobiol 2000; 26: 361–367.

    CAS  PubMed  Google Scholar 

  5. Kluwe L, Hagel C, Tatagiba M, Thomas S, Stavrou D, Ostertag H et al. Loss of NF1 alleles distinguish sporadic from NF1-associated pilocytic astrocytomas. J Neuropathol Exp Neurol 2001; 60: 917–920.

    CAS  PubMed  Google Scholar 

  6. Lau N, Feldkamp MM, Roncari L, Loehr AH, Shannon P, Gutmann DH et al. Loss of neurofibromin is associated with activation of RAS/MAPK and PI3-K/AKT signaling in a neurofibromatosis 1 astrocytoma. J Neuropathol Exp Neurol 2000; 59: 759–767.

    CAS  PubMed  Google Scholar 

  7. Listernick R, Ferner RE, Liu GT, Gutmann DH . Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 2007; 61: 189–198.

    CAS  PubMed  Google Scholar 

  8. Guillamo JS, Creange A, Kalifa C, Grill J, Rodriguez D, Doz F et al. Prognostic factors of CNS tumours in Neurofibromatosis 1 (NF1): a retrospective study of 104 patients. Brain 2003; 126: 152–160.

    PubMed  Google Scholar 

  9. Wimmer K, Eckart M, Meyer-Puttlitz B, Fonatsch C, Pietsch T . Mutational and expression analysis of the NF1 gene argues against a role as tumor suppressor in sporadic pilocytic astrocytomas. J Neuropathol Exp Neurol 2002; 61: 896–902.

    CAS  PubMed  Google Scholar 

  10. Jones DT, Kocialkowski S, Liu L, Pearson DM, Bäcklund LM, Ichimura K et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 2008; 68: 8673–8677.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 2008; 118: 1739–1749.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990; 249: 181–186.

    CAS  PubMed  Google Scholar 

  13. Andersen LB, Ballester R, Marchuk DA, Chang E, Gutmann DH, Saulino AM et al. A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase-activating protein activity. Mol Cell Biol 1993; 13: 487–495.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Costa RM, Yang T, Huynh DP, Pulst SM, Viskochil DH, Silva AJ et al. Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1. Nat Genet 2001; 27: 399–405.

    CAS  PubMed  Google Scholar 

  15. Gutmann DH, Geist RT, Rose K, Wright DE . Expression of two new protein isoforms of the neurofibromatosis type 1 gene product, neurofibromin, in muscle tissues. Dev Dyn 1995; 202: 302–311.

    CAS  PubMed  Google Scholar 

  16. Gutmann DH, Geist RT, Wright DE, Snider WD . Expression of the neurofibromatosis 1 (NF1) isoforms in developing and adult rat tissues. Cell Growth Differ 1995; 6: 315–323.

    CAS  PubMed  Google Scholar 

  17. Gutmann DH, Zhang Y, Hirbe A . Developmental regulation of a neuron-specific neurofibromatosis 1 isoform. Ann Neurol 1999; 46: 777–782.

    CAS  PubMed  Google Scholar 

  18. Basu TN, Gutmann DH, Fletcher JA, Glover TW, Collins FS, Downward J . Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 1992; 356: 713–715.

    CAS  PubMed  Google Scholar 

  19. Bollag G, Clapp DW, Shih S, Adler F, Zhang YY, Thompson P et al. Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet 1996; 12: 144–148.

    CAS  PubMed  Google Scholar 

  20. Xu GF, Lin B, Tanaka K, Dunn D, Wood D, Gesteland R et al. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 1990; 63: 835–841.

    CAS  PubMed  Google Scholar 

  21. Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 1990; 63: 843–849.

    CAS  PubMed  Google Scholar 

  22. Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG . Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 2008; 67: 878–887.

    CAS  PubMed  Google Scholar 

  23. Sievert AJ, Jackson EM, Gai X, Hakonarson H, Judkins AR, Resnick AC et al. Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol 2009; 19: 449–458.

    CAS  PubMed  Google Scholar 

  24. Eisenhardt AE, Olbrich H, Roring M, Janzarik W, Anh TN, Cin H et al. Functional characterization of a BRAF insertion mutant associated with pilocytic astrocytoma. Int J Cancer 2011; 129: 2297–2303.

    CAS  PubMed  Google Scholar 

  25. Janzarik WG, Kratz CP, Loges NT, Olbrich H, Klein C, Schäfer T et al. Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. Neuropediatrics 2007; 38: 61–63.

    CAS  PubMed  Google Scholar 

  26. Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP . Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 2009; 28: 2119–2123.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C et al. Analysis of BRAF V600E mutation in 1320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011; 121: 397–405.

    CAS  PubMed  Google Scholar 

  28. Sharma MK, Zehnbauer BA, Watson MA, Gutmann DH . RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma. Neurology 2005; 65: 1335–1336.

    PubMed  Google Scholar 

  29. Cin H, Meyer C, Herr R, Janzarik WG, Lambert S, Jones DT et al. Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol 2011; 121: 763–774.

    CAS  PubMed  Google Scholar 

  30. Dasgupta B, Yi Y, Chen DY, Weber JD, Gutmann DH . Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors. Cancer Res 2005; 65: 2755–2760.

    CAS  PubMed  Google Scholar 

  31. Lee dY, Yeh TH, Emnett RJ, White CR, Gutmann DH . Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner. Genes Dev 2010; 24: 2317–2329.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Hegedus B, Banerjee D, Yeh TH, Rothermich S, Perry A, Rubin JB et al. Preclinical cancer therapy in a mouse model of neurofibromatosis-1 optic glioma. Cancer Res 2008; 68: 1520–1528.

    CAS  PubMed  Google Scholar 

  33. Banerjee S, Crouse NR, Emnett RJ, Gianino SM, Gutmann DH . Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner. Proc Natl Acad Sci USA 2011; 108: 15996–16001.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kaul A, Chen YH, Emnett RJ, Dahiya S, Gutmann DH . Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes Dev 2012; 26: 2561–2566.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Alcantara LS, Chen J, Kwon CH, Jackson EL, Li Y, Burns DK et al. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 2009; 15: 45–56.

    Google Scholar 

  36. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 2010; 468: 1095–1099.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Kalamarides M, Stemmer-Rachamimov AO, Niwa-Kawakita M, Chareyre F, Taranchon E, Han ZY et al. Identification of a progenitor cell of origin capable of generating diverse meningioma histological subtypes. Oncogene 2011; 30: 2333–2344.

    CAS  PubMed  Google Scholar 

  38. Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, Jensen P et al. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 2005; 8: 323–335.

    CAS  PubMed  Google Scholar 

  39. Merkle FT, Tramontin AD, Garcia-Verdugo JM, Alvarez-Buylla A . Radial glia give rise to adult neural stem cells in the subventricular zone. Proc Natl Acad Sci USA 2004; 101: 17528–17532.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Johnson RA, Wright KD, Poppleton H, Mohankumar KM, Finkelstein D, Pounds SB et al. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 2010; 466: 632–636.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 2012; 123: 465–472.

    CAS  PubMed  Google Scholar 

  42. Schuller U, Heine VM, Mao J, Kho AT, Dillon AK, Han YG et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 2008; 14: 123–134.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang Y, Yang J, Zheng H, Tomasek GJ, Zhang P, McKeever PE et al. Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell 2009; 15: 514–526.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Assanah M, Lochhead R, Ogden A, Bruce J, Goldman J, Canoll P . Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses. J Neurosci 2006; 26: 6781–6790.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Lindberg N, Kastemar M, Olofsson T, Smits A, Uhrbom L . Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma. Oncogene 2009; 28: 2266–2275.

    CAS  PubMed  Google Scholar 

  46. Liu C, Sage JC, Miller MR, Verhaak RG, Hippenmeyer S, Vogel H et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 2011; 146: 209–221.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Masui K, Suzuki SO, Torisu R, Goldman JE, Canoll P, Iwaki T . Glial progenitors in the brainstem give rise to malignant gliomas by platelet-derived growth factor stimulation. Glia 2010; 58: 1050–1065.

    PubMed  Google Scholar 

  48. Sugiarto S, Persson AI, Munoz EG, Waldhuber M, Lamagna C, Andor N et al. Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell 2011; 20: 328–340.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ et al. Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 2002; 1: 269–277.

    CAS  PubMed  Google Scholar 

  50. Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 2012; 338: 1080–1084.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Solga A, Gianino SM, Gutmann DH . NG2-cells are not the cell of origin for murine neurofibromatosis-1 (Nf1) optic glioma. Oncogene (e-pub ahead of print 14 January 2013; doi:10.1038/onc.2012.580).

    PubMed  PubMed Central  Google Scholar 

  52. Lee dY, Gianino SM, Gutmann DH . Innate neural stem cell heterogeneity determines the patterning of glioma formation in children. Cancer Cell 2012; 22: 131–138.

    PubMed  PubMed Central  Google Scholar 

  53. Tchoghandjian A, Fernandez C, Colin C, El Ayachi I, Voutsinos-Porche B, Fina F et al. Pilocytic astrocytoma of the optic pathway: a tumour deriving from radial glia cells with a specific gene signature. Brain 2009; 132: 1523–1535.

    PubMed  Google Scholar 

  54. Gronych J, Korshunov A, Bageritz J, Milde T, Jugold M, Hambardzumyan D et al. An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice. J Clin Invest 2011; 121: 1344–1348.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Lyustikman Y, Momota H, Pao W, Holland EC . Constitutive activation of Raf-1 induces glioma formation in mice. Neoplasia 2008; 10: 501–510.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Robinson JP, VanBrocklin MW, Guilbeault AR, Signorelli DL, Brandner S, Holmen SL . Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation. Oncogene 2010; 29: 335–344.

    CAS  PubMed  Google Scholar 

  57. Jacob K, Albrecht S, Sollier C, Faury D, Sader E, Montpetit A et al. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer 2009; 101: 722–733.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Jacob K, Quang-Khuong DA, Jones DT, Witt H, Lambert S, Albrecht S et al. Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 2011; 17: 4650–4660.

    CAS  PubMed  Google Scholar 

  59. Raabe EH, Lim KS, Kim JM, Meeker A, Mao XG, Nikkhah G et al. BRAF activation induces transformation and then senescence in human neural stem cells: a pilocytic astrocytoma model. Clin Cancer Res 2011; 17: 3590–3599.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Hasselblatt M, Riesmeier B, Lechtape B, Brentrup A, Stummer W, Albert FK et al. BRAF-KIAA1549 fusion transcripts are less frequent in pilocytic astrocytomas diagnosed in adults. Neuropathol Appl Neurobiol 2011; 37: 803–806.

    CAS  PubMed  Google Scholar 

  61. Hawkins C, Walker E, Mohamed N, Zhang C, Jacob K, Shirinian M et al. BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 2011; 17: 4790–4798.

    CAS  PubMed  Google Scholar 

  62. Sharma MK, Mansur DB, Reifenberger G, Perry A, Leonard JR, Aldape KD et al. Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin. Cancer Res 2007; 67: 890–900.

    CAS  PubMed  Google Scholar 

  63. Yeh TH, Lee dY, Gianino SM, Gutmann DH . Microarray analyses reveal regional astrocyte heterogeneity with implications for neurofibromatosis type 1 (NF1)-regulated glial proliferation. Glia 2009; 57: 1239–1249.

    PubMed  PubMed Central  Google Scholar 

  64. Brannan CI, Perkins AS, Vogel KS, Ratner N, Nordlund ML, Reid SW et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev 1994; 8: 1019–1029.

    CAS  PubMed  Google Scholar 

  65. Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA . Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet 1994; 7: 353–361.

    CAS  PubMed  Google Scholar 

  66. Bajenaru ML, Zhu Y, Hedrick NM, Donahoe J, Parada LF, Gutmann DH . Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. Mol Cell Biol 2002; 22: 5100–5113.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhu Y, Harada T, Liu L, Lush ME, Guignard F, Harada C et al. Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development 2005; 132: 5577–5588.

    CAS  PubMed  Google Scholar 

  68. Bajenaru ML, Hernandez MR, Perry A, Zhu Y, Parada LF, Garbow JR et al. Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res 2003; 63: 8573–8577.

    CAS  PubMed  Google Scholar 

  69. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007; 11: 69–82.

    CAS  PubMed  Google Scholar 

  70. Hanisch UK . Microglia as a source and target of cytokines. Glia 2002; 40: 140–155.

    PubMed  Google Scholar 

  71. Bajenaru ML, Garbow JR, Perry A, Hernandez MR, Gutmann DH . Natural history of neurofibromatosis 1-associated optic nerve glioma in mice. Ann Neurol 2005; 57: 119–127.

    CAS  PubMed  Google Scholar 

  72. Watters JJ, Schartner JM, Badie B . Microglia function in brain tumors. J Neurosci Res 2005; 81: 447–455.

    CAS  PubMed  Google Scholar 

  73. Marin-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M . Microglia promote the death of developing Purkinje cells. Neuron 2004; 41: 535–547.

    CAS  PubMed  Google Scholar 

  74. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005; 438: 1017–1021.

    CAS  PubMed  Google Scholar 

  75. Roumier A, Bechade C, Poncer JC, Smalla KH, Tomasello E, Vivier E et al. Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse. J Neurosci 2004; 24: 11421–11428.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Elkabes S, DiCicco-Bloom EM, Black IB . Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 1996; 16: 2508–2521.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Amankulor NM, Hambardzumyan D, Pyonteck SM, Becher OJ, Joyce JA, Holland EC . Sonic hedgehog pathway activation is induced by acute brain injury and regulated by injury-related inflammation. J Neurosci 2009; 29: 10299–10308.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Lin EY, Pollard JW . Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res 2007; 67: 5064–5066.

    CAS  PubMed  Google Scholar 

  79. Daginakatte GC, Gutmann DH . Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. Hum Mol Genet 2007; 16: 1098–1112.

    CAS  PubMed  Google Scholar 

  80. Simmons GW, Pong WW, Emnett RJ, White CR, Gianino SM, Rodriguez FJ et al. Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth. J Neuropathol Exp Neurol 2011; 70: 51–62.

    CAS  PubMed  Google Scholar 

  81. Daginakatte GC, Gianino SM, Zhao NW, Parsadanian AS, Gutmann DH . Increased c-Jun-NH2-kinase signaling in neurofibromatosis-1 heterozygous microglia drives microglia activation and promotes optic glioma proliferation. Cancer Res 2008; 68: 10358–10366.

    CAS  PubMed  Google Scholar 

  82. Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 2000; 20: 4106–4114.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Hoshiko M, Arnoux I, Avignone E, Yamamoto N, Audinat E . Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J Neurosci 2012; 32: 15106–15111.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Pong WW, Higer SB, Gianino SM, Emnett RJ, Gutmann DH . Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann Neurol 2013; 73: 303–308.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Kostianovsky AM, Maier LM, Anderson RC, Bruce JN, Anderson DE . Astrocytic regulation of human monocytic/microglial activation. J Immunol 2008; 181: 5425–5432.

    CAS  PubMed  Google Scholar 

  86. Markovic DS, Vinnakota K, Chirasani S, Synowitz M, Raguet H, Stock K et al. Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci USA 2009; 106: 12530–12535.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Platten M, Kretz A, Naumann U, Aulwurm S, Egashira K, Isenmann S et al. Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas. Ann Neurol 2003; 54: 388–392.

    CAS  PubMed  Google Scholar 

  88. Wesolowska A, Kwiatkowska A, Slomnicki L, Dembinski M, Master A, Sliwa M et al. Microglia-derived TGF-beta as an important regulator of glioblastoma invasion—an inhibition of TGF-beta-dependent effects by shRNA against human TGF-beta type II receptor. Oncogene 2008; 27: 918–930.

    CAS  PubMed  Google Scholar 

  89. Calatozzolo C, Canazza A, Pollo B, Di Pierro E, Ciusani E, Maderna E et al. Expression of the new CXCL12 receptor, CXCR7, in gliomas. Cancer Biol Ther 2011; 11: 242–253.

    CAS  PubMed  Google Scholar 

  90. Warrington NM, Woerner BM, Daginakatte GC, Dasgupta B, Perry A, Gutmann DH et al. Spatiotemporal differences in CXCL12 expression and cyclic AMP underlie the unique pattern of optic glioma growth in neurofibromatosis type 1. Cancer Res 2007; 67: 8588–8595.

    CAS  PubMed  Google Scholar 

  91. Dasgupta B, Dugan LL, Gutmann DH . The neurofibromatosis 1 gene product neurofibromin regulates pituitary adenylate cyclase-activating polypeptide-mediated signaling in astrocytes. J Neurosci 2003; 23: 8949–8954.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Tong J, Hannan F, Zhu Y, Bernards A, Zhong Y . Neurofibromin regulates G protein-stimulated adenylyl cyclase activity. Nat Neurosci 2002; 5: 95–96.

    CAS  PubMed  Google Scholar 

  93. Warrington NM, Gianino SM, Jackson E, Goldhoff P, Garbow JR, Piwnica-Worms D et al. Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1. Cancer Res 2010; 70: 5717–5727.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Binning MJ, Niazi T, Pedone CA, Lal B, Eberhart CG, Kim KJ et al. Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth. Cancer Res 2008; 68: 7838–7845.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Fanelli M, Caprodossi S, Ricci-Vitiani L, Porcellini A, Tomassoni-Ardori F, Amatori S et al. Loss of pericentromeric DNA methylation pattern in human glioblastoma is associated with altered DNA methyltransferases expression and involves the stem cell compartment. Oncogene 2008; 27: 358–365.

    CAS  PubMed  Google Scholar 

  96. Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C et al. Epigenetic stem cell signature in cancer. Nat Genet 2007; 39: 157–158.

    CAS  PubMed  Google Scholar 

  97. Reilly KM, Loisel DA, Bronson RT, McLaughlin ME, Jacks T . Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet 2000; 26: 109–113.

    CAS  PubMed  Google Scholar 

  98. Reilly KM, Tuskan RG, Christy E, Loisel DA, Ledger J, Bronson RT et al. Susceptibility to astrocytoma in mice mutant for Nf1 and Trp53 is linked to chromosome 11 and subject to epigenetic effects. Proc Natl Acad Sci USA 2004; 101: 13008–13013.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Amlin-Van Schaick J, Kim S, Broman KW, Reilly KM . Scram1 is a modifier of spinal cord resistance for astrocytoma on mouse Chr 5. Mamm Genome 2012; 23: 277–285.

    CAS  PubMed  Google Scholar 

  100. Amlin-Van Schaick JC, Kim S, DiFabio C, Lee MH, Broman KW, Reilly KM . Arlm1 is a male-specific modifier of astrocytoma resistance on mouse Chr 12. Neuro Oncol 2012; 14: 160–174.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Armstrong GT, Conklin HM, Huang S, Srivastava D, Sanford R, Ellison DW et al. Survival and long-term health and cognitive outcomes after low-grade glioma. Neuro Oncol 2011; 13: 223–234.

    PubMed  Google Scholar 

  102. Wisoff JH, Sanford RA, Heier LA, Sposto R, Burger PC, Yates AJ et al. Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional study from the Children's Oncology Group. Neurosurgery 2011; 68: 1548–1554 discussion 54-5.

    PubMed  Google Scholar 

  103. Sharif S, Ferner R, Birch JM, Gillespie JE, Gattamaneni HR, Baser ME et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol 2006; 24: 2570–2575.

    PubMed  Google Scholar 

  104. Shalitin S, Gal M, Goshen Y, Cohen I, Yaniv I, Phillip M . Endocrine outcome in long-term survivors of childhood brain tumors. Horm Res Paediatr 2011; 76: 113–122.

    CAS  PubMed  Google Scholar 

  105. Fisher MJ, Loguidice M, Gutmann DH, Listernick R, Ferner RE, Ullrich NJ et al. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro Oncol 2012; 14: 790–797.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants from the National Institutes of Health (NS065527) and National Brain Tumor Society (to DHG). Y-HC is a fellow of the American Brain Tumor Association.

Author information

Authors and Affiliations

  1. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

    Y-H Chen & D H Gutmann

Authors
  1. Y-H Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D H Gutmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D H Gutmann.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, YH., Gutmann, D. The molecular and cell biology of pediatric low-grade gliomas. Oncogene 33, 2019–2026 (2014). https://doi.org/10.1038/onc.2013.148

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.148

Keywords

This article is cited by

Search

Advanced search

Quick links