Advertisement

Chemoresistance and Chemotherapy Targeting Stem-Like Cells in Malignant Glioma

  • Mia Dahl Sørensen
  • Sigurd Fosmark
  • Sofie Hellwege
  • Dagmar Beier
  • Bjarne Winther Kristensen
  • Christoph Patrick BeierEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 853)

Abstract

Glioblastoma remains a tumor with a dismal prognosis because of failure of current treatment. Glioblastoma cells with stem cell (GSC) properties survive chemotherapy and give rise to tumor recurrences that invariably result in the death of the patients. Here we summarize the current knowledge on chemoresistance of malignant glioma with a strong focus on GSC. Chemoresistant GSC are the most likely cause of tumor recurrence, but it remains controversial if GSC and under which conditions GSC are more chemoresistant than non-GSC within the tumor. Regardless of this uncertainty, the chemoresistance varies and it is mainly mediated by intrinsic factors. O6-methyl-guanidine methyltransferase (MGMT) remains the most potent mediator of chemoresistance, but disturbed mismatch repair system and multidrug resistance proteins contribute substantially. However, the intrinsic resistance by MGMT expression is regulated by extrinsic factors like hypoxia increasing MGMT expression and thereby resistance to alkylating chemotherapy. The search of new biomarkers helping to predict the tumor response to chemotherapy is ongoing and will complement the already known markers like MGMT.

Keywords

Glioblastoma stem cell Cancer stem cell Temozolomide MGMT MMR MDR Glioblastoma 

References

  1. 1.
    Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO. 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.PubMedGoogle Scholar
  2. 2.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.PubMedGoogle Scholar
  3. 3.
    Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol (Berl). 2005;109(1):93–108.Google Scholar
  4. 4.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol (Berl). 2007;114(2):97–109.Google Scholar
  5. 5.
    Curran WJ, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ, Chang CH, Rotman M, Asbell SO, Krisch RE, Nelson DF. Recursive Partitioning Analysis of Prognostic Factors in 3 Radiation-Therapy Oncology Group Malignant Glioma Trials. J Natl Cancer Inst. 1993;85(9):704–10. doi: 10.1093/jnci/85.9.704.PubMedGoogle Scholar
  6. 6.
    Kleihues P, Ohgaki H. Primary and secondary glioblastomas: from concept to clinical diagnosis. Neuro Oncol. 1999;1(1):44–51.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K. 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.PubMedGoogle Scholar
  8. 8.
    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. 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.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Huse JT, Phillips HS, Brennan CW. Molecular subclassification of diffuse gliomas: seeing order in the chaos. Glia. 2011;59(8):1190–9. doi: 10.1002/glia.21165.PubMedGoogle Scholar
  10. 10.
    Varghese M, Olstorn H, Sandberg C, Vik-Mo EO, Noordhuis P, Nister M, Berg-Johnsen J, Moe MC, Langmoen IA. A comparison between stem cells from the adult human brain and from brain tumors. Neurosurgery. 2008;63(6):1022–33.PubMedGoogle Scholar
  11. 11.
    Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F, Vescovi A. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64(19):7011–21.PubMedGoogle Scholar
  12. 12.
    Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia. 2002;39(3):193–206.PubMedGoogle Scholar
  13. 13.
    Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63(18):5821–8.PubMedGoogle Scholar
  14. 14.
    Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med. 2005;353(8):811–22.PubMedGoogle Scholar
  15. 15.
    Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J, Terzis AJ. Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer. 2005;5(11):899–904.PubMedGoogle Scholar
  16. 16.
    Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.PubMedGoogle Scholar
  17. 17.
    Hamburger AW, Salmon SE. Primary bioassay of human tumor stem cells. Science. 1977;197(4302):461–3.PubMedGoogle Scholar
  18. 18.
    Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14(3):275–91. doi: 10.1016/j.stem.2014.02.006.PubMedGoogle Scholar
  19. 19.
    Luchman HA, Stechishin OD, Dang NH, Blough MD, Chesnelong C, Kelly JJ, Nguyen SA, Chan JA, Weljie AM, Cairncross JG, Weiss S. An in vivo patient-derived model of endogenous IDH1-mutant glioma. Neuro Oncol. 2012;14(2):184–91. doi: 10.1093/neuonc/nor207.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Pollard SM, Yoshikawa K, Clarke ID, Danovi D, Stricker S, Russell R, Bayani J, Head R, Lee M, Bernstein M, Squire JA, Smith A, Dirks P. Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell. 2009;4(6):568–80.PubMedGoogle Scholar
  21. 21.
    Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.PubMedGoogle Scholar
  22. 22.
    Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U, Beier CP. CD133+ and CD133− glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 2007;67(9):4010–5.PubMedGoogle Scholar
  23. 23.
    Eramo A, Ricci-Vitiani L, Zeuner A, Pallini R, Lotti F, Sette G, Pilozzi E, Larocca LM, Peschle C, De Maria R. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 2006;13(7):1238–41.PubMedGoogle Scholar
  24. 24.
    Gunther HS, Schmidt NO, Phillips HS, Kemming D, Kharbanda S, Soriano R, Modrusan Z, Meissner H, Westphal M, Lamszus K. Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene. 2008;27(20):2897–909.PubMedGoogle Scholar
  25. 25.
    Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A. 2003;100(25):15178–83.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL, Black KL, Yu JS. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene. 2004;23(58):9392–400.PubMedGoogle Scholar
  27. 27.
    Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM, Pastorino S, Purow BW, Christopher N, Zhang W, Park JK, Fine HA. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell. 2006;9(5):391–403.PubMedGoogle Scholar
  28. 28.
    Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O, Ellisman MH, Verma IM. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science. 2012;338(6110):1080–4. doi: 10.1126/science.1226929.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet. 2000;25(1):55–7.PubMedGoogle Scholar
  30. 30.
    Zhu Y, Guignard F, Zhao D, Liu L, Burns DK, Mason RP, Messing A, Parada LF. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell. 2005;8(2):119–30.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Alcantara Llaguno S, Chen J, Kwon CH, Jackson EL, Li Y, Burns DK, Alvarez-Buylla A, Parada LF. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell. 2009;15(1):45–56.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, Perry SR, Tonon G, Chu GC, Ding Z, Stommel JM, Dunn KL, Wiedemeyer R, You MJ, Brennan C, Wang YA, Ligon KL, Wong WH, Chin L, DePinho RA. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature. 2008;455(7216):1129–33.PubMedCentralPubMedGoogle Scholar
  33. 33.
    Jang T, Litofsky NS, Smith TW, Ross AH, Recht LD. Aberrant nestin expression during ethylnitrosourea-(ENU)-induced neurocarcinogenesis. Neurobiol Dis. 2004;15(3):544–52.PubMedGoogle Scholar
  34. 34.
    Alvarez-Buylla A, Lim DA. For the long run: maintaining germinal niches in the adult brain. Neuron. 2004;41(5):683–6.PubMedGoogle Scholar
  35. 35.
    Zhao CM, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132(4):645–60. doi: 10.1016/j.cell.2008.01.033.PubMedGoogle Scholar
  36. 36.
    Glass R, Synowitz M, Kronenberg G, Walzlein JH, Markovic DS, Wang LP, Gast D, Kiwit JRR, Kempermann G, Kettenmann H. Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci. 2005;25(10):2637–46. doi:10.1523/jneurosci. 5118-04.2005.Google Scholar
  37. 37.
    Doetsch F, Petreanu L, Caille I, Garcia-Verdugo JM, Alvarez-Buylla A. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron. 2002;36(6):1021–34.PubMedGoogle Scholar
  38. 38.
    Chua C, Zaiden N, Chong KH, See SJ, Wong MC, Ang BT, Tang C. Characterization of a side population of astrocytoma cells in response to temozolomide. J Neurosurg. 2008;109(5):856–66.PubMedGoogle Scholar
  39. 39.
    Wan F, Zhang S, Xie R, Gao B, Campos B, Herold-Mende C, Lei T. The utility and limitations of neurosphere assay, CD133 immunophenotyping and side population assay in glioma stem cells research. Brain Pathol. 2010;9999(999A).Google Scholar
  40. 40.
    Chen R, Nishimura MC, Bumbaca SM, Kharbanda S, Forrest WF, Kasman IM, Greve JM, Soriano RH, Gilmour LL, Rivers CS, Modrusan Z, Nacu S, Guerrero S, Edgar KA, Wallin JJ, Lamszus K, Westphal M, Heim S, James CD, VandenBerg SR, Costello JF, Moorefield S, Cowdrey CJ, Prados M, Phillips HS. A hierarchy of self-renewing tumor-initiating cell types in glioblastoma. Cancer Cell. 2010;17(4):362–75.PubMedGoogle Scholar
  41. 41.
    Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, Rich JN. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell. 2009;15(6):501–13.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Chen J, Li YJ, Yu TS, McKay RM, Burns DK, Kernie SG, Parada LF. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488(7412):522. doi: 10.1038/nature11287.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Auffinger B, Tobias AL, Han Y, Lee G, Guo D, Dey M, Lesniak MS, Ahmed AU. Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy. Cell Death Differ. 2014;21(7):1119–31. doi: 10.1038/cdd.2014.31.PubMedGoogle Scholar
  44. 44.
