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Cytomegalovirus and glioblastoma; controversies and opportunities

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Abstract

One of the more polarized ongoing debates in the brain tumor field over recent years has centered on the association of cytomegalovirus (CMV) with glioblastoma. Several laboratories have reported the presence of CMV antigens in glioblastoma patient specimens, whereas others have failed to detect them. CMV genomic DNA and mRNAs have been detected by PCR, but not in next-generation sequencing studies. CMV promotes high grade glioma progression in a mouse genetic model, and many CMV proteins promote cancer hallmarks in vitro, but actively replicating virus has not been isolated from tumor samples. A consensus is gradually emerging in which the presence of CMV antigens in glioblastoma is increasingly accepted. However, it remains challenging to understand this mechanistically due to the low levels of CMV nucleic acids and the absence of viral replication observed in tumors thus far. Nonetheless, these observations have inspired the development of novel therapeutic approaches based on anti-viral drugs and immunotherapy. The potential benefit of valganciclovir in glioblastoma has generated great interest, but efficacy remains to be established in a randomized trial. Also, early stage immunotherapy trials targeting CMV have shown promise. In the near future we will know more answers to these questions, and although areas of controversy may remain, and the mechanisms and roles of CMV in tumor growth are yet to be clearly defined, this widespread virus may have created important new therapeutic concepts and opportunities for the treatment of glioblastoma.

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References

  1. zur Hausen H (2009) Papillomaviruses in the causation of human cancers—a brief historical account. Virology 384(2):260–265

    Article  CAS  PubMed  Google Scholar 

  2. Martin D, Gutkind JS (2008) Human tumor-associated viruses and new insights into the molecular mechanisms of cancer. Oncogene 27(Suppl 2):S31–S42

    Article  CAS  PubMed  Google Scholar 

  3. Cobbs et al (2002) Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 62(12):3347–3350

    CAS  PubMed  Google Scholar 

  4. Mitchell DA et al (2008) Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol 10(1):10–18

    Article  PubMed Central  PubMed  Google Scholar 

  5. Scheurer ME et al (2008) Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol 116(1):79–86

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Rahbar A et al (2013) Human cytomegalovirus infection levels in glioblastoma multiforme are of prognostic value for survival. J Clin Virol 57(1):36–42

    Article  PubMed  Google Scholar 

  7. Libard S et al (2014) Human cytomegalovirus tegument protein pp65 is detected in all intra-and extra-axial brain tumors independent of the tumour type or grade. PLoS ONE 9(9):e108861

    Article  PubMed Central  PubMed  Google Scholar 

  8. Bhattacharjee B, Renzette N, Kowalik TE (2012) Genetic analysis of cytomegalovirus in malignant gliomas. J Virol 86(12):6815–6824

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Ranganathan P et al (2012) Significant association of multiple human cytomegalovirus genomic loci with glioblastoma multiforme samples. J Virol 86(2):854–864

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Price RL et al (2013) Cytomegalovirus contributes to glioblastoma in the context of tumor suppressor mutations. Cancer Res 73(11):3441–3450

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Cobbs CS (2013) Cytomegalovirus and brain tumor: epidemiology, biology and therapeutic aspects. Curr Opin Oncol 25(6):682–688

    Article  PubMed  Google Scholar 

  12. Ludwig A, Hengel H (2009) Epidemiological impact and disease burden of congenital cytomegalovirus infection in Europe. Euro Surveill 14(9):26–32

    CAS  PubMed  Google Scholar 

  13. Mustakangas P et al (2000) Human cytomegalovirus seroprevalence in three socioeconomically different urban areas during the first trimester: a population-based cohort study. Int J Epidemiol 29(3):587–591

    Article  CAS  PubMed  Google Scholar 

  14. Staras SAS et al (2006) Seroprevalence of cytomegalovirus infection in the United States, 1988–1994. Clin Infect Dis 43(9):1143–1151

    Article  PubMed  Google Scholar 

  15. Murphy E, Shenk T (2008) Human cytomegalovirus genome. Curr Top Immunol 325:1–19

    CAS  Google Scholar 

  16. Dölken L, Pfeffer S, Koszinowski UH (2009) Cytomegalovirus microRNAs. Virus Genes 38(3):355–364

    Article  PubMed  Google Scholar 

  17. Plachter B, Sinzger C, Jahn G (1996) Cell types involved in replication and distribution of human cytomegalovirus. Adv Virus Res 46:195–261

    Article  CAS  PubMed  Google Scholar 

  18. Taylor-Wiedeman J et al (1991) Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol 72(9):2059–2064

    Article  CAS  PubMed  Google Scholar 

  19. Luo MH et al (2010) Human cytomegalovirus infection causes premature and abnormal differentiation of human neural progenitor cells. J Virol 84(7):3528–3541

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Cobbs CS et al (2007) Human cytomegalovirus induces cellular tyrosine kinase signaling and promotes glioma invasiveness. J Neurooncol 85(3):271–280

    Article  CAS  PubMed  Google Scholar 

  21. Straat K et al (2009) Activation of telomerase by human cytomegalovirus. J Natl Cancer Inst 101(7):488–497

    Article  CAS  PubMed  Google Scholar 

  22. Soroceanu L, Akhavan A, Cobbs CS (2008) Platelet-derived growth factor-a receptor activation is required for human cytomegalovirus infection. Nature 455(18):391–396

    Article  CAS  PubMed  Google Scholar 

  23. Slinger E et al (2010) HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis. Sci Signal 3(133):ra58

    PubMed  Google Scholar 

  24. Dziurzynski K et al (2011) Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin Cancer Res 17(14):4642–4649

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Price RL et al (2012) Cytomegalovirus infection leads to pleomorphic rhabdomyosarcomas in Trp53+/− mice. Cancer Res 72(22):5669–5674

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Taher C et al (2013) High prevalence of human cytomegalovirus proteins and nucleic acids in primary breast cancer and metastatic sentinel lymph nodes. PLoS ONE 8(2):e56795

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Baryawno N et al (2011) Detection of human cytomegalovirus in medulloblastoma reveals a potential therapeutic target. J Clin Invest 121(10):4043–4055

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Lau et al (2005) Lack of association of cytomegalovirus with human brain tumors. Mod Pathol 18(6):838–843

    Article  CAS  PubMed  Google Scholar 

  29. Poltermann S et al (2006) Lack of association of herpesviruses with brain tumors. J Neuro Virol 12(2):90–99

    CAS  Google Scholar 

  30. Baumgarten P et al (2014) Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics. Neuro Oncol 16(11):1469–1477

    Article  PubMed  Google Scholar 

  31. Hellstrand K, Martner A, Bergstrom T (2013) Valganciclovir in patients with glioblastoma. New Engl J Med 369(21):2066

    Article  CAS  PubMed  Google Scholar 

  32. Tang KW et al (2013) The landscape of viral expression and host gene fusion and adaptation in human cancer. Nat Commun 4:2513

    PubMed Central  PubMed  Google Scholar 

  33. Renzette N et al (2011) Extensive genome-wide variability of human cytomegalovirