Library Subscription: Guest
Begell Digital Portal Begell Digital Library eBooks Journals References & Proceedings Research Collections
Critical Reviews™ in Oncogenesis
SJR: 0.631 SNIP: 0.503 CiteScore™: 2

ISSN Print: 0893-9675
ISSN Online: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.2019032655
pages 307-338

Role of Epstein-Barr Virus in Glioblastoma

Sergio Zavala-Vega
Área de Virología, Laboratorio de Infectología, Hospital Infantil de México Federico Gómez, Ciudad de México, México; Departamento de Neuropatología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
Icela Palma-Lara
Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, México; Departamento de Morfología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, México
Elizabeth Ortega-Soto
Laboratorio de Inmunovirología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Ciudad de México, México
Cristina Trejo-Solis
Departamento de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, Ciudad de México, México
Israel Torres-Ramirez de Arellano
Departamento de Neuropatología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
Luis Eduardo Ucharima-Corona
Departamento de Neuropatología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México; Facultad de Ciencias, Universidad Nacional Autónoma de México
Guadalupe Garcia-Chacón
Área de Virología, Laboratorio de Infectología, Hospital Infantil de México Federico Gómez, Ciudad de México, México
Sara A. Ochoa
Laboratorio de Bacteriología Intestinal, Hospital Infantil de México Federico Gómez, Ciudad de México, México
Juan Xicohtencatl-Cortes
Laboratorio de Bacteriología Intestinal, Hospital Infantil de México Federico Gómez, Ciudad de México, México
Ariadna Cruz-Córdova
Laboratorio de Bacteriología Intestinal, Hospital Infantil de México Federico Gómez, Ciudad de México, México
Victor Manuel Luna-Pineda
Laboratorio de Bacteriología Intestinal, Hospital Infantil de México Federico Gómez, Ciudad de México, México
Elva Jiménez-Hernández
Unidad Médica de Alta Especialidad, Hematopediatría, Centro Médico Nacional la Raza IMSS
Eugenio Vázquez-Meraz
Banco de Sangre, Hospital las Américas, Ecatepec Estado de México
Juan Manuel Mejía-Aranguré
Coordinación de Investigación en Salud, IMSS, Torre Academia Nacional de Medicina, Ciudad de México, México
Simón Guzmán-Bucio
Área de Virología, Laboratorio de Infectología, Hospital Infantil de México Federico Gómez, Ciudad de México, México
Daniel Rembao-Bojorquez
Departamento de Neuropatología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, México
Concepción Sánchez-Gómez
Laboratorio de Biología del Desarrollo y Teratogénesis Experimental, Hospital Infantil de México Federico Gómez
Marcela Salazar-Garcia
Laboratorio de Biología del Desarrollo y Teratogénesis Experimental, Hospital Infantil de México Federico Gómez
José Arellano-Galindo
Área de Virología, Laboratorio de Infectología, Hospital Infantil de México Federico Gómez, Ciudad de México, México

ABSTRACT

Gliomas are the most common and most lethal primary malignant adult brain tumors, and glioblastomas are the most frequent. Several risk factors are involved in their pathogenesis; these include environmental factors as well as host factors. The etiology of most gliomas remains unknown. Epstein-Barr Virus (EBV), a member of the Herpesviridae family, was the first tumoral virus to be described, and several viruses in connection with cancer were discovered thereafter. During the complex interaction between host and EBV, several events take place. In the context of survival, EBV can drive its host cells with subsequent disruption of the cellular machinery, leading to tumorigenesis as the final outcome. Thus, the EBV infection has been associated with different tumors. In this review, we discuss EBV and cancer. We have analyzed previously published papers and have conducted a critical analysis on the role of the viral infection in glioblastoma. Several works have described the presence of the virus, but none have shown a conclusive association. Thus, there is need to continue analyzing the interaction between host and virus to determine whether the viral presence is incidental or has some association with glioblastoma.

REFERENCES

  1. Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011-2015. Neuro-Oncol. 2018 Oct 1;20(Suppl 4):iv1-86.

  2. Wood MD, Halfpenny AM, Moore SR. Applications of molecular neuro-oncology-a review of diffuse glioma integrated diagnosis and emerging molecular entities. Di agn Pathol. 2019 Dec;14(1):29.

  3. Omuro A. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013 Nov 6;310(17):1842.

  4. Goodwin CR, Ahmed AK, Xia S. UDP-a-D-glucose 6-dehydrogenase: a promising target for glioblastoma. Oncotarget. 2019 Feb 22;10(16):1542-43.

  5. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008 Jul 31;359(5):492-507.

  6. Soto JM, Lyon KA, Benardete EA. Glioblastoma multiforme presenting as cryptogenic intracerebral hemorrhage. Bayl Univ Med Cent Proc. 2018 Oct 2;31(4):516-18.

  7. Lukas RV, Wainwright DA, Ladomersky E, Sachdev S, Sonabend AM, Stupp R. Newly diagnosed glioblastoma: a review on clinical management. Oncology (Williston Park, NY). 2019 13;33(3):91-100.

  8. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, Wolinsky Y, Kruchko, C, Barnholtz-Sloan J. CB-TRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007.

  9. World Health Organization. WHO classification of tumours of the central nervous system, revised 4th edition. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. Lyon, France: International Agency for Research on Cancer; 2016.

  10. Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro-Oncol. 2017 Nov 6;19(Suppl 5):v1-88.

  11. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, Pekmezci M, Schwartzbaum JA, Turner MC, Walsh KM, Wrensch MR, Barnholtz-Sloan JS. The epidemiology of glioma in adults: a "state of the science" review. Neuro-Oncol. 2014 Jul 1;16(7):896-913.

  12. Philips A, Henshaw DL, Lamburn G, O'Carroll MJ. Brain tumours: rise in glioblastoma multiforme incidence in England 1995-2015 suggests an adverse environmental or lifestyle factor. J Environ Public Health. 2018 Jun 24;2018:1-10.

  13. Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res. 2013 Feb 15;19(4):764-72.

  14. Elsamadicy AA, Babu R, Kirkpatrick JP, Adamson DC. Radiation-induced malignant gliomas: a current review. World Neurosurg. 2015 Apr;83(4):530-42.

  15. Taylor AJ, Little MP, Winter DL, Sugden E, Ellison DW, Stiller CA, Stovall M, Frobisher C, Lancashire ER, Reulen RC, Hawkins MM. Population-based risks of CNS tumors in survivors of childhood cancer: the British childhood cancer survivor study. J Clin Oncol. 2010 Dec 20;28(36):5287-93.

  16. Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, Yasui Y, Kasper CE, Mertens AC, Donaldson SS, Meadows AT, Inskip PD. New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst. 2006 Nov 1;98(21):1528-37.

  17. Krishnamachari B, Il'yasova D, Scheurer ME, Bondy M, Zhou R, Wrensch M, Davis F. A pooled multisite analysis of the effects of atopic medical conditions in glioma risk in different ethnic groups. Ann Epidemiol. 2015 Apr;25(4):270-74.