    Brennan C, Momota H, Hambardzumyan D, Ozawa T, Tandon A, Pedraza A, Holland E. Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLoS One. 2009;4(11):e7752.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Bhat KP, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, James JD, Gumin J, Diefes KL, Kim SH, Turski A, Azodi Y, Yang Y, Doucette T, Colman H, Sulman EP, Lang FF, Rao G, Copray S, Vaillant BD, Aldape KD. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev. 2011;25(24):2594–609. doi: 10.1101/gad.176800.111.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Beier F, Beier CP, Aschenbrenner I, Hildebrandt GC, Brummendorf TH, Beier D. Identification of CD133(−)/telomerase(low) progenitor cells in glioblastoma-derived cancer stem cell lines. Cell Mol Neurobiol. 2011;31(3):337–43. doi: 10.1007/s10571-010-9627-4.PubMedGoogle Scholar
  47. 47.
    Grant R, Liang BC, Slattery J, Greenberg HS, Junck L. Chemotherapy response criteria in malignant glioma. Neurology. 1997;48(5):1336–40.PubMedGoogle Scholar
  48. 48.
    Beier D, Schulz JB, Beier CP. Chemoresistance of glioblastoma cancer stem cells–much more complex than expected. Mol Cancer. 2011;10:128. doi: 10.1186/1476-4598-10-128.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Pallini R, Ricci-Vitiani L, Banna GL, Signore M, Lombardi D, Todaro M, Stassi G, Martini M, Maira G, Larocca LM, De Maria R. Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme. Clin Cancer Res. 2008;14(24):8205–12.PubMedGoogle Scholar
  50. 50.
    Pallini R, Ricci-Vitiani L, Montano N, Mollinari C, Biffoni M, Cenci T, Pierconti F, Martini M, De Maria R, Larocca LM. Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis. Cancer. 2011;117(1):162–74. doi: 10.1002/cncr.25581.PubMedGoogle Scholar
  51. 51.
    Wang J, Wakeman TP, Lathia JD, Hjelmeland AB, Wang XF, White RR, Rich JN, Sullenger BA. Notch promotes radioresistance of glioma stem cells. Stem Cells. 2010;28(1):17–28. doi: 10.1002/stem.261.PubMedCentralPubMedGoogle Scholar
  52. 52.
    Beier D, Rohrl S, Pillai DR, Schwarz S, Kunz-Schughart LA, Leukel P, Proescholdt M, Brawanski A, Bogdahn U, Trampe-Kieslich A, Giebel B, Wischhusen J, Reifenberger G, Hau P, Beier CP. Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Res. 2008;68(14):5706–15.PubMedGoogle Scholar
  53. 53.
    Bleau AM, Hambardzumyan D, Ozawa T, Fomchenko EI, Huse JT, Brennan CW, Holland EC. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell. 2009;4(3):226–35.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Liu GT, Yuan XP, Zeng ZH, Tunici P, Ng HS, Abdulkadir IR, Lu LZ, Irvin D, Black KL, Yu JS. Analysis of gene expression and chemoresistance of CDI33(+) cancer stem cells in glioblastoma. Mol Cancer. 2006;5:12. doi: 10.1186/1476-4598-5-67.Google Scholar
  55. 55.
    Ghods AJ, Irvin D, Liu G, Yuan X, Abdulkadir IR, Tunici P, Konda B, Wachsmann-Hogiu S, Black KL, Yu JS. Spheres isolated from 9L gliosarcoma rat cell line possess chemoresistant and aggressive cancer stem-like cells. Stem Cells. 2007;25(7):1645–53.PubMedGoogle Scholar
  56. 56.
    Hong X, Chedid K, Kalkanis SN. Glioblastoma cell line-derived spheres in serum-containing medium versus serum-free medium: a comparison of cancer stem cell properties. Int J Oncol. 2012;41(5):1693–700. doi: 10.3892/ijo.2012.1592.PubMedGoogle Scholar
  57. 57.
    Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A. HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol. 2007;17(2):165–72.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Villalva C, Martin-Lanneree S, Cortes U, Dkhissi F, Wager M, Le Corf A, Tourani J, Dusanter-Fourt I, Turhan A, Karayan-Tapon L. STAT3 is essential for the maintenance of neurosphere-initiating tumor cells in patients with glioblastomas: a potential for targeted therapy? Int J Cancer. 2011;128(4):826–38.PubMedGoogle Scholar
  59. 59.
    Happold C, Roth P, Silginer M, Florea AM, Lamszus K, Frei K, Deenen R, Reifenberger G, Weller M. Interferon-beta induces loss of spherogenicity and overcomes therapy resistance of glioblastoma stem cells. Mol Cancer Ther. 2014;13(4):948–61. doi: 10.1158/1535-7163.MCT-13-0772.PubMedGoogle Scholar
  60. 60.
    Gilbert CA, Daou MC, Moser RP, Ross AH. Gamma-secretase inhibitors enhance temozolomide treatment of human gliomas by inhibiting neurosphere repopulation and xenograft recurrence. Cancer Res. 2010;70(17):6870–9.PubMedCentralPubMedGoogle Scholar
  61. 61.
    Beier D, Schriefer B, Brawanski K, Hau P, Weis J, Schulz JB, Beier CP. Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines. J Neurooncol. 2012;109(1):45–52. doi: 10.1007/s11060-012-0878-4.PubMedGoogle Scholar
  62. 62.
    Fouse SD, Nagarajan RP, Nakamura J, James CD, Chang S, Costello JF. Therapeutic response in primary glioblastoma neural stem cells relative to patient-matched non-stem tumor cells. Neuro Oncol. 2011;13:151–2.Google Scholar
  63. 63.
    Meads MB, Hazlehurst LA, Dalton WS. The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res. 2008;14(9):2519–26.PubMedGoogle Scholar
  64. 64.
    Adamson C, Kanu OO, Mehta AI, Di CH, Lin NJ, Mattox AK, Bigner DD. Glioblastoma multiforme: a review of where we have been and where we are going. Expert Opin Investig Drugs. 2009;18(8):1061–83. doi: 10.1517/13543780903052764.PubMedGoogle Scholar
  65. 65.
    Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014;15(9):943–53. doi: 10.1016/S1470-2045(14)70314-6.PubMedGoogle Scholar
  66. 66.
    Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28(7):1168–74. doi: 10.1200/JCO.2009.23.2595.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jaaskelainen J, Ram Z. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003;5(2):79–88. doi: 10.1215/S1522-8517-02-00023-6.PubMedCentralPubMedGoogle Scholar
  68. 68.
    Batista LF, Roos WP, Christmann M, Menck CF, Kaina B. Differential sensitivity of malignant glioma cells to methylating and chloroethylating anticancer drugs: p53 determines the switch by regulating xpc, ddb2, and DNA double-strand breaks. Cancer Res. 2007;67(24):11886–95.PubMedGoogle Scholar
  69. 69.
    Hermisson M, Klumpp A, Wick W, Wischhusen J, Nagel G, Roos W, Kaina B, Weller M. O-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells. J Neurochem. 2005.Google Scholar
  70. 70.
    Roos WP, Batista LF, Naumann SC, Wick W, Weller M, Menck CF, Kaina B. Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene. 2007;26(2):186–97.PubMedGoogle Scholar
  71. 71.
    Margison GP, Santibanez-Koref MF. O6-alkylguanine-DNA alkyltransferase: role in carcinogenesis and chemotherapy. BioEssays. 2002;24(3):255–66. doi: 10.1002/bies.10063.PubMedGoogle Scholar
  72. 72.
    Day III RS, Ziolkowski CH, Scudiero DA, Meyer SA, Lubiniecki AS, Girardi AJ, Galloway SM, Bynum GD. Defective repair of alkylated DNA by human tumour and SV40-transformed human cell strains. Nature. 1980;288(5792):724–7.PubMedGoogle Scholar
  73. 73.
    Nakagawachi T, Soejima H, Urano T, Zhao W, Higashimoto K, Satoh Y, Matsukura S, Kudo S, Kitajima Y, Harada H, Furukawa K, Matsuzaki H, Emi M, Nakabeppu Y, Miyazaki K, Sekiguchi M, Mukai T. Silencing effect of CpG island hypermethylation and histone modifications on O6-methylguanine-DNA methyltransferase (MGMT) gene expression in human cancer. Oncogene. 2003;22(55):8835–44. doi: 10.1038/sj.onc.1207183.PubMedGoogle Scholar
  74. 74.
    von Deimling A, Korshunov A, Hartmann C. The next generation of glioma biomarkers: MGMT methylation, BRAF fusions and IDH1 mutations. Brain Pathol (Zurich, Switzerland). 2011;21(1):74–87. doi: 10.1111/j.1750-3639.2010.00454.x.Google Scholar
  75. 75.
    Pegg AE, Fang Q, Loktionova NA. Human variants of O6-alkylguanine-DNA alkyltransferase. DNA Repair. 2007;6(8):1071–8. doi: 10.1016/j.dnarep.2007.03.012.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Sharma S, Salehi F, Scheithauer BW, Rotondo F, Syro LV, Kovacs K. Role of MGMT in tumor development, progression, diagnosis, treatment and prognosis. Anticancer Res. 2009;29(10):3759–68.PubMedGoogle Scholar
  77. 77.
    Weller M, Stupp R, Reifenberger G, Brandes AA, van den Bent MJ, Wick W, Hegi ME. MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol. 2010;6(1):39–51. doi: 10.1038/nrneurol.2009.197.PubMedGoogle Scholar
  78. 78.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003.PubMedGoogle Scholar
  79. 79.
    Gerson SL. MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer. 2004;4(4):296–307. doi: 10.1038/nrc1319.PubMedGoogle Scholar
  80. 80.
    Gong X, Schwartz PH, Linskey ME, Bota DA. Neural stem/progenitors and glioma stem-like cells have differential sensitivity to chemotherapy. Neurology. 2011;76(13):1126–34. doi: 10.1212/WNL.0b013e318212a89f.PubMedCentralPubMedGoogle Scholar
  81. 81.
    Riemenschneider MJ, Jeuken JW, Wesseling P, Reifenberger G. Molecular diagnostics of gliomas: state of the art. Acta Neuropathol. 2010;120(5):567–84. doi: 10.1007/s00401-010-0736-4.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Preusser M, Janzer RC, Felsberg J, Reifenberger G, Hamou MF, Diserens AC, Stupp R, Gorlia T, Marosi C, Heinzl H, Hainfellner JA, Hegi M. Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker. Brain Pathol. 2008;18(4):520–32. doi: 10.1111/j.1750-3639.2008.00153.x.PubMedGoogle Scholar
  83. 83.
    Christmann M, Nagel G, Horn S, Krahn U, Wiewrodt D, Sommer C, Kaina B. MGMT activity, promoter methylation and immunohistochemistry of pretreatment and recurrent malignant gliomas: a comparative study on astrocytoma and glioblastoma. Int J Cancer. 2010;127(9):2106–18. doi: 10.1002/ijc.25229.PubMedGoogle Scholar
  84. 84.
    Sciuscio D, Diserens AC, van Dommelen K, Martinet D, Jones G, Janzer RC, Pollo C, Hamou MF, Kaina B, Stupp R, Levivier M, Hegi ME. Extent and patterns of MGMT promoter methylation in glioblastoma- and respective glioblastoma-derived spheres. Clin Cancer Res. 2011;17(2):255–66. doi: 10.1158/1078-0432.ccr-10-1931.PubMedGoogle Scholar
  85. 85.
    Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med. 2000;343(19):1350–4.PubMedGoogle Scholar
  86. 86.
    Sarkaria JN, Kitange GJ, James CD, Plummer R, Calvert H, Weller M, Wick W. Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clin Cancer Res. 2008;14(10):2900–8. doi: 10.1158/1078-0432.ccr-07-1719.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Zhang J, Stevens MF, Bradshaw TD. Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012;5(1):102–14.PubMedGoogle Scholar
  88. 88.
    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8. doi: 10.1038/nature07385.Google Scholar
  89. 89.
    Cahill DP, Levine KK, Betensky RA, Codd PJ, Romany CA, Reavie LB, Batchelor TT, Futreal PA, Stratton MR, Curry WT, Iafrate AJ, Louis DN. Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res. 2007;13(7):2038–45.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Hunter C, Smith R, Cahill DP, Stephens P, Stevens C, Teague J, Greenman C, Edkins S, Bignell G, Davies H, O'Meara S, Parker A, Avis T, Barthorpe S, Brackenbury L, Buck G, Butler A, Clements J, Cole J, Dicks E, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Richardson D, Shepherd R, Small A, Solomon H, Tofts C, Varian J, West S, Widaa S, Yates A, Easton DF, Riggins G, Roy JE, Levine KK, Mueller W, Batchelor TT, Louis DN, Stratton MR, Futreal PA, Wooster R. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 2006;66(8):3987–91.PubMedGoogle Scholar
  91. 91.
    Yip S, Miao J, Cahill DP, Iafrate AJ, Aldape K, Nutt CL, Louis DN. MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res. 2009;15(14):4622–9.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Tentori L, Ricci-Vitiani L, Muzi A, Ciccarone F, Pelacchi F, Calabrese R, Runci D, Pallini R, Caiafa P, Graziani G. Pharmacological inhibition of poly(ADP-ribose) polymerase-1 modulates resistance of human glioblastoma stem cells to temozolomide. BMC Cancer. 2014;14(1):151.PubMedCentralPubMedGoogle Scholar
  93. 93.
    Kanai R, Rabkin SD, Yip S, Sgubin D, Zaupa CM, Hirose Y, Louis DN, Wakimoto H, Martuza RL. Oncolytic virus-mediated manipulation of DNA damage responses: synergy with chemotherapy in killing glioblastoma stem cells. J Natl Cancer Inst. 2012;104(1):42–55. doi: 10.1093/jnci/djr509.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Silber JR, Bobola MS, Kolstoe DD, Blank A, Chamberlain MC. Repair of 3-methyladenine and abasic sites by base excision repair mediates glioblastoma resistance to temozolomide. Front Oncol. 2012;2:176. doi: 10.3389/fonc.2012.00176.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Fu D, Calvo JA, Samson LD. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer. 2012;12(2):104–20. doi: 10.1038/nrc3185.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Smith SA, Engelward BP. In vivo repair of methylation damage in Aag 3-methyladenine DNA glycosylase null mouse cells. Nucleic Acids Res. 2000;28(17):3294–300. doi: 10.1093/nar/28.17.3294.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Bobola MS, Silber JR, Ellenbogen RG, Geyer JR, Blank A, Goff RD. O6-methylguanine-DNA methyltransferase, O6-benzylguanine, and resistance to clinical alkylators in pediatric primary brain tumor cell lines. Clin Cancer Res. 2005;11(7):2747–55.PubMedGoogle Scholar
  98. 98.
    Hang B, Singer B, Margison GP, Elder RH. Targeted deletion of alkylpurine-DNA-N-glycosylase in mice eliminates repair of 1, N-6-ethenoadenine and hypoxanthine but not of 3, N-4-ethenocytosine or 8-oxoguanine. Proc Natl Acad Sci U S A. 1997;94(24):12869–74. doi: 10.1073/pnas.94.24.12869.PubMedCentralPubMedGoogle Scholar
  99. 99.
    Engelward BP, Dreslin A, Christensen J, Huszar D, Kurahara C, Samson L. Repair-deficient 3-methyladenine DNA glycosylase homozygous mutant mouse cells have increased sensitivity to alkylation-induced chromosome damage and cell killing. EMBO J. 1996;15(4):945–52.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Tentori L, Portarena I, Torino F, Scerrati M, Navarra P, Graziani G. Poly(ADP-ribose) polymerase inhibitor increases growth inhibition and reduces G(2)/M cell accumulation induced by temozolomide in malignant glioma cells. Glia. 2002;40(1):44–54. doi: 10.1002/glia.10113.PubMedGoogle Scholar
  101. 101.
    Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science (New York, NY). 2002;297(5579):259–63. doi: 10.1126/science.1072221.Google Scholar
  102. 102.
    Silber JR, Bobola MS, Blank A, Schoeler KD, Haroldson PD, Huynh MB, Kolstoe DD. The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress. Clin Cancer Res. 2002;8(9):3008–18.PubMedGoogle Scholar
  103. 103.
    Bobola MS, Emond MJ, Blank A, Meade EH, Kolstoe DD, Berger MS, Rostomily RC, Silbergeld DL, Spence AM, Silber JR. Apurinic endonuclease activity in adult gliomas and time to tumor progression after alkylating agent-based chemotherapy and after radiotherapy. Clin Cancer Res. 2004;10(23):7875–83. doi: 10.1158/1078-0432.ccr-04-1161.PubMedGoogle Scholar
  104. 104.
    Agnihotri S, Gajadhar A, Ternamian C, Gorlia T, Diefes K, Mischel P, Kelly J, McGown G, Thorncroft M, Carlson B, Sarkaria J, Margison G, Aldape K, Hawkins C, Hegi M, Guha A. Alkylpurine-DNA-N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients. J Clin Invest. 2012;122:253–66.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Agnihotri S, Wolf A, Munoz DM, Smith CJ, Gajadhar A, Restrepo A, Clarke ID, Fuller GN, Kesari S, Dirks PB, McGlade CJ, Stanford WL, Aldape K, Mischel PS, Hawkins C, Guha A. A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas. J Exp Med. 2011;208(4):689–702. doi: 10.1084/jem.20102099.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Lu C, Shervington A. Chemoresistance in gliomas. Mol Cell Biochem. 2008;312(1–2):71–80. doi: 10.1007/s11010-008-9722-8.PubMedGoogle Scholar
  107. 107.
    Schaich M, Kestel L, Pfirrmann M, Robel K, Illmer T, Kramer M, Dill C, Ehninger G, Schackert G, Krex D. A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann Oncol. 2009;20(1):175–81.PubMedGoogle Scholar
  108. 108.
    Spiegl-Kreinecker S, Buchroithner J, Elbling L, Steiner E, Wurm G, Bodenteich A, Fischer J, Micksche M, Berger W. Expression and functional activity of the ABC-transporter proteins P-glycoprotein and multidrug-resistance protein 1 in human brain tumor cells and astrocytes. J Neurooncol. 2002;57(1):27–36.PubMedGoogle Scholar
  109. 109.
    Peignan L, Garrido W, Segura R, Melo R, Rojas D, Carcamo JG, San Martin R, Quezada C. Combined use of anticancer drugs and an inhibitor of multiple drug resistance-associated protein-1 increases sensitivity and decreases survival of glioblastoma multiforme cells in vitro. Neurochem Res. 2011;36(8):1397–406. doi: 10.1007/s11064-011-0464-8.PubMedGoogle Scholar
  110. 110.
    Yan YR, Xie Q, Li F, Zhang Y, Ma JW, Xie SM, Li HY, Zhong XY. Epithelial-to-mesenchymal transition is involved in BCNU resistance in human glioma cells. Neuropathology. 2013;34(2):128–34. doi: 10.1111/neup.12062.PubMedGoogle Scholar
  111. 111.
    Sun S, Wong TS, Zhang XQ, Pu JK, Lee NP, Day PJ, Ng GK, Lui WM, Leung GK. Protein alterations associated with temozolomide resistance in subclones of human glioblastoma cell lines. J Neurooncol. 2012;107(1):89–100. doi: 10.1007/s11060-011-0729-8.PubMedCentralPubMedGoogle Scholar
  112. 112.
    Wang X, Li C, Chen Y, Hao Y, Zhou W, Chen C, Yu Z. Hypoxia enhances CXCR4 expression favoring microglia migration via HIF-1alpha activation. Biochem Biophys Res Commun. 2008;371(2):283–8. doi: 10.1016/j.bbrc.2008.04.055.PubMedGoogle Scholar
  113. 113.
    Hermansen SK, Kristensen BW. MicroRNA biomarkers in glioblastoma. J Neurooncol. 2013;114(1):13–23. doi: 10.1007/s11060-013-1155-x.PubMedGoogle Scholar
  114. 114.
    Koshkin PA, Chistiakov DA, Chekhonin VP. Role of microRNAs in mechanisms of glioblastoma resistance to radio- and chemotherapy. Biochem Biokhim. 2013;78(4):325–34. doi: 10.1134/s0006297913040019.Google Scholar
  115. 115.
    Ujifuku K, Mitsutake N, Takakura S, Matsuse M, Saenko V, Suzuki K, Hayashi K, Matsuo T, Kamada K, Nagata I, Yamashita S. miR-195, miR-455-3p and miR-10a(*) are implicated in acquired temozolomide resistance in glioblastoma multiforme cells. Cancer Lett. 2010;296(2):241–8. doi: 10.1016/j.canlet.2010.04.013.PubMedGoogle Scholar
  116. 116.
    Oliva CR, Moellering DR, Gillespie GY, Griguer CE. Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production. PLoS One. 2011;6(9):e24665. doi: 10.1371/journal.pone.0024665.PubMedCentralPubMedGoogle Scholar
  117. 117.
    Ye F, Zhang Y, Liu Y, Yamada K, Tso JL, Menjivar JC, Tian JY, Yong WH, Schaue D, Mischel PS, Cloughesy TF, Nelson SF, Liau LM, McBride W, Tso CL. Protective properties of radio-chemoresistant glioblastoma stem cell clones are associated with metabolic adaptation to reduced glucose dependence. PLoS One. 2013;8(11):e80397. doi: 10.1371/journal.pone.0080397.PubMedCentralPubMedGoogle Scholar
  118. 118.
    Mousseau M, Chauvin C, Nissou MF, Chaffanet M, Plantaz D, Pasquier B, Schaerer R, Benabid A. A study of the expression of four chemoresistance-related genes in human primary and metastatic brain tumours. Eur J Cancer (Oxford, Engl 1990). 1993;29a(5):753–9.Google Scholar
  119. 119.
    Schafer A, Teufel J, Ringel F, Bettstetter M, Hoepner I, Rasper M, Gempt J, Koeritzer J, Schmidt-Graf F, Meyer B, Beier CP, Schlegel J. Aldehyde dehydrogenase 1A1–a new mediator of resistance to temozolomide in glioblastoma. Neuro Oncol. 2012;14(12):1452–64. doi: 10.1093/neuonc/nos270.PubMedCentralPubMedGoogle Scholar
  120. 120.
    Oberstadt MC, Bien-Moller S, Weitmann K, Herzog S, Hentschel K, Rimmbach C, Vogelgesang S, Balz E, Fink M, Michael H, Zeden JP, Bruckmuller H, Werk AN, Cascorbi I, Hoffmann W, Rosskopf D, Schroeder HW, Kroemer HK. Epigenetic modulation of the drug resistance genes MGMT, ABCB1 and ABCG2 in glioblastoma multiforme. BMC Cancer. 2013;13:617. doi: 10.1186/1471-2407-13-617.PubMedCentralPubMedGoogle Scholar
  121. 121.
