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A comprehensive overview on the molecular biology of human glioma: what the clinician needs to know

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Abstract

The molecular biology of human glioma is a complex and fast-growing field in which basic research needs to meet clinical expectations in terms of anti-tumor efficacy. Although much effort is being done in molecular biology research, significant contribution to the quality of life and overall survival still lacks. The vastness of molecular biology literature makes it virtually impossible for clinicians to keep up to date in the field. This paper reviews some practical concepts regarding glioma tumorigenesis from the clinician’s perspective. Five main aspects are discussed: major intracellular signaling pathways involved in glioma formation; genomic, epigenetic and transcriptomic relevant features of glioma; the prognostic and predictive values of molecular markers according to the new WHO classification of glial tumors; the importance of molecular and cellular heterogeneity in glioblastoma, responsible for its therapy resistance; and the interaction between glioma and the immune system, in view of the novel and promising targeted therapies.

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References

  1. Delgado-López PD, Corrales-García EM, Martino J, Lastra-Aras E, Dueñas-Polo MT. Diffuse low-grade glioma: a review on the new molecular classification, natural history and current management strategies. Clin Transl Oncol. 2017;19(8):931–44. https://doi.org/10.1007/s12094-017-1631-4.

    Article  PubMed  Google Scholar 

  2. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–66. https://doi.org/10.1016/S1470-2045(09)70025-7.

    Article  CAS  PubMed  Google Scholar 

  3. Duffau H. Diffuse low-grade glioma, oncological outcome and quality of life: a surgical perspective. Curr Opin Oncol. 2018;30(6):383–9. https://doi.org/10.1097/CCO.0000000000000483.

    Article  PubMed  Google Scholar 

  4. Delgado-López PD, Corrales-García EM. Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol. 2016;18(11):1062–71.

    Article  PubMed  Google Scholar 

  5. Pessina F, Navarria P, Cozzi L, Ascolese AM, Simonelli M, Santoro A, et al. Maximize surgical resection beyond contrast-enhancing boundaries in newly diagnosed glioblastoma multiforme: is it useful and safe? A single institution retrospective experience. J Neurooncol. 2017;135(1):129–39. https://doi.org/10.1007/s11060-017-2559-9.

    Article  PubMed  Google Scholar 

  6. Szopa W, Burley TA, Kramer-Marek G, Kaspera W. Diagnostic and therapeutic biomarkers in glioblastoma: current status and future perspectives. Biomed Res Int. 2017;2017:8013575. https://doi.org/10.1155/2017/8013575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Aum DJ, Kim DH, Beaumont TL, Leuthardt EC, Dunn GP, Kim AH. Molecular and cellular heterogeneity: the hallmark of glioblastoma. Neurosurg Focus. 2014;37(6):E11. https://doi.org/10.3171/2014.9.FOCUS14521.

    Article  PubMed  Google Scholar 

  8. Ramos AD, Magge RS, Ramakrishna R. Molecular pathogenesis and emerging treatment for glioblastoma. World Neurosurg. 2018;116:495–504. https://doi.org/10.1016/j.wneu.2018.04.021.

    Article  PubMed  Google Scholar 

  9. Zong H, Verhaak RG, Canoll P. The cellular origin for malignant glioma and prospects for clinical advancements. Expert Rev Mol Diagn. 2012;12(4):383–94. https://doi.org/10.1586/erm.12.30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Braganza MZ, Kitahara CM, de González AB, Inskip PD, Johnson KJ, Rajaraman P. Ionizing radiation and the risk of brain and central nervous system tumors: a systematic review. Neuro Oncol. 2012;14(11):1316–24. https://doi.org/10.1093/neuonc/nos208.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rous P. A transmissible avian neoplasm (Sarcoma of the common fowl) by Peyton Rous, M.D., experimental Medicine for Sept. 1, 1910, vol. 12, pp. 696–705. J Exp Med. 1979;150(4):738–53.

    Article  CAS  PubMed  Google Scholar 

  12. Bird A. Perceptions of epigenetics. Nature. 2007;447(7143):396–8.

    Article  CAS  PubMed  Google Scholar 

  13. Javaid N, Choi S. Acetylation- and methylation-related epigenetic proteins in the context of their targets. Genes (Basel). 2017. https://doi.org/10.3390/genes8080196.

