• NIKOLAOS ANDREAS CHRYSANTHAKOPOULOS Department of Pathological Anatomy, Medical School, University of Athens, Athens, Greece.
  • PANAGIOTIS ANDREAS CHRYSANTHAKOPOULOS Department of Neurosurgery, Military Hospital of Athens, Athens, Greece.



Gliomas, Glioblastoma, Signaling Pathways, Inflammation


Gliomas are the most common primary and aggressive intracranial tumors, represent 80% of malignant brain tumors, and despite the fact that are relatively rare tumors are responsible for significant mortality and morbidity. Glioblastoma multiforme (GBM) or diffuse astrocytoma, WHO grade IV, is the most common and aggressive primary central nervous system malignancy, represents 45% of all gliomas, shows an average incidence of 3.19/100,000 individuals, its median age of diagnosis is 64 years, and the median survival is 15 months as the 5-year relative survival is 5%. Previous studies have investigated the possible role of genetic and environmental factors in GBM pathogenesis; however, the majority of GBM cases were sporadic and certain risk factors have not been detected. GBM is divided into primary and secondary subtypes which develop through different genetic pathways, affect patients at different ages, and have differences in clinical outcomes, as show a great morphological and genetic heterogeneity. The role of traumatic brain injury (TBI) in GBM formation has been investigated in many previous reports which have hypothesized that TBI may predispose to gliomagenesis; however, the outcomes were highly controversial. Some of those researches have proposed a supposed pathogenesis model that involves a post-traumatic inflammation, stem and progenitor cell transformation, and gliomagenesis. Other similar studies have involved transcription factors associated with TBI such as p53, hypoxia-inducible factor-1a (HIF-1a), and c-Myc. On the other hand, the possibility of a pre-existing tumor rather than a trauma-induced tumor is very possible in such cases.


Agnihotri S, Burrell KE, Wolf A, Jalali S, Hawkins C, Rutka JT, et al. Glioblastoma, a brief review of history, molecular genetics, animal models and novel therapeutic strategies. Arch Immunol Ther Exp 2013;61:25-41.

Schwartzbaum JA, Fisher JL, Aldape KD, Wrensch M. Epidemiology and molecular pathology of glioma. Nat Clin Pract Neurol 2006;2:494-503.

Gigineishvili D, Shengelia N, Shalashvili G, Rohrmann S, Tsiskaridze A, Shakarishvili R. Primary brain tumour epidemiology in Georgia: First year results of a population based study. J Neurooncol 2013;112:241-6.

Dubrow R, Darefsky AS. Demographic variation in incidence of adult glioma by subtype. United States, 1992-2007. BMC Cancer 2011;11:325.

Jovčevska I, Kočevar N, Komel R. Glioma and glioblastoma-how much do we (not) know? Mol Clin Oncol 2013;1:935-41.

Rock K, McArdle O, Forde P, Dunne M, Fitzpatrick D, O’Neill B, et al. A clinical review of treatment outcomes in glioblastom multiforme the validation in a non-trial population of the results of a randomised Phase III clinical trial: Has a more radical approach improved survival? Br J Radiol 2014;85:729-33.

Ohka F, Natsume A, Wakabayashi T. Current trends in targeted therapies for glioblastoma multiforme. Neurol Res Int 2012;2012:878425.

Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner, Barnholtz-Sloanet JS, et al. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomark Prev 2014;23:1985-96.

Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol 2005;109:93-108.

Salcman M. Epidemiology and factors affecting survival. In: Apuzzo ML, editor. Malignant Cerebral Glioma Neurosurgical Topic Series. Vol. 3. Park Ridge: American Association of Neurological Surgeons; 1990. p. 95-110.

Bondy ML, Scheurer ME, Malmer B, Barnholtz-Sloan JS, Davis FG, Il’yasova D, et al. Brain tumor epidemiology: Consensus from the brain tumor epidemiology consortium. Cancer 2008;113:1953-68.

Ohgaki H. Epidemiology of brain tumors. Methods Mol Biol 2009;472:323-42.