  18. Amirian ES, Zhou R, Wrensch MR, Olson SH, Scheurer ME, Il'yasova D, Lachance D, Armstrong GN, McCoy LS, Lau CC, Claus EB, Barnholtz-Sloan JS, Schildkraut J, Ali-Osman F, Sadetzki S, Johansen C, Houlston RS, Jenkins RB, Bernstein JL, Merrell RT, Davis FG, Lai R, Shete S, Amos CI, Melin BS, Bondy ML. Approaching a scientific consensus on the association between allergies and glioma risk: a report from the glioma international case-control study. Cancer Epidemiol Biomarkers Prev. 2016 Feb 1;25(2):282-90.

  19. Schwartzbaum JA, Huang K, Lawler S, Ding B, Yu J, Chiocca EA. Allergy and inflammatory transcriptome is pre-dominantly negatively correlated with CD133 expression in glioblastoma. Neuro-Oncol. 2010 Apr 1;12(4):320-27.

  20. Bailey P, Cushing H. A classification of the tumours of the glioma group on a histogenetic basis, with a correlated study of prognosis. Philadelphia: J.B. Lippincott; 1926.

  21. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Bernd W. Scheithauer, Paul Kleihues. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol (Berl). 2007 Jul 12;114(2):97-109.

  22. Lee JH, Lee JE, Kahng JY, Kim SH, Park JS, Yoon SJ, Um JY, Kim WK, Lee JK, Park J, Kim EH, Lee JH, Lee JH, Chung WS, Ju YS, Park SH, Chang JH, Kang SG, Lee JH. Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature. 2018 Aug;560(7717):243-47.

  23. Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. N Engl J Med. 2005 Aug 25;353(8):811-22.

  24. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol (Berl). 2016 Jun;131(6):803-20.

  25. Happold C, Gorlia T, Chinot O, Gilbert MR, Nabors LB, Wick W, Pugh SL, Hegi M, Cloughesy T, Roth P, Reardon DA, Perry JR, Mehta MP, Stupp R, Weller M. Does valproic acid or levetiracetam improve survival in glioblastoma? A pooled analysis of prospective clinical trials in newly diagnosed glioblastoma. J Clin Oncol. 2016 Mar;34(7):731-39.

  26. DeAngelis LM. Brain tumors. N Engl J Med. 2001 Jan 11;344(2):114-23.

  27. Vecht CJ, Kerkhof M, Duran-Pena A. Seizure prognosis in brain tumors: new insights and evidence-based management. Oncologist. 2014 Jul;19(7):751-59.

  28. 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 Nov 1;14(Suppl 5):v1-49.

  29. Reifenberger G, Weber RG, Riehmer V, Kaulich K, Willscher E, Wirth H, Gietzelt J, Hentschel B, Westphal M, Simon M, Schackert G, Schramm J, Matschke J, Sabel MC, Gramatzki D, Felsberg J, Hartmann C, Steinbach JP, Schlegel U, Wick W, Radlwimmer B, Pietsch T, Tonn JC, von Deimling A, Binder H, Weller M, Loeffler M. Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling: molecular profiles of glioblastoma long-term survivors. Int J Cancer. 2014 Oct 15;135(8): 1822-31.

  30. 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 May;10(5):459-66.

  31. Hartmann C, Hentschel B, Simon M, Westphal M, Schackert G, Tonn JC, Loeffler M, Reifenberger G, Pietsch T, von Deimling A, Weller M. Long-term survival in primary glioblastoma with versus without isocitrate dehydrogenase mutations. Clin Cancer Res. 2013 Sep 15;19(18):5146-57.

  32. Hasan T, Caragher SP, Shireman JM, Park CH, Atashi F, Baisiwala S, Lee G, Guo D, Wang JY, Dey M, Wu M, Lesniak MS, Horbinski CM, James CD, Ahmed AU. Interleukin-8/CXCR2 signaling regulates therapy-induced plasticity and enhances tumorigenicity in glioblastoma. Cell Death Dis. 2019 Apr;10(4):292.

  33. Bruce J, Kennedy B, Engelhard H, Shepard R. Glioblastoma multiforme: practice essentials, background, patho-physiology. Available from: http://emedicine.medscape. com/article/283252-overview.

  34. Czapski B, Baluszek S, Herold-Mende C, Kaminska B. Clinical and immunological correlates of long term survival in glioblastoma. Wspolczesna Onkol. 2018;2018(1):81-5.

  35. Zanders ED, Svensson F, Bailey DS. Therapy for glioblastoma: is it working? Drug Discov Today. 2019 May;24(5):1193-201.

  36. Parsons DW, Jones S, Zhang X, Lin JC-H, Leary RJ, An genendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. An integrated genomic analysis of human glio-blastoma multiforme. Science. 2008 Sep 26;321(5897): 1807-12.

  37. Losman J-A, Kaelin WG. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 2013 Apr 15;27(8):836-52.

  38. Duncan CG, Barwick BG, Jin G, Rago C, Kapoor-Vazirani P, Powell DR, Chi JT, Bigner DD, Vertino PM, Yan H. A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation. Genome Res. 2012 Dec 1;22(12):2339-55.

  39. Waitkus MS, Diplas BH, Yan H. Isocitrate dehydrogenase mutations in gliomas. Neuro-Oncol. 2016 Jan;18(1):16-26.

  40. Capper D, Sahm F, Hartmann C, Meyermann R, von Deimling A, Schittenhelm J. Application of mutant IDH1 antibody to differentiate diffuse glioma from nonneoplastic central nervous system lesions and therapy-induced changes. Am J Surg Pathol. 2010 Aug;34(8):1199-204.

  41. Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A. Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol (Berl). 2009 Nov;118(5):599-601.

  42. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22.

  43. Mistry AM. On the subventricular zone origin of human glioblastoma. Transl Cancer Res. 2019 Feb;8(1):11-13.

  44. Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers. 2017 May 17;9(12):52.

  45. Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, Makino K, Saya H, Hirano H, Kuratsu J, Oka K, Ishimaru Y, Ushio Y. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res. 2003 Oct 15;63(20): 6962-70.

  46. Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013 Nov;280(21):5350-70.

  47. Crespo I, Vital AL, Nieto AB, Rebelo O, Tao H, Lopes MC, Oliveira CR, French PJ, Orfao A, Tabernero MD. Detailed characterization of alterations of chromosomes 7, 9, and 10 in glioblastomas as assessed by single-nucleotide polymorphism arrays. J Mol Diagn. 2011 Nov;13(6):634-47.

  48. Ochs K, Kaina B. Apoptosis induced by DNA damage O6-methylguanine is Bcl-2 and caspase-9/3 regulated and Fas/caspase-8 independent. Cancer Res. 2000 Oct 15;60(20):5815-24.

  49. 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 Nov 9;343(19):1350-54.

  50. Hegi ME, Diserens A-C, Gorlia T, Hamou M-F, 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 Mar 10;352(10):997-1003.

  51. Millward CP, Brodbelt AR, Hay lock B, Zakaria R, Baborie A, Crooks D, Husband D, Shenoy A, Wong H, Jenkinson MD. The impact of MGMT methylation and IDH-1 mutation on long-term outcome for glioblastoma treated with chemoradiotherapy. Acta Neurochir (Wien). 2016;158(10):1943-53.