    Article  Google Scholar 

  14. Geraldo LHM, Garcia C, da Fonseca ACC, Dubois LGF, de Sampaio E, Spohr TCL, Matias D, et al. Glioblastoma therapy in the age of molecular medicine. Trends Cancer. 2019;5(1):46–65. https://doi.org/10.1016/j.trecan.2018.11.002.

    Article  CAS  PubMed  Google Scholar 

  15. Lu QR, Qian L, Zhou X. Developmental origins and oncogenic pathways in malignant brain tumors. Wiley Interdiscip Rev Dev Biol. 2019;8(4):e342. https://doi.org/10.1002/wdev.342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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(6110):1080–4. https://doi.org/10.1126/science.1226929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell. 2013;152(1–2):25–38. https://doi.org/10.1016/j.cell.2012.12.012.

    Article  CAS  PubMed  Google Scholar 

  18. Gulaia V, Kumeiko V, Shved N, Cicinskas E, Rybtsov S, Ruzov A, et al. Molecular mechanisms governing the stem cell's fate in brain cancer: factors of stemness and quiescence. Front Cell Neurosci. 2018;12:388. https://doi.org/10.3389/fncel.2018.00388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Malumbres M, Barbacid M. To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer. 2001;1(3):222–31.

    Article  CAS  PubMed  Google Scholar 

  20. Knudsen ES, Wang JY. Targeting the RB-pathway in cancer therapy. Clin Cancer Res. 2010;16(4):1094–9. https://doi.org/10.1158/1078-0432.CCR-09-0787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Meletis K, Wirta V, Hede SM, Nistér M, Lundeberg J, Frisén J. p53 suppresses the self-renewal of adult neural stem cells. Development. 2006;133(2):363–9.

    Article  CAS  PubMed  Google Scholar 

  22. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10(8):789–99.

    Article  CAS  PubMed  Google Scholar 

  23. Louis DN, von Deimling A, Chung RY, Rubio MP, Whaley JM, Eibl RH, et al. Comparative study of p53 gene and protein alterations in human astrocytic tumors. J Neuropathol Exp Neurol. 1993;52(1):31–8.

    Article  CAS  PubMed  Google Scholar 

  24. van Meyel DJ, Ramsay DA, Casson AG, Keeney M, Chambers AF, Cairncross JG. p53 mutation, expression, and DNA ploidy in evolving gliomas: evidence for two pathways of progression. J Natl Cancer Inst. 1994;86(13):1011–7.

    Article  CAS  PubMed  Google Scholar 

  25. Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP, et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell. 2005;8(2):119–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fraser MM, Zhu X, Kwon CH, Uhlmann EJ, Gutmann DH, Baker SJ. Pten loss causes hypertrophy and increased proliferation of astrocytes in vivo. Cancer Res. 2004;64(21):7773–9.

    Article  CAS  PubMed  Google Scholar 

  27. Groszer M, Erickson R, Scripture-Adams DD, Dougherty JD, Le Belle J, Zack JA, et al. PTEN negatively regulates neural stem cell self-renewal by modulating G0–G1 cell cycle entry. Proc Natl Acad Sci USA. 2006;103(1):111–6.

    Article  CAS  PubMed  Google Scholar 

  28. Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, et al. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature. 2008;455(7216):1129–33. https://doi.org/10.1038/nature07443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kwon CH, Zhao D, Chen J, Alcantara S, Li Y, Burns DK, et al. Pten haploinsufficiency accelerates formation of high-grade astrocytomas. Cancer Res. 2008;68(9):3286–94. https://doi.org/10.1158/0008-5472.CAN-07-6867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, et al. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell. 2018;173(2):400–416.e11. https://doi.org/10.1016/j.cell.2018.02.052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cline MS, Craft B, Swatloski T, Goldman M, Ma S, Haussler D, et al. Exploring TCGA pan-cancer data at the UCSC cancer genomics browser. Sci Rep. 2013;2(3):2652. https://doi.org/10.1038/srep02652.

    Article  Google Scholar 

  32. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013. https://doi.org/10.1126/scisignal.2004088.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4. https://doi.org/10.1158/2159-8290.CD-12-0095.

    Article  PubMed  Google Scholar 

  34. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8. https://doi.org/10.1038/nature07385.