Salvati M, Frati A, Russo N, Caroli E, Polli FM, Minniti G, et al. Radiation-induced gliomas: Report of 10 cases and review of the literature. Surg Neurol 2003;60:60-7.

Prasad G, Haas-Kogan DA. Radiation-induced gliomas. Expert Rev Neurother 2009;9:1511-7.

Fisher JL, Schwartzbaum JA, Wrensch M, Wiemels JL. Epidemiology of brain tumors. Neurol Clin 2007;25:867-90.

Adamson C, Kanu OO, Mehta AI, Di C, Lin N, Mattox AK, et al. Glioblastoma multiforme: A review of where we have been and where we are going. Expert Opin Investig Drugs 2009;18:1061-83.

Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: A clinical review. J Am Med Assoc 2013;310:1842-50.

Kabat GC, Etgen AM, Rohan TE. Do steroid hormones play a role in the etiology of glioma? Cancer Epidemiol Biomarkers Prev 2010;19:2421 7.

Rajaraman P, Melin BS, Wang Z, McKean-Cowdin R, Michaud DS, Wang SS, et al. Genome-wide association study of glioma and meta-analysis. Hum Genet 2012;131:1877-88.

Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B, et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet 2009;41:899-904.

Simon M, Hosking FJ, Marie Y, Gousias K, Boisselier B, Carpentier C, et al. Genetic risk profiles identify different molecular etiologies for glioma. Clinl Cancer Res 2010;16:5252-9.

Wibom C, Ghasimi S, Van Loo P, Brännström T, Trygg J, Lau C, et al. EGFR gene variants are associated with specific somatic aberrations in glioma. PLoS One 2012;7:e47929.

Wrensch M, Jenkins RB, Chang JS, Yeh RF, Xiao Y, Decker PA, et al. Variants in the CDK N2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat Genet 2009;41:905-8.

Yang TH, Kon M, Hung JH, Delisi C. Combinations of newly confirmed Glioma-Associated loci link regions on chromosomes 1 and 9 to increased disease risk. BMC Medical Genomics 2011;4:63.

Anselmi E, Vallisa D, Bertè R, Vanzo C, Cavanna L. Post-traumatic glioma: Report of two cases. Tumori 2006;92:175-7.

Chrysanthakopoulos NA, Chrysanthakopoulos PA. Potential risk factors of glioblastoma multiforme in Greek adults: A case-control study J Clin Med Res 2020;1:1-17.

Zhou B, Liu W. Post-traumatic glioma: Report of one case and review of the literature. Int J Med Sci 2010;7:248-50.

Munch TN, Gørtz S, Wohlfahrt J, Melbye M. The long-term risk of malignant astrocytic tumors after structural brain injury--a nationwide cohort study. Neuro Oncol 2015;17:718-24.

Inskip PD, Mellemkjaer L, Gridley G, Olsen JH. Incidence of intracranial tumors following hospitalization for head injuries (Denmark). Cancer Causes Control 1998;9:109-16.

Nygren C, Adami J, Ye W, Bellocco R, af Geijerstam JL, Borg J, et al. Primary brain tumors following traumatic brain injury--a population-based cohort study in Sweden. Cancer Causes Control 2001;12:733-7.

Chen YH, Keller JJ, Kang JH, Lin HC. Association between traumatic brain injury and the subsequent risk of brain cancer. J Neurotrauma 2012;29:1328-33.

Monteiro GT, Pereira RA, Koifman RJ, Koifman S, Head injury and brain tumours in adults: A case-control study in Rio de Janeiro, Brazil. Eur J Cancer 2006;42:917-21.

Gurney JG, Preston-Martin S, McDaniel AM, Mueller BA, Holly EA. Head injury as a risk factor for brain tumors in children: Results from a multicenter case-control study. Epidemiology 1996;7:485-9.

Zampieri P, Meneghini F, Grigoletto F, Gerosa M, Licata C, Casentini L, et al. Risk factors for cerebral glioma in adults: A case-control study in an Italian population. J Neuro Oncol 1994;19:61-7.