    Galia A, Calogero AE, Condorelli R, Fraggetta F, La Corte A, Ridolfo F, Bosco P, Castiglione R, Salemi M. PARP-1 protein expression in glioblastoma multiforme. Eur J Histochem. 2012;56(1):e9. doi: 10.4081/ejh.2012.e9.PubMedCentralPubMedGoogle Scholar
  122. 122.
    Kase M, Vardja M, Lipping A, Asser T, Jaal J. Impact of PARP-1 and DNA-PK expression on survival in patients with glioblastoma multiforme. Radiother Oncol. 2011;101(1):127–31. doi: 10.1016/j.radonc.2011.06.024.PubMedGoogle Scholar
  123. 123.
    Zhang L, Wang M, Wang W, Mo J. Incidence and prognostic value of multiple gene promoter methylations in gliomas. J Neurooncol. 2014;116(2):349–56. doi: 10.1007/s11060-013-1301-5.PubMedGoogle Scholar
  124. 124.
    Bhat KP, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, Wani K, Heathcock L, James JD, Goodman LD, Conroy S, Long L, Lelic N, Wang S, Gumin J, Raj D, Kodama Y, Raghunathan A, Olar A, Joshi K, Pelloski CE, Heimberger A, Kim SH, Cahill DP, Rao G, Den Dunnen WF, Boddeke HW, Phillips HS, Nakano I, Lang FF, Colman H, Sulman EP, Aldape K. Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma. Cancer Cell. 2013;24(3):331–46. doi: 10.1016/j.ccr.2013.08.001.PubMedGoogle Scholar
  125. 125.
    Pistollato F, Abbadi S, Rampazzo E, Persano L, Della Puppa A, Frasson C, Sarto E, Scienza R, D'Avella D, Basso G. Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem Cells. 2010;28(5):851–62. doi: 10.1002/stem.415.PubMedGoogle Scholar
  126. 126.
    Persano L, Pistollato F, Rampazzo E, Della Puppa A, Abbadi S, Frasson C, Volpin F, Indraccolo S, Scienza R, Basso G. BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1 alpha stability and MGMT expression. Cell Death Dis. 2012;3:e412. doi: 10.1038/cddis.2012.153.PubMedCentralPubMedGoogle Scholar
  127. 127.
    Weiler M, Blaes J, Pusch S, Sahm F, Czabanka M, Luger S, Bunse L, Solecki G, Eichwald V, Jugold M, Hodecker S, Osswald M, Meisner C, Hielscher T, Rubmann P, Pfenning PN, Ronellenfitsch M, Kempf T, Schnolzer M, Abdollahi A, Lang F, Bendszus M, von Deimling A, Winkler F, Weller M, Vajkoczy P, Platten M, Wick W. mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy. Proc Natl Acad Sci U S A. 2014;111(1):409–14. doi: 10.1073/pnas.1314469111.PubMedCentralPubMedGoogle Scholar
  128. 128.
    Glas M, Rath BH, Simon M, Reinartz R, Schramme A, Trageser D, Eisenreich R, Leinhaas A, Keller M, Schildhaus HU, Garbe S, Steinfarz B, Pietsch T, Steindler DA, Schramm J, Herrlinger U, Brustle O, Scheffler B. Residual tumor cells are unique cellular targets in glioblastoma. Ann Neurol. 2010;68(2):264–9. doi: 10.1002/ana.22036.PubMedGoogle Scholar
  129. 129.
    Quinn JA, Jiang SX, Reardon DA, Desjardins A, Vredenburgh JJ, Rich JN, Gururangan S, Friedman AH, Bigner DD, Sampson JH, McLendon RE, Herndon JE, Walker A, Friedman HS. Phase II trial of temozolomide plus O-6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol. 2009;27(8):1262–7.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Mia Dahl Sørensen
    • 1
    • 2
  • Sigurd Fosmark
    • 1
    • 2
  • Sofie Hellwege
    • 1
    • 2
  • Dagmar Beier
    • 2
    • 3
  • Bjarne Winther Kristensen
    • 1
    • 2
  • Christoph Patrick Beier
    • 2
    • 3
    Email author
  1. 1.Department of PathologyOdense University HospitalOdense CDenmark
  2. 2.Institute of Clinical ResearchUniversity of Southern DenmarkOdense MDenmark
  3. 3.Department of NeurologyUniversity of Southern DenmarkOdense CDenmark

Personalised recommendations