    Article  CAS  Google Scholar 

  35. Teo WY, Sekar K, Seshachalam P, Shen J, Chow WY, Lau CC, et al. Relevance of a TCGA-derived glioblastoma subtype gene-classifier among patient populations. Sci Rep. 2019;9(1):7442. https://doi.org/10.1038/s41598-019-43173-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell. 2016;164(3):550–63. https://doi.org/10.1016/j.cell.2015.12.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462–77. https://doi.org/10.1016/j.cell.2013.09.034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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(2):97–109.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007;170(5):1445–533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res. 2013;19(4):764–72. https://doi.org/10.1158/1078-0432.CCR-12-3002.

    Article  CAS  PubMed  Google Scholar 

  41. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20. https://doi.org/10.1007/s00401-016-1545-1.

    Article  PubMed  Google Scholar 

  42. Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372(26):2481–98. https://doi.org/10.1056/NEJMoa1402121.

    Article  CAS  Google Scholar 

  43. Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–22. https://doi.org/10.1016/j.ccr.2010.03.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016;529(7584):110–4. https://doi.org/10.1038/nature16490.

    Article  CAS  PubMed  Google Scholar 

  45. Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, et al. DNA methylation-based classification of central nervous system tumors. Nature. 2018;555(7697):469–74. https://doi.org/10.1038/nature26000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9(3):157–73.

    Article  CAS  PubMed  Google Scholar 

  47. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110. https://doi.org/10.1016/j.ccr.2009.12.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bhat KPL, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, et al. Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell. 2013;24(3):331–46. https://doi.org/10.1016/j.ccr.2013.08.001.

    Article  CAS  PubMed  Google Scholar 

  49. Batchelor TT, Reardon DA, de Groot JF, Wick W, Weller M. Antiangiogenic therapy for glioblastoma: current status and future prospects. Clin Cancer Res. 2014;20(22):5612–9. https://doi.org/10.1158/1078-0432.CCR-14-0834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008;8(6):425–37. https://doi.org/10.1038/nrc2397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ahn GO, Brown JM. Role of endothelial progenitors and other bone marrow-derived cells in the development of the tumor vasculature. Angiogenesis. 2009;12(2):159–64. https://doi.org/10.1007/s10456-009-9135-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA. Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res. 2006;66(18):9054–64.

    Article  CAS  PubMed  Google Scholar 

  53. Yue WY, Chen ZP. Does vasculogenic mimicry exist in astrocytoma? J Histochem Cytochem. 2005;53(8):997–1002.

    Article  CAS  PubMed  Google Scholar 

  54. Soda Y, Marumoto T, Friedmann-Morvinski D, Soda M, Liu F, Michiue H, et al. Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci USA. 2011;108(11):4274–80. https://doi.org/10.1073/pnas.1016030108.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153(1):139–52. https://doi.org/10.1016/j.cell.2013.02.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hardee ME, Zagzag D. Mechanisms of glioma-associated neovascularization. Am J Pathol. 2012;181(4):1126–41. https://doi.org/10.1016/j.ajpath.2012.06.030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Park JS, Kim IK, Han S, Park I, Kim C, Bae J, et al. Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell. 2016;30(6):953–67. https://doi.org/10.1016/j.ccell.2016.10.018.

    Article  CAS  PubMed  Google Scholar 

  58. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumours of the central nervous system. 4th ed. Lyon: IARC Press; 2016.

    Google Scholar 

  59. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumours of the central nervous system. 4th ed. Lyon: IARC Press; 2007.

    Google Scholar 

  60. Park SH, Won J, Kim SI, Lee Y, Park CK, Kim SK, et al. Molecular testing of brain tumor. J Pathol Transl Med. 2017;51(3):205–23. https://doi.org/10.4132/jptm.2017.03.08.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Louis DN, Wesseling P, Paulus W, Giannini C, Batchelor TT, Cairncross JG, Capper D, Figarella-Branger D, Lopes MB, Wick W, van den Bent M. cIMPACT-NOW UPDATE 1: not otherwise specified (NOS) and not elsewhere classified (NEC). Acta Neuropathol. 2018;135(3):481–4.

    Article  PubMed  Google Scholar 

  62. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tomczak K, Czerwińska P, Wiznerowicz M. The cancer genome atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn). 2015;19(1A):A68–77. https://doi.org/10.5114/wo.2014.47136.

    Article  Google Scholar 

  64. Hartmann C, Hentschel B, Wick W, Capper D, Felsberg J, Simon M, et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 2010;120(6):707–18.

    Article  PubMed  Google Scholar 

  65. Weller M, Stupp R, Hegi ME, van den Bent M, Tonn JC, Sanson M. Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro-Oncology. 2012;14:100–8.