Preston-Martin S, Pogoda JM, Schlehofer B, Blettner M, Howe GR, Ryan P, Menegoz F, et al. An international case-control study of adult glioma and meningioma: The role of head trauma. Int J Epidemiol 1998;27:579-86.

Hu J, Johnson KC, Mao Y, Guo L, Zhao X, Jia X, et al. Risk factors for glioma in adults: A case-control study in northeast China. Cancer Detect Prev 1998;22:100-8.

Hochberg F, Toniolo P, Cole P. Head trauma and seizures as risk factors of glioblastoma. Neurology 1984;34:1511-4.

Magnavita N, Placentino RA, Mei D, Ferraro D, Di Trapani G. Occupational head injury and subsequent Glioma. Neurol Sci 2003;24:31-3.

Moorthy RK, Rajshekhar V. Development of glioblastoma multiforme following traumatic cerebral contusion: Case report and review of literature. Surg Neurol 2004;61:180-4.

Mrowka R, Bogunska C, Kulesza J, Bazowski P, Wencel T. Grave cranio-cerebral trauma 30 years ago as cause of the brain glioma at the locus of the trauma particulars of the case. Zen Tralbl Neurochir 1978;39:57-64.

Sabel M, Felsberg J, Messing-Junger M, Neuen-Jacob E, Piek J. Glioblastoma multiforme at the site of metal splinter injury: A coincidence? Case report. J Neurosurg 1999;91:1041-4.

Witzmann A, Jellinger K, Weiss R. Glioblastoma multiforme developing after a gunshot injury of the brain. Neurochir (Stuttg) 1981;24:202-6.

Annegers JF, Laws ER Jr., Kurland LT. Head trauma and subsequent brain tumours. Neuro Surg 1976;4:203-6.

Coskun S, Coskun A, Gursan N, Aydin MD. Post-traumatic glioblastoma multiforme: A case report. Eur J Med 2011;43:50-3.

Henderson RD, Campbell SF. Head trauma and brain tumours revisited. J Clin Neurosci 2000;7:262-4.

Henry PT, Rajshekhar V. Post-traumatic malignant glioma: Case report and review of litera-ture. Br J Neurosurg 2000;14:64-7.

Hill-Felberg SJ, McIntosh TK, Oliver DL, Raghupathi R, Barbarese E. Concurrent loss and proliferation of astrocytes following lateral fluid percussion brain injury in the adult rat. J Neurosci Res 1999;57:271-9.

Kernie SG, Erwin TM, Parada LF. Brain remodeling due to neuronal and astrocytic proliferation after controlled cortical injury in mice. J Neuroci Res 2001;66:317-26.

Manuelidis EE. Glioma in trauma. In: Minckler J, editor. Pathology of the Nervous System. Vol. 2. New York: McGraw-Hill; 1978. p. 2237-40.

Perez-Diaz C, Cabello A, Lobato RD, Rivas JJ, Cabrera . Oligodendrogliomas arising in the scar of a brain contusion. Surg Neurol 1985;24:581-6.

Han Z, Du Y, Qi H, Yin W. Post-traumatic malignant glioma in a pregnant woman: Case report and review of the literature. Neurol Med Chir (Tokyo) 2013;53:630-4.

Candolf M, Curtin JF, Nichols WS, Muhammad AK, King GD, Pluhar GE, et al. Intracranial glioblastoma models in preclinical neurooncology: Neuropathological characterization and tumor progression. J Neuro Oncol 2007;85:133-48.

Modrek AS, Bayin NS, Placantonakis DG. Brain stem cells as the cell of origin in glioma. World J Stem Cells 2014;6:43-52.

Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med 2005;353:811-22.

Elvira G, García I, Gallo J, Benito M, Montesinos P, Holgado-Martin E, et al. Detection of mouse endogenous Type B astrocytes migrating towards brain lesions. Stem Cell Res 2015;14:114-29.