  52. Gerber NK, Goenka A, Turcan S, Reyngold M, Makarov V, Kannan K, Beal K, Omuro A, Yamada Y, Gutin P, Brennan CW, Huse JT, Chan TA. Transcriptional diversity of long-term glioblastoma survivors. Neuro-Oncol. 2014 Sep;16(9):1186-95.

  53. Leu S, von Felten S, Frank S, Vassella E, Vajtai I, Taylor E, Schulz M, Hutter G, Hench J, Schucht P, Boulay JL, Mariani L. IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival. Neuro-Oncol. 2013 Apr;15(4):469-79.

  54. Chen J, McKay RM, Parada LF. Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell. 2012 Mar 30;149(1):36-47.

  55. Blackadar CB. Historical review of the causes of cancer. World J Clin Oncol. 2016 Feb 10;7(1):54-86.

  56. Shope RE, Hurst EW. Infectious papillomatosis of rabbits: with a note on the histopathology. J Exp Med. 1933 Oct 31;58(5):607-24.

  57. Bittner JJ. Some possible effects of nursing on the mammary gland tumor incidence in mice. Science. 1936 Aug 14;84(2172):162.

  58. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA. 1980 Dec;77(12):7415-19.

  59. Murall CL, Alizon S. Modelling the evolution of viral oncogenesis. Philos Trans R Soc Lond B Biol Sci. 2019 May 27;374(1773):20180302.

  60. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from burkitt's lymphoma. Lancet. 1964 Mar 28;1(7335):702-3.

  61. Javier RT, Butel JS. The history of tumor virology. Cancer Res. 2008 Oct 1;68(19):7693-706.

  62. Henle G, Henle W, Clifford P, Diehl V, Kafuko GW, Kirya BG, Klein G, Morrow RH, Munube GM, Pike P, Tukei PM, Ziegler JL. Antibodies to Epstein-Barr virus in Burkitt's lymphoma and control groups. J Natl Cancer Inst. 1969 Nov;43(5):1147-57.

  63. de-The G, Geser A, Day NE, Tukei PM, Williams EH, Beri DP, Smith PG, Dean AG, Bronkamm GW, Feorino P, Henle W. Epidemiological evidence for causal relationship between Epstein-Barr virus and Burkitt's lymphoma from Ugandan prospective study. Nature. 1978 Aug 24;274(5673):756-61.

  64. Raab-Traub N, Flynn K. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell. 1986 Dec 26;47(6):883-89.

  65. Mesri EA, Feitelson M, Munger K. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe. 2014 Mar 12;15(3):266-82.

  66. Chang Y, Moore PS, Weiss RA. Human oncogenic viruses: nature and discovery. Philos Trans R Soc B Biol Sci. 2017 Oct 19;372(1732).

  67. Vereide D, Sugden B. Insights into the evolution of lymphomas induced by Epstein-Barr virus. Adv Cancer Res. 2010;108:1-19.

  68. Davison AJ, Eberle R, Ehlers B, Hayward GS, McGeoch DJ, Minson AC, Pellett PE, Roizman B, Studdert MJ, Thiry E. The order Herpesvirales. Arch Virol. 2009 Jan 1;154(1):171-77.

  69. Majerciak V, Yang W, Zheng J, Zhu J, Zheng Z-M. A genome-wide epstein-barr virus polyadenylation map and its antisense RNA to EBNA. J Virol. 2019 Jan 15;93(2):e01593-18.

  70. Owen DJ, Crump CM, Graham SC. Tegument assembly and secondary envelopment of alphaherpesviruses. Viruses. 2015 Sep 18;7(9):5084-114.

  71. Lussignol M, Esclatine A. Herpesvirus and autophagy: "All right, everybody be cool, this is a robbery!" Viruses. 2017 Dec 4;9(12). pii: E372. doi: 10.3390/v9120372.

  72. Li Q, Spriggs MK, Kovats S, Turk SM, Comeau MR, Nepom B, Hutt-Fletcher LM. Epstein-Barr virus uses HLA class II as a cofactor for infection of B lymphocytes. J Virol. 1997 Jun;71(6):4657-62.

  73. Sathiyamoorthy K, Chen J, Longnecker R, Jardetzky TS. The complexity in herpesvirus entry. Curr Opin Virol. 2017;24:97-104.

  74. Xiao J, Palefsky JM, Herrera R, Berline J, Tugizov SM. The Epstein-Barr virus BMRF-2 protein facilitates virus attachment to oral epithelial cells. Virology. 2008 Jan 20;370(2):430-42.

  75. Scott RS. Epstein-Barr virus: a master epigenetic manipulator. Curr Opin Virol. 2017 Oct 1;26:74-80.

  76. Li D, Fu W, Swaminathan S. Continuous DNA replication is required for late gene transcription and maintenance of replication compartments in gamma herpesviruses. PLoS Pathog. 2018;14(5):e1007070.

  77. Heming JD, Conway JF, Homa FL. Herpesvirus capsid assembly and DNA packaging. Adv Anat Embryol Cell Biol. 2017;223:119-42.

  78. Granzow H, Klupp BG, Fuchs W, Veits J, Osterrieder N, Mettenleiter TC. Egress of alphaherpesviruses: comparative ultrastructural study. J Virol. 2001 Apr;75(8):3675-84.

  79. Johnson DC, Baines JD. Herpesviruses remodel host membranes for virus egress. Nat Rev Microbiol. 2011 May;9(5):382-94.

  80. El-Sharkawy A, Al Zaidan L, Malki A. Epstein-Barr virus-associated malignancies: roles of viral oncoproteins in carcinogenesis. Front Oncol. 2018;8:265.

  81. Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer. 2004 Oct;4(10):757-68.

  82. Kapoor P, Shire K, Frappier L. Reconstitution of Epstein-Barr virus-based plasmid partitioning in budding yeast. EMBO J. 2001 Jan 15;20(1-2):222-30.

  83. Vrzalikova K, Ibrahim M, Nagy E, Vockerodt M, Perry T, Wei W, Woodman C, Murray P. Co-expression of the Epstein-Barr virus-encoded latent membrane proteins and the pathogenesis of classic Hodgkin lymphoma. Cancers. 2018 Aug 24;10(9):285.

  84. Caldwell RG, Wilson JB, Anderson SJ, Longnecker R. Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity. 1998 Sep;9(3):405-11.

  85. Barth S, Pfuhl T, Mamiani A, Ehses C, Roemer K, Kremmer E, Jaker C, Hock J, Meister G, Grasser FA. Epstein-Barr virus-encoded microRNA miR-BART2 down-regulates the viral DNA polymerase BALF5. Nucleic Acids Res. 2008 Feb;36(2):666-75.

  86. Chen Y, Fachko D, Ivanov NS, Skinner CM, Skalsky RL. Epstein-Barr virus microRNAs regulate B cell receptor signal transduction and lytic reactivation. PLoS Pathog. 2019;15(1):e1007535.

  87. Miller G, El-Guindy A, Countryman J, Ye J, Gradoville L. Lytic cycle switches of oncogenic human gammaherpes-viruses. Adv Cancer Res. 2007;97:81-109.

  88. Quinlivan EB, Holley-Guthrie EA, Norris M, Gutsch D, Bachenheimer SL, Kenney SC. Direct BRLF1 binding is required for cooperative BZLF1/BRLF1 activation of the Epstein-Barr virus early promoter, BMRF1. Nucleic Acids Res. 1993 Jul 11;21(14):1999-2007.

  89. Schaeffner M, Mrozek-Gorska P, Buschle A, Woellmer A, Tagawa T, Cernilogar FM, Schotta G, Krietenstein N, Lieleg C, Korber P, Hammerschmidt W. BZLF1 interacts with chromatin remodelers promoting escape from latent infections with EBV. Life Sci Alliance. 2019;2(2): pii: e201800108. doi: 10.26508/lsa.201800108.

  90. Morrison TE, Kenney SC. BZLF1, an Epstein-Barr virus immediate-early protein, induces p65 nuclear translocation while inhibiting p65 transcriptional function. Virology. 2004 Oct 25;328(2):219-32.

  91. Crombie JL, LaCasce AS. Epstein-Barr virus associated B-cell lymphomas and iatrogenic lymphoproliferative disorders. Front Oncol. 2019;9:109.

  92. Pattle SB, Farrell PJ. The role of Epstein-Barr virus in cancer. Expert Opin Biol Ther. 2006 Nov;6(11):1193-205.

  93. Polack A, Hortnagel K, Pajic A, Christoph B, Baier B, Falk M, Mautner J, Geltinger C, Bornkamm GW, Kempkes B. C-myc activation renders proliferation of Epstein-Barr virus (EBV)-transformed cells independent of EBV nuclear antigen 2 and latent membrane protein 1. Proc Natl Acad Sci USA. 1996 Sep 17;93(19):10411-16.

  94. Kelly GL, Milner AE, Baldwin GS, Bell AI, Rickinson AB. Three restricted forms of Epstein-Barr virus latency counteracting apoptosis in c-mycexpressing Burkitt lymphoma cells. Proc Natl Acad Sci USA. 2006 Oct 3;103(40):14935-40.

  95. Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms estab-lished rodent cells. Cell. 1985 Dec;43(3 Pt 2):831-40.

  96. Fukuda M, Longnecker R. Epstein-Barr virus latent membrane protein 2A mediates transformation through constitutive activation of the Ras/PI3-K/Akt pathway. J Virol. 2007 Sep 1;81(17):9299-306.

  97. Minamitani T, Ma Y, Zhou H, Kida H, Tsai C-Y, Obana M, Okuzaki D, Fujio Y, Kumanogoh A, Zhao B, Kikutani H, Kieff E, Gewurz BE, Yasui T. Mouse model of Epstein-Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease. Proc Natl Acad Sci USA. 2017 02;114(18):4751-56.

  98. Ma S-D, Tsai M-H, Romero-Masters JC, Ranheim EA, Huebner SM, Bristol JA, Delecluse HJ, Kenney SC. Latent membrane protein 1 (LMP1) and LMP2A collaborate to promote epstein-barr virus-induced b cell lymphomas in a cord blood-humanized mouse model but are not essential. J Virol. 2017 01;91(7): pii: e01928-16. doi: 10.1128/JVI.01928-16.

  99. Humme S, Reisbach G, Feederle R, Delecluse H-J, Bous- set K, Hammerschmidt W, Schepers A. The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold. Proc Natl Acad Sci USA. 2003 Sep 16;100(19):10989-94.

  100. Gruhne B, Sompallae R, Marescotti D, Kamranvar SA, Gastaldello S, Masucci MG. The Epstein-Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species. Proc Natl Acad Sci USA. 2009 Feb 17;106(7):2313-18.

  101. Kheimar A, Kaufer BB. Epstein-Barr virus-encoded RNAs (EBERs) complement the loss of Herpesvirus telomerase RNA (vTR) in virus-induced tumor formation. Sci Rep. 2018 09;8(1):209.

  102. Dong M, Chen J-N, Huang J-T, Gong L-P, Shao C-K. The roles of EBV-encoded microRNAs in EBV-associated tumors. Crit Rev Oncol Hematol. 2019 Mar;135:30-38.

  103. Qiu J, Smith P, Leahy L, Thorley-Lawson DA. The Epstein-Barr virus encoded BART miRNAs potentiate tumor growth in vivo. PLoS Pathog. 2015 Jan;11(1):e1004561.

  104. Cao P, Zhang M, Wang L, Sai B, Tang J, Luo Z, Shuai C, Zhang L, Li Z, Wang Y, Li G. miR-18a reactivates the Epstein-Barr virus through defective DNA damage response and promotes genomic instability in EBV-associated lymphomas. BMC Cancer. 2018;18:1293.

  105. Choy EY, Siu KL, Kok KH, Lung RW, Tsang CM, To KF, Kwong DL, Tsao SW, Jin DY. An Epstein-Barr virus-encoded microRNA targets PUMA to promote host cell survival. J Exp Med. 2008 Oct 27;205(11):2551-60.

  106. Barth S, Pfuhl T, Mamiani A, Ehses C, Roemer K, Kremmer E, Jaker C, Hock J, Meister G, Grasser FA. Epstein-Barr virus-encoded microRNA miR-BART2 down-regulates the viral DNA polymerase BALF5. Nucleic Acids Res. 2008 Feb;36(2):666-75.

  107. Ye Y, Zhou Y, Zhang L, Chen Y, Lyu X, Cai L, Lu Y, Deng Y, Wang J, Yao K, Fang W, Cai H, Li X. EBV-miR-BART1 is involved in regulating metabolism-associated genes in nasopharyngeal carcinoma. Biochem Biophys Res Commun. 2013 Jun 21;436(1):19-24.

  108. Schulz TF, Cordes S. Is the Epstein-Barr virus EBNA-1 protein an oncogen? Proc Natl Acad Sci USA. 2009 Feb 17;106(7):2091-92.

  109. Gunnell A, Webb HM, Wood CD, McClellan MJ, Wichaidit B, Kempkes B, Jenner RG, Osborne C, Farrell PJ, West MJ. RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth. Nucleic Acids Res. 2016 02;44(10):4636-50.

  110. Fuchs KP, Bommer G, Dumont E, Christoph B, Vidal M, Kremmer E, Kempkes B. Mutational analysis of the J recombination signal sequence binding protein (RBP-J)/Epstein-Barr virus nuclear antigen 2 (EBNA2) and RBP-J/Notch interaction. Eur J Biochem. 2001 Sep;268(17):4639-46.

  111. Kusano S, Raab-Traub N. An Epstein-Barr virus protein interacts with Notch. J Virol. 2001 Jan;75(1):384-95.

  112. Johansen LM, Deppmann CD, Erickson KD, Coffin WF, Thornton TM, Humphrey SE, Humphrey SE, Martin JM, Taparowsky EJ. EBNA2 and activated Notch induce expression of BATF. J Virol. 2003 May;77(10):6029-40.

  113. Rowe M, Raithatha S, Shannon-Lowe C. Counteracting effects of cellular Notch and Epstein-Barr virus EBNA2: implications for stromal effects on virus-host interactions. J Virol. 2014 Oct;88(20):12065-76.

  114. Kanda T, Yajima M, Ikuta K. Epstein-Barr virus strain variation and cancer. Cancer Sci. 2019 Apr;110(4):1132-39.

  115. Balfour HH, Odumade OA, Schmeling DO, Mullan BD, Ed JA, Knight JA, Vezina HE, Thomas W, Hogquist KA. Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J Infect Dis. 2013 Jan 1;207(1):80-88.

  116. Yin H, Qu J, Peng Q, Gan R. Molecular mechanisms of EBV-driven cell cycle progression and oncogenesis. Med Microbiol Immunol (Berl). 2019 Oct;208(5):573-83.

  117. Saha A, Robertson ES. Mechanisms of B-cell oncogenesis induced by Epstein-Barr virus. J Virol. 2019 Jul 1;93(13).

  118. Wang R, Wang J, Zhang N, Wan Y, Liu Y, Zhang L, Pan S, Zhang C, Zhang H, Cao Y. The interaction between Vav1 and EBNA1 promotes survival of Burkitt's lymphoma cells by down-regulating the expression of Bim. Biochem Biophys Res Commun. 2019 Apr 16;511(4):787-93.

  119. Vockerodt M, Yap L-F, Shannon-Lowe C, Curley H, Wei W, Vrzalikova K, Murray PG. The Epstein-Barr virus and the pathogenesis of lymphoma. J Pathol. 2015 Jan;235(2):312-22.

  120. Yue W, Zhu M, Zuo L, Xin S, Zhang J, Liu L, Li S, Dang W, Zhang S, Xie Y, Zhu F, Lu J. Early pattern of epstein-barr virus infection in gastric epithelial cells by "cell-in-cell." Virol Sin. 2019 Jun;34(3):253-61.

  121. Desai K, Hubben A, Ahluwalia M. Combination of oncolytic viruses and immune checkpoint inhibitors in glio-blastoma. Glioma. 2019 Jan 1;2(1):7.

  122. Meng Q, Valentini D, Rao M, Dodoo E, Maeurer M. CMV and EBV targets recognized by tumor-infiltrating B lymphocytes in pancreatic cancer and brain tumors. Sci Rep. 2018 Nov 20;8(1):1-11.

  123. Akhtar S, Vranic S, Cyprian FS, Al Moustafa A-E. Epstein-Barr virus in gliomas: cause, association, or artifact? Front Oncol. 2018 Apr 20;8:123.

  124. Nowalk A, Green M. Epstein-Barr virus. Microbiol Spectr. 2016;4(3). doi: 10.1128/microbiolspec.DMIH2-0 011-2015.

  125. Correia S, Bridges R, Wegner F, Venturini C, PalserA, Middeldorp JM, Cohen JI, Lorenzetti MA, Bassano I, White RE, Kellam P, Breuer J, Farrell PJ. Sequence variation of epstein-barr virus: viral types, geography, codon usage, and diseases. J Virol. 2018 Nov 15;92(22):e01132-18.

  126. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, Gabrilovich DI, Ostrand-Rosenberg S, Hedrick CC, Vonderheide RH, Pittet MJ, Jain RK, Zou W, Howcroft TK, Woodhouse EC, Weinberg RA, Krummel MF. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24(5):541-50.

  127. Asha K, Sharma-Walia N. Virus and tumor microenvironment induced ER stress and unfolded protein response: from complexity to therapeutics. Oncotarget. 2018 Aug 7;9(61):31920-36.

  128. Ma J, Li J, Hao Y, Nie Y, Li Z, Qian M, Liang Q, Yu J, Zeng M, Wu K. Differentiated tumor immune microen vironment of Epstein-Barr virus-associated and negative gastric cancer: implication in prognosis and immunotherapy. Oncotarget. 2017 Sep 15;8(40):67094-103.

  129. Teng MWL, Ngiow SF, Ribas A, Smyth MJ. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res. 2015 Jun 1;75(11):2139-45.

  130. Duffield AS, Ascierto ML, Anders RA, Taube JM, Meeker AK, Chen S, McMiller TL, Phillips NA, Xu H, Ogurtsova A, Berger AE, Pardoll DM, Topalian SL, Ambinder RF. Th17 immune microenvironment in Epstein-Barr virus-negative Hodgkin lymphoma: implications for immunotherapy. Blood Adv. 2017 Jul 21;1(17):1324-34.

  131. Varol C. Tumorigenic interplay between macrophages and collagenous matrix in the tumor microenvironment. Methods Mol Biol. 2019;1944:203-20.

  132. Hida K, Maishi N, Annan DA, Hida Y. Contribution of tumor endothelial cells in cancer progression. Int J Mol Sci. 2018 Apr 24;19(5): pii: E1272.

  133. Akino T, Hida K, Hida Y, Tsuchiya K, Freedman D, Muraki C, Ohga N, Matsuda K, Akiyama K, Harabayashi T, Shinohara N, Nonomura K, Klagsbrun M, Shindoh M. Cytogenetic abnormalities of tumor-associated endothelial cells in human malignant tumors. Am J Pathol. 2009 Dec;175(6):2657-67.

  134. Kondoh M, Ohga N, Akiyama K, Hida Y, Maishi N, Towfik AM, Nobuo Inoue, Masanobu Shindoh, and Kyoko Hida. Hypoxia-induced reactive oxygen species cause chromosomal abnormalities in endothelial cells in the tumor microenvironment. PLoS One. 2013 Nov 15;8(11):e80349.

  135. Wang G, Yang Q, Li M, Zhang Y, Cai Y, Liang X, Fu Y, Xiao Z, Zhou M, Xie Z, Huang H, Huang Y, Chen Y, He Q, Peng F, Chen Z. Quantitative proteomic profiling of tumor-associated vascular endothelial cells in colorectal cancer. Biol Open. 2019 May 13;8(5). pii: bio042838. doi: 10.1242/bio.042838.

  136. Duan HX, Li BW, Zhuang X, Wang LT, Cao Q, Tan LH, Qu GF, Xiao S. TCF21 inhibits tumor-associated angiogenesis and suppresses the growth of cholangiocarcinoma by targeting PI3K/Akt and ERK signaling. Am J Physiol-Gastrointest Liver Physiol. 2019 Jun 1;316(6):G763-73.

  137. Salazar N, Zabel BA. Support of tumor endothelial cells by chemokine receptors. Front Immunol. 2019 Feb 8;10:147.

  138. Maishi N, Hida K. Tumor endothelial cells accelerate tumor metastasis. Cancer Sci. 2017 Oct;108(10):1921-26.

  139. Glavey SV, Naba A, Manier S, Clauser K, Tahri S, Park J, Reagan MR, Moschetta M, Mishima Y, Gambella M, Rocci A, Sacco A, O'Dwyer ME, Asara JM, Palumbo A, Roccaro AM, Hynes RO, Ghobrial IM. Proteomic characterization of human multiple myeloma bone marrow extracellular matrix. Leukemia. 2017 Nov;31(11):2426-34.

  140. Eble JA, Niland S. The extracellular matrix in tumor progression and metastasis. Clin Exp Metastasis. 2019 Jun;36(3):171-98.

  141. Nissen NI, Karsdal M, Willumsen N. Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to cancer biology. J Exp Clin Cancer Res. 2019 Dec;38(1):115.

  142. Wang T-H, Hsia S-M, Shieh T-M. Lysyl oxidase and the tumor microenvironment. Int J Mol Sci. 2016 Dec 29;18(1). pii: E62. doi: 10.3390/ijms18010062.

  143. Spill F, Reynolds DS, Kamm RD, Zaman MH. Impact of the physical microenvironment on tumor progression and metastasis. Curr Opin Biotechnol. 2016 Aug;40:41-48.

  144. Mezawa Y, Orimo A. The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas. Cell Tissue Res. 2016;365(3):675-89.

  145. Awaji M, Singh RK. Cancer-associated fibroblasts' functional heterogeneity in pancreatic ductal adenocarcinoma. Cancers. 2019 Mar 1;11(3):290.

  146. Nguyen EV, Pereira BA, Lawrence MG, Ma X, Rebello RJ, Chan H, Niranjan B, Wu Y, Ellem S, Guan X, Wu J, Skhinas JN, Cox TR, Risbridger GP, Taylor RA, Lister NL, Daly RJ. Proteomic profiling of human prostate cancer-associated fibroblasts (CAF) reveals LOXL2-depen dent regulation of the tumor microenvironment. Mol Cell Proteom MCP. 2019 Jul;18(7):1410-27.

  147. Dvorak KM, Pettee KM, Rubinic-Minotti K, Su R, Nestor-Kalinoski A, Eisenmann KM. Carcinoma associated fibroblasts (CAFs) promote breast cancer motility by suppressing mammalian Diaphanous-related formin-2 (mDia2). PLoS One. 2018;13(3):e0195278.

  148. Sun Q, Zhang B, Hu Q, Qin Y, Xu W, Liu W, Yu X, Xu J. The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer. Theranostics. 2018 Oct 6;8(18):5072-87.

  149. Scholle F, Longnecker R, Raab-Traub N. Analysis of the phosphorylation status of Epstein-Barr virus LMP2A in epithelial cells. Virology. 2001 Dec 20;291(2):208-14.

  150. Qiao F, Pan P, Yan J, Sun J, Zong Y, Wu Z, Lu X, Chen N, Mi R, Ma Y, Ji Y. Role of tumor-derived extracellular vesicles in cancer progression and their clinical applications (Review). Int J Oncol. 2019 May;54(5):1525-33.

  151. Kholia S, Jorfi S, Thompson PR, Causey CP, Nicholas AP, Inal JM, Lange S. A novel role for peptidylarginine deiminases in microvesicle release reveals therapeutic potential of PAD inhibition in sensitizing prostate cancer cells to chemotherapy. J Extracell Vesicles. 2015;4:26192.

  152. Phan AT, Fernandez SG, Somberg JJ, Keck KM, Miranda JL. Epstein-Barr virus latency type and spontaneous reactivation predict lytic induction levels. Biochem Biophys Res Commun. 2016 20;474(1):71-75.

  153. Wang LW, Jiang S, Gewurz BE. Epstein-Barr virus LMP1-mediated oncogenicity. Gack MU, editor. J Virol. 2017 Nov 1;91(21):e01718-16. doi: 10.1128/JVI. 01718-16.

  154. Salahuddin S, Fath EK, Biel N, Ray A, Moss CR, Patel A, Patel S, Hilding L, Varn M, Ross T, Cramblet WT, Lowrey A, Pagano JS, Shackelford J, Bentz GL. Epstein-Barr virus latent membrane protein-1 induces the expression of SUMO-1 and SUMO-2/3 in LMP1-positive lymphomas and cells. Sci Rep. 2019 Dec;9(1):208.

  155. Liu X, Li Y, Peng S, Yu X, Li W, Shi F, Luo X, Tang M, Tan Z, Bode AM, Cao Y. Epstein-Barr virus encoded latent membrane protein 1 suppresses necroptosis through targeting RIPK1/3 ubiquitination. Cell Death Dis. 2018 Feb;9(2):53.

  156. Xu S, Bai J, Zhuan Z, Li B, Zhang Z, Wu X, Luo X, Yang L. EBV/LMP1 is involved in vasculogenic mimicry formation via VEGFA/VEGFR1 signaling in nasopharyngeal carcinoma. Oncol Rep. 2018 Jul;40(1):377-84.

  157. Sora RP, Ikeda M, Longnecker R. Two pathways of p27Kip1 degradation are required for murine lymphoma driven by Myc and EBV latent membrane protein 2A. mBio. 2019 Apr 30;10(2):e00548-19.

  158. Baba T, Mukaida N. Role of macrophage inflammatory protein (MIP)-1a/CCL3 in leukemogenesis. Mol Cell Oncol. 2014 Jul 15;1(1):e29899.

  159. Incrocci R, McAloon J, Montesano M, Bardahl J, Vagvala S, Stone A, Swanson-Mungerson M. Epstein-Barr virus LMP2A utilizes Syk and PI3K to activate NF-KB in B-cell lymphomas to increase MIP-1a production. J Med Virol. 2019 May;91(5):845-55.

  160. DeKroon RM, Gunawardena HP, Edwards R, Raab-Traub N. Global proteomic changes induced by the epstein-barr virus oncoproteins latent membrane protein 1 and 2A. mBio. 2018 Jul 5;9(3):e00959-18.

  161. Borestrom C, Forsman A, Ruetschi U, Rymo L. E2F1, ARID3A/Bright and Oct-2 factors bind to the Epstein-Barr virus C promoter, EBNA1 and oriP, participating in long-distance promoter-enhancer interactions. J Gen Virol. 2012 May;93(Pt 5):1065-75.

  162. Wilson JB, Manet E, Gruffat H, Busson P, Blondel M, Fahraeus R. EBNA1: oncogenic activity, immune evasion and biochemical functions provide targets for novel therapeutic strategies against epstein-barr virus-associated cancers. Cancers. 2018 Apr 6;10(4):109.

  163. AlQarni S, Al-Sheikh Y, Campbell D, Drotar M, Hannigan A, Boyle S, Herzyk P, Kossenkov A, Armfield K, Jamieson L, Bailo M, Lieberman PM, Tsimbouri P, Wilson JB. Lymphomas driven by Epstein-Barr virus nuclear antigen-1 (EBNA1) are dependent upon Mdm2. Oncogene. 2018;37(29):3998-4012.

  164. Boudreault S, Armero VES, Scott MS, Perreault J-P, Bisaillon M. The Epstein-Barr virus EBNA1 protein modulates the alternative splicing of cellular genes. Virol J. 2019 04;16(1):29.

  165. Price AM, Luftig MA. Dynamic Epstein-Barr virus gene expression on the path to B-cell transformation. Adv Virus Res. 2014;88:279-313.

  166. Saha A, Robertson ES. Mechanisms of B-cell oncogenesis induced by Epstein-Barr virus. J Virol. 2019 Jul 1;93(13): pii: e00238-19. doi: 10.1128/JVI.00238-19.

  167. Pei Y, Banerjee S, Sun Z, Jha HC, Saha A, Robertson ES. EBV nuclear antigen 3C mediates regulation of E2F6 to inhibit E2F1 transcription and promote cell proliferation. PLoS Pathog. 2016;12(8):e1005844.

  168. Ahmed W, Khan G. The labyrinth of interactions of Epstein-Barr virus-encoded small RNAs. Rev Med Virol. 2014 Jan;24(1):3-14.

  169. Morales-Sanchez A, Fuentes-Panana EM. Epstein-Barr virus-associated gastric cancer and potential mechanisms of oncogenesis. Curr Cancer Drug Targets. 2017;17(6): 534-54.

  170. Seth RB, Sun L, Ea C-K, Chen ZJ. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 2005 Sep 9;122(5):669-82.

  171. Hagemeier SR, Dickerson SJ, Meng Q, Yu X, Mertz JE, Kenney SC. Sumoylation of the Epstein-Barr virus BZLF1 protein inhibits its transcriptional activity and is regulated by the virus-encoded protein kinase. J Virol. 2010 May 1;84(9):4383-94.

  172. Li J, Callegari S, Masucci MG. The Epstein-Barr virus miR-BHRF1-1 targets RNF4 during productive infection to promote the accumulation of SUMO conjugates and the release of infectious virus. PLOS Pathog. 2017 Apr 17;13(4):e1006338.

  173. Dong M, Chen J, Huang J, Gong L, Shao C. The roles of EBV-encoded microRNAs in EBV-associated tumors. Crit Rev Oncol Hematol. 2019 Mar 1;135:30-38.

  174. Yang Y-C, Liem A, Lambert PF, Sugden B. Dissecting the regulation of EBV's BART miRNAs in carcinomas. Virology. 2017;505:148-54.

  175. Neves M, Marinho-Dias J, Ribeiro J, Sousa H. Epstein-Barr virus strains and variations: geographic or disease-specific variants? J Med Virol. 2017;89(3):373-87.

  176. Burns KL, Ueki K, Jhung SL, Koh J, Louis DN. Molecular genetic correlates of p16, cdk4, and pRb immunohis-tochemistry in glioblastomas. J Neuropathol Exp Neurol. 1998 Feb;57(2):122-30.

  177. Biernat W, Tohma Y, Yonekawa Y, Kleihues P, Ohgaki H. Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas. Acta Neuropathol (Berl). 1997 Oct;94(4):303-9.

  178. Ueki K, Ono Y, Henson JW, Efird JT, von Deimling A, Louis DN. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res. 1996 Jan 1;56(1):150-53.

  179. Ono Y, Tamiya T, Ichikawa T, Kunishio K, Matsumoto K, Furuta T, Ohmoto T, Ueki K, Louis DN. Malignant astrocytomas with homozygous CDKN2/p16 gene deletions have higher Ki-67 proliferation indices. J Neuropathol Exp Neurol. 1996 0ct;55(10):1026-31.

  180. Raub TJ, Wishart GN, Kulanthaivel P, Staton BA, Ajamie RT, Sawada GA, Gelbert LM, Shannon HE, Sanchez-Martinez C, De Dios A. Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos Biol Fate Chem. 2015 Sep;43(9): 1360-71.

  181. Sippl C, Urbschat S, Kim YJ, Senger S, Oertel J, Ketter R. Promoter methylation of RB1, P15, P16, and MGMT and their impact on the clinical course of pilocytic astrocytomas. Oncol Lett. 2018 Feb;15(2):1600-6.

  182. Joerger AC, Fersht AR. The p53 pathway: origins, inactivation in cancer, and emerging therapeutic approaches. Annu Rev Biochem. 2016 Jun 2;85:375-404.

  183. Hickman ES, Moroni MC, Helin K. The role of p53 and pRB in apoptosis and cancer. Curr Opin Genet Dev. 2002 Feb;12(1):60-66.

  184. White E. Autophagy and p53. Cold Spring Harb Perspect Med. 2016 Apr 1;6(4):a026120.

  185. Vousden KH, Ryan KM. p53 and metabolism. Nat Rev Cancer. 2009 Oct;9(10):691-700.

  186. Ghimenti C, Fiano V, Chiado-Piat L, Chio A, Cavalla P, Schiffer D. Deregulation of the p14ARF/Mdm2/p53 path-way and G1/S transition in two glioblastoma sets. J Neurooncol. 2003 Jan;61(2):95-102.

  187. Ichimura K, Bolin MB, Goike HM, Schmidt EE, Moshref A, Collins VP. Deregulation of the p14ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G1-S transition control gene abnormalities. Cancer Res. 2000 Jan 15;60(2):417-24.

  188. Tyagi D, Sharma BS, Gupta SK, Kaul D, Vasishta RK, Khosla VK. Expression of Bcl2 proto-oncogene in primary tumors of the central nervous system. Neurol India. 2002 Sep;50(3):290-94.

  189. Steinbach JP, Weller M. Apoptosis in gliomas: molecular mechanisms and therapeutic implications. J Neurooncol. 2004 Nov;70(2):245-54.

  190. Strik H, Deininger M, Streffer J, Grote E, Wickboldt J, Dichgans J, Weller M, Meyermann R. BCL-2 family protein expression in initial and recurrent glioblastomas: modulation by radiochemotherapy. J Neurol Neurosurg Psychiatry. 1999 Dec;67(6):763-68.

  191. Trejo-Solis C, Serrano-Garcia N, Escamilla-Ramirez A, Castillo-Rodriguez RA, Jimenez-Farfan D, Palencia G, Calvillo M, Alvarez-Lemus MA, Flores-Najera A, Cruz-Salgado A, Sotelo J. Autophagic and apoptotic pathways as targets for chemotherapy in glioblastoma. Int J Mol Sci. 2018 Nov 27;19(12): pii: E3773. doi: 10.3390/ijms19123773.

  192. Pirtoli L, Cevenini G, Tini P, Vannini M, Oliveri G, Marsili S, Mourmouras V, Rubino G, Miracco C. The prognostic role of beclin 1 protein expression in high-grade gliomas. Autophagy. 2009 Oct;5(7):930-36.

  193. Shukla S, Patric IRP, Patil V, Shwetha SD, Hegde AS, Chandramouli BA, Arivazhagan A, Santosh V, Somasundaram K. Methylation silencing of ULK2, an autophagy gene, is essential for astrocyte transformation and tumor growth. J Biol Chem. 2014 Aug 8;289(32):22306-18.

  194. Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol (Berl). 2008 Dec;116(6):597-602.

  195. Nobusawa S, Watanabe T, Kleihues P, Ohgaki H. IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res. 2009 Oct 1;15(19):6002-7.

  196. Liu X, Ling Z-Q. Role of isocitrate dehydrogenase 1/2 (IDH 1/2) gene mutations in human tumors. Histol Histopathol. 2015 Oct;30(10):1155-60.

  197. Rossetto M, Ciccarino P, Boisselier B, Labussiere M, Sanson M. Metabolism of glioma and IDH1/IDH2 mutations. Rev Neurol (Paris, France). 2011 Oct;167(10):699-703.

  198. Huang Y, Rao A. Connections between TET proteins and aberrant DNA modification in cancer. Trends Genet TIG. 2014 Oct;30(10):464-74.

  199. Ko M, An J, Pastor WA, Koralov SB, Rajewsky K, Rao A. TET proteins and 5-methylcytosine oxidation in hemato-logical cancers. Immunol Rev. 2015 Jan;263(1):6-21.

  200. Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HS. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol. 1997 Dec;8(12):1197-206.

  201. 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(2):e32453.

  202. Machein MR, Plate KH. VEGF in brain tumors. J Neurooncol. 2000 Nov;50(1-2):109-20.

  203. Feldkamp MM, Lau N, Guha A. Signal transduction path-ways and their relevance in human astrocytomas. J Neu- rooncol. 1997 Dec;35(3):223-48.

  204. Chakravarti A, Delaney MA, Noll E, Black PM, Loeffler JS, Muzikansky A, Dyson NJ. Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas. Clin Cancer Res Off J Am Assoc Cancer Res. 2001 Aug;7(8):2387-95.

  205. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007 Nov 1;21(21):2683-710.

  206. Ohgaki H, Kleihues P. Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci. 2009 Dec;100(12):2235-41.

  207. Prados MD, Levin V. Biology and treatment of malignant glioma. Semin Oncol. 2000 Jun;27(3 Suppl 6):1-10.

  208. Ohgaki H, Kleihues P. Genetic profile of astrocytic and oligodendroglial gliomas. Brain Tumor Pathol. 2011 Jul;28(3):177-83.

  209. Ducray F, El Hallani S, Idbaih A. Diagnostic and prognostic markers in gliomas. Curr Opin Oncol. 2009 Nov;21(6):537-42.

  210. Ye F, Huang J, Wang H, Luo C, Zhao K. Targeting epigenetic machinery: emerging novel allosteric inhibitors. Pharmacol Ther. 2019 Sep 12;107406. doi: 10.1016/j. pharmthera.2019.107406.

  211. Angeloni A, Bogdanovic O. Enhancer DNA methylation: implications for gene regulation. Essays Biochem. 2019 Sep 24; pii: EBC20190030. doi: 10.1042/EBC20190030.

  212. Kuznetsova SA, Petrukov KS, Pletnev FI, Sergiev PV, Dontsova OA. RNA (C5-cytosine) methyltransferases. Biochem Biokhimiia. 2019 Aug;84(8):851-69.

  213. Carella A, Tejedor JR, Garcia MG, Urdinguio RG, Bayon GF, Sierra M, Lopez V, Garcia-Torano E, Santamarina-Ojeda P, Perez RF, Bigot T, Mangas C, Corte-Torres MD, Saenz-de-Santa-Maria I, Mollejo M, Melendez B, Astudillo A, Chiara MD, Fernandez AF, Fraga MF. Epigenetic downregulation of TET3 reduces genome-wide 5hmC levels and promotes glioblastoma tumorigenesis. Int J Cancer. 2019 Jun 18. doi: 10.1002/ijc.32520.

  214. Uhlmann K, Rohde K, Zeller C, Szymas J, Vogel S, Marczinek K, Thiel G, Nurnberg P, Laird PW. Distinct methylation profiles of glioma subtypes. Int J Cancer. 2003 Aug 10;106(1):52-59.

  215. Kloosterhof NK, de Rooi JJ, Kros M, Eilers PHC, Sillevis Smitt PA, van den Bent MJ, French PJ. Molecular subtypes of glioma identified by genome-wide methylation profiling. Genes Chromosomes Cancer. 2013 Jul;52(7):665-74.

  216. Alaminos M, Davalos V, Ropero S, Setien F, Paz MF, Herranz M, Fraga MF, Mora J, Cheung NK, Gerald WL, Esteller M. EMP3, a myelin-related gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma. Cancer Res. 2005 Apr 1;65(7):2565-71.

  217. zur Hausen H, Schulte-Holthausen H, Klein G, Henle W, Henle G, Clifford P, Santesson L. EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the naso-pharynx. Nature. 1970 Dec 12;228(5276):1056-58.

  218. Elgui de Oliveira D, Muller-Coan BG, Pagano JS. Viral carcinogenesis beyond malignant transformation: EBV in the progression of human cancers. Trends Microbiol. 2016;24(8):649-64.

  219. Sjostrom S, Hjalmars U, Juto P, Wadell G, Hallmans G, Tjonneland A, Halkjaer J, Manjer J, Almquist M, Melin BS. Human immunoglobulin G levels of viruses and associated glioma risk. Cancer Causes Control CCC. 2011 Sep;22(9):1259-66.

  220. Fonseca RF, Rosas SL, Oliveira JA, Teixeira A, Alves G, Carvalho Mda G. Frequency of Epstein-Barr virus DNA sequences in human gliomas. Sao Paulo Med J. 2015;133(1):51-54.

  221. Zakaria Z, Fenton E, Khalil A, Sattar MT, Molnar P. Stupp-treated glioblastoma ccompanied by EBV-positive primary CNS lymphoma. Br J Neurosurg. 2014;28(2): 287-89.

  222. Zavala-Vega S, Castro-Escarpulli G, Hernandez-Santos H, Salinas-Lara C, Palma I, Mejia-Arangure JM, Gelista-Herrera N, Rembao-Bojorquez D, Ochoa SA, Cruz-Cordova A, Xicohtencatl-Cortes J, Uribe-Gutierrez G, Arellano-Galindo J. An overview of the infection of CMV, HSV 1/2 and EBV in Mexican patients with glio-blastoma multiforme. Pathol Res Pract. 2017 Mar;213(3): 271-76.

  223. Limam S, Missaoui N, Mestiri S, Yacoubi MT, Krifa H, Selmi B, Mokni M. Epstein-Barr virus infection in gliomas. Curr Res Transl Med. 2019 Nov 1;67(4):129-33.

  224. Cobbs CS. Evolving evidence implicates cytomegalovirus as a promoter of malignant glioma pathogenesis. Herpes- viridae. 2011 Oct 26;2(1):10.

  225. Hochhalter CB, Carr C, Neill BEO, Ware ML, Strong, MJ. The association between human cytomegalovirus and glioblastomas: a review. Neuroimmunol Neuroinflammation. 2017;4:96-108.

  226. Wilski NA, Snyder CM. From vaccine vector to onco-modulation: understanding the complex interplay between CMV and cancer. Vaccines. 2019;7(3):pii: E62.

  227. Wu K, Oberstein A, Wang W, Shenk T. Role of PDGF receptor-a during human cytomegalovirus entry into fibroblasts. Proc Natl Acad Sci USA. 2018 Oct 16;115(42):E9889-E9898.