    Google Scholar 

  66. Solomon DA, Wood MD, Tihan T, Bollen AW, Gupta N, Phillips JJ, et al. Diffuse midline gliomas with histone H3–K27M mutation: A series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol. 2016;26(5):569–80.

    Article  CAS  PubMed  Google Scholar 

  67. Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 2012;22(4):425–37.

    Article  CAS  PubMed  Google Scholar 

  68. Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C, et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 2011;121(3):397–405. https://doi.org/10.1007/s00401-011-0802-6.

    Article  CAS  PubMed  Google Scholar 

  69. Kaley T, Touat M, Subbiah V, Hollebecque A, Rodon J, Lockhart AC, et al. BRAF inhibition in BRAFV600-mutant gliomas: results from the VE-BASKET study. J Clin Oncol. 2018. https://doi.org/10.1200/JCO.2018.78.9990.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, et al. The epidemiology of glioma in adults: a "state of the science" review. Neuro Oncol. 2014;16(7):896–913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Andronesi OC, Rapalino O, Gerstner E, Chi A, Batchelor TT, Cahill DP, et al. Detection of oncogenic IDH1 mutations using magnetic resonance spectroscopy of 2-hydroxyglutarate. J Clin Invest. 2013;123(9):3659–63. https://doi.org/10.1172/JCI67229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kalpathy-Cramer J, Gerstner ER, Emblem KE, Andronesi O, Rosen B. Advanced magnetic resonance imaging of the physical processes in human glioblastoma. Cancer Res. 2014;74(17):4622–37. https://doi.org/10.1158/0008-5472.CAN-14-0383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Carrillo JA, Lai A, Nghiemphu PL, Kim HJ, Phillips HS, Kharbanda S, et al. Relationship between tumor enhancement, edema, IDH1 mutational status, MGMT promoter methylation, and survival in glioblastoma. AJNR Am J Neuroradiol. 2012;33(7):1349–55. https://doi.org/10.3174/ajnr.A2950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science. 2014;343(6167):189–93. https://doi.org/10.1126/science.1239947.

    Article  CAS  PubMed  Google Scholar 

  75. Beiko J, Suki D, Hess KR, Fox BD, Cheung V, Cabral M, et al. IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection. Neuro Oncol. 2014;16(1):81–91. https://doi.org/10.1093/neuonc/not159.

    Article  CAS  PubMed  Google Scholar 

  76. Ma Y, Tang N, Thompson RC, Mobley BC, Clark SW, Sarkaria JN, et al. InsR/IGF1R pathway mediates resistance to EGFR inhibitors in glioblastoma. Clin Cancer Res. 2016;22(7):1767–76. https://doi.org/10.1158/1078-0432.CCR-15-1677.

    Article  CAS  PubMed  Google Scholar 

  77. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396–401. https://doi.org/10.1126/science.1254257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401.

    Article  CAS  PubMed  Google Scholar 

  79. Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488(7412):522–6. https://doi.org/10.1038/nature11287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.

    Article  CAS  PubMed  Google Scholar 

  81. Suvà ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell. 2014;157(3):580–94. https://doi.org/10.1016/j.cell.2014.02.030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lathia JD, Heddleston JM, Venere M, Rich JN. Deadly teamwork: neural cancer stem cells and the tumor microenvironment. Cell Stem Cell. 2011;8(5):482–5. https://doi.org/10.1016/j.stem.2011.04.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523:337–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Laman JD, Weller RO. Drainage of cells and soluble antigen from the CNS to regional lymph nodes. J Neuro Pharmacol. 2013;8:840–56.

    Google Scholar 

  85. Woroniecka KI, Rhodin KE, Chongsathidkiet P, Keith KA, Fecci PE. T-cell dysfunction in glioblastoma: applying a new framework. Clin Cancer Res. 2018;24(16):3792–802. https://doi.org/10.1158/1078-0432.CCR-18-0047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, Lang FF, McCutcheon IE, Hassenbusch SJ, Holland E, Hess K, Michael C, Miller D, Sawaya R. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95(2):190–8.

    Article  CAS  PubMed  Google Scholar 

  87. Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg. 2011;115(1):3–8. https://doi.org/10.3171/2011.2.JNS10998.

    Article  PubMed  Google Scholar 

  88. Díez Valle R, Becerra Castro V, Marigil Sánchez M, Gállego Pérez-Larraya J, Núñez-Córdoba JM, Tejada SS. Results of a policy of fast tapering of steroids after resection surgery in glioblastoma. World Neurosurg. 2018;109:e845–e852852. https://doi.org/10.1016/j.wneu.2017.10.110.