Goings GE, Sahni V, Szele FG. Migration patterns of subventricular zone cells in adult mice change after cerebral cortex injury. Brain Res 2004;996:213-26.

Jin K, Sun Y, Xie L, Peel A, Mao XO, Batteur S, et al. Directed migration of neuronal pre-cursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci 2003;24:171-89.

Tong J, Latzman JM, Rauch J, Zagzag DS, Huang JH, Samadani U. Sonic hedgehog agonist fails to induce neural stem cell precursors in a porcine model of experimental intracranial hemorrhage. Acta Neurochir Suppl 2011;111:151-4.

Yamashita T, Ninomiya M, Acosta PH, García-Verdugo GM, Sunabori T, Sakagu-Chi M, et al. Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci 2006;26:6627-36.

Tyagi V, Theobald J, Barger J, Bustoros M, Bayin NS, Modrek AS, et al. Traumatic brain injury and subsequent glioblastoma development: Review of the literature and case reports. Surg Neurol Int 2016;7:78.

Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860-7.

Buffo A, Rite I, Tripathi P, Lepier A, Colak D, Horn AP, et al. Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain. Proc Natl Acad Sci USA 2008;105:3581-6.

Lang B, Liu HL, Liu R, Feng GD, Jiao XY, Ju G. Astrocytes in injured adult rat spinal cord may acquire the potential of neural stem cells. Neuroscience 2004;128:775-83.

Hopewell JW. The subependymal plate and the genesis of gliomas. J Pathol 1975;117:101-3.

Vick NA, Lin MJ, Bigner DD. The role of the subependymal plate in glial tumorigenesis. Acta Neuropathol 1977;40:63-71.

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;338:1080-4.

Marumoto T, Tashiro A, Friedmann-Morvinski D, Scadeng M, Soda Y, Gage FH, et al. Development of a novel mouse glioma model using lentiviral vectors. Nat Med 2009;15:110-6.

Barnabé-Heider F, Göritz C, Sabelström H, Takebayashi H, Pfrieger FW, Meletis K, et al. Origin of new glial cells in intact and injured adult spinal cord. Cell Stem Cell 2010;7:470-82.

Carlén M, Meletis K, Göritz C, Darsalia V, Evergren E, Tanigaki K, et al. Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke. Nat Neurosci 2009;12:259-67.

Adeberg S, König L, Bostel T, Harrabi S, Welzel T, Debus J, et al. Glioblastoma recurrence patterns after radiation therapy with regard to the subventricular zone. Int J Radiat Oncol Biol Phys 2014;90:886-93.

Bohman LE, Swanson KR, Moore JL, Rockne R, Mandigo C, Hankinson T, et al. Magnetic resonance imaging characteristics of glioblastoma multiforme: Implications for understanding glioma ontogeny. Neurosurgery 2010;67:1319-28.

Chaichana KL, McGirt MJ, Frazier J, Attenello F, Guerrero-Cazares H, Quinones-Hinojosa A. Relationship of glioblastoma multiforme to the lateral ventricles predicts survival following tumor resection. J Neuro Oncol 2008;89:219-24.

Barres BA. The mystery and magic of glia: A perspective on their roles in health and disease. Neuron 2008;60:430-40.

Robel S, Berninger B, Gotz M. The stem cell potential of glia: Lessons from reactive gliosis. Nat Rev Neurosci 2011;12:88-104.

Sofroniew MV, Vinters HV. Astrocytes: Biology and pathology. Acta Neuropathol 2010;119:7-35.

Laird MD, Vender JR, Dhandapani KM. Opposing roles for reactive astrocytes following traumatic brain injury. Neurosignals 2008;16:154-64.

Katz AM, Amankulor NM, Pitter K, Helmy K, Squatrito M, Holland EC. Astrocyte-specific expression patterns associated with the PDGF-induced glioma microenvironment. PLoS One 2012;7:e32453.

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;146:209-21.

Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 2013;136:28-42.

Liao Y, Liu P, Guo F, Zhang ZY, Zhang Z. Oxidative burst of circulating neutrophils following traumatic brain injury in human. PLoS One 2013;8:e68963.

Murray KN, Parry-Jones AR, Allan SM. Interleukin 1 and acute brain injury. Front Cell Neurosci 2015;9:18.

Woodcock T, Morganti-Kossmann MC. The role of markers of inflammation in traumatic brain injury. Front Neurol 2013;4:18.

Kuperman DA, Schleimer RP. Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma. Curr Mol Med 2008;8:384-92.

Schwartzbaum J, Ahlbom A, Malmer B, Lönn S, Brookes AJ, Doss H, et al. Polymorphisms associated with asthma are inversely related to glioblastoma multiforme. Cancer Res 2005;65:6459-65.

Curran CS, Bertics PJ. Eosinophils in glioblastoma biology. J Neuroinflammation 2012;9:11.

Fredens K, Dahl R, Venge P. The Gordon phenomenon induced by the eosinophil cationic protein and eosinophil protein X. J Allergy Clin Immunol 1982;70:361-6.

Yang D, Chen Q, Su SB, Zhang P, Kurosaka K, Caspi PP, et al. Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses. J Exp Med 2008;205:79-90.

Grauer OM, Molling JW, Bennink E, Toonen LW, Sutmuller RP, Nierkenset S, et al. TLR ligands in the local treatment of established intracerebral murine gliomas. J Immunol 2008;181:6720-9.

Curtin JF, Liu N, Candolfi M, Xiong W, Assi H, Yagiz K, et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med 2009;6:e10.

Mossman BT. Introduction to serial reviews on the role of reactive oxygen and nitrogen species (ROS/RNS) in lung injury and diseases. Free Radic Biol Med 2003;34:1115-6.

Sipos F, Firneisz G, Muzes G. Therapeutic aspects of c-MYC signaling in inflammatory and cancerous colonic diseases. World J Gastroenterol 2016;22:7938-50.

Fang WH, Wang DL, Wang F. Expression of c-Myc protein on rats brains after concussion, FaYi Xue Zha Zhi 2006;22:333-4.

Wan C, Jiang J, Mao H, Cao J, Wu X, Cui G. Involvement of upregulated p53-induced death domain protein (PIDD) in neuronal apoptosis after rat traumatic brain injury. J Mol Neurosci 2013;51:695-702.

Ohana N, Benharroch D, Sheinis D, Cohen A. Traumatic glioblastoma: Commentary and suggested mechanism. J Int Med Res 2018;46:2170 6.

Xiong Y, Peterson PL, Lee CP. Alterations in cerebral energy metabolism induced by traumatic brain injury. Neurol Res 2001;23:129-38.

Arif T, Krelin Y, Nakdimon I, Benharroch D, Paul A, Dadon-Klein D, et al. VDAC1 is a molecular target in glioblastoma, with its depletion leading to reprogrammed metabolism and reverse oncogenic properties. Neuro Oncol 2017;19:951-64.

Khan M, Khan H, Singh I, Singh AK. Hypoxia inducible factor 1 a stabilization for regenerative therapy in traumatic brain injury. Neural Regen Res 2017;12:696-701.

Higashida T, Kreipke CW, Rafols JA, Peng C, Schafer S, Schafer P,et al. The role of hypoxia inducible factor 1-a, aquaporin-4 and matrix metalloprotein-9 in blood-brain-barrier disruption and brain edema after traumatic brain injury. J Neurosurg 2011;114:92-101.

Benharroch D, Osyntsov L. Infectious diseases are analogous with cancer. Hypothesis and implications. J Cancer 2012;3:117-21.

Kappler M, Tauber H, Schubert J, Vordermark D, Eckert AW. The real face of HIF 1 a in the tumor process. Cell Cycle 2012;11:3932-6.

Palsson-McDermott EM, O’Neil LA. The Warburg effect then and now: From cancer to inflammatory diseases. Bioessays 2013;35:965-73.



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