    Article  PubMed  Google Scholar 

  89. Platten M. EGFRvIII vaccine in glioblastoma-InACT-IVe or not ReACTive enough? Neuro Oncol. 2017;19(11):1425–6. https://doi.org/10.1093/neuonc/nox167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Inogés S, Tejada S, de Cerio AL, Gállego Pérez-Larraya J, Espinós J, Idoate M, et al. A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fluorescence-guided surgery in newly diagnosed glioblastoma patients. J Transl Med. 2017;15(1):104. https://doi.org/10.1186/s12967-017-1202-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, López-Janeiro A, Porciuncula A, Idoate MA, et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat Med. 2019;25(3):470–6. https://doi.org/10.1038/s41591-018-0339-5.

    Article  CAS  PubMed  Google Scholar 

  92. Lang FF, Conrad C, Gomez-Manzano C, Yung WKA, Sawaya R, Weinberg JS, et al. Phase I study of DNX-2401 (delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol. 2018;36(14):1419–27. https://doi.org/10.1200/JCO.2017.75.8219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Desjardins A, Gromeier M, Herndon JE 2nd, Beaubier N, Bolognesi DP, Friedman AH, et al. Recurrent glioblastoma treated with recombinant poliovirus. N Engl J Med. 2018;379(2):150–61. https://doi.org/10.1056/NEJMoa1716435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Philbrick BD, Adamson DC. Early clinical trials of Toca 511 and Toca FC show a promising novel treatment for recurrent malignant glioma. Expert Opin Investig Drugs. 2019;28(3):207–16. https://doi.org/10.1080/13543784.2019.1572112.

    Article  CAS  PubMed  Google Scholar 

  95. Reardon DA, Wen PY, Mellinghoff IK. Targeted molecular therapies against epidermal growth factor receptor: past experiences and challenges. Neuro Oncol. 2014;16(Suppl 8):7–13. https://doi.org/10.1093/neuonc/nou232.

    Article  CAS  Google Scholar 

  96. Seystahl K, Wick W, Weller M. Therapeutic options in recurrent glioblastoma—an update. Crit Rev Oncol Hematol. 2016;99:389–408. https://doi.org/10.1016/j.critrevonc.2016.01.018.

    Article  PubMed  Google Scholar 

  97. Touat M, Idbaih A, Sanson M, Ligon KL. Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann Oncol. 2017;28(7):1457–72. https://doi.org/10.1093/annonc/mdx106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Fujii T, Khawaja MR, DiNardo CD, Atkins JT, Janku F. Targeting isocitrate dehydrogenase (IDH) in cancer. Discov Med. 2016;21(117):373–80.

    PubMed  Google Scholar 

  99. Pellegatta S, Valletta L, Corbetta C, Patanè M, Zucca I, Riccardi Sirtori F, et al. Effective immuno-targeting of the IDH1 mutation R132H in a murine model of intracranial glioma. Acta Neuropathol Commun. 2015;21(3):4. https://doi.org/10.1186/s40478-014-0180-0.

    Article  CAS  Google Scholar 

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Funding

No specific financing was used for the composition of this manuscript. R.G. reports receiving grants from the AECC Scientific Foundation.

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Authors and Affiliations

  1. Servicio de Neurocirugía, Hospital Universitario de Burgos, Avda Islas Baleares 3, 09006, Burgos, Spain

    P. D. Delgado-López

  2. Servicio Anatomía Patológica, Hospital Universitario de Burgos, Burgos, Spain

    P. Saiz-López

  3. Unidad de Neurooncología, Instituto de Salud Carlos III-UFIEC, Madrid, Spain

    R. Gargini

  4. Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Madrid, Spain

    R. Gargini

  5. Servicio de Anatomía Patológica, Hospital General Universitario “Gregorio Marañón”, Madrid, Spain

    E. Sola-Vendrell

  6. Servicio de Neurocirugía, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain

    S. Tejada

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  1. P. D. Delgado-López
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  2. P. Saiz-López
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  3. R. Gargini
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  4. E. Sola-Vendrell
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Delgado-López, P.D., Saiz-López, P., Gargini, R. et al. A comprehensive overview on the molecular biology of human glioma: what the clinician needs to know. Clin Transl Oncol 22, 1909–1922 (2020). https://doi.org/10.1007/s12094-020-02340-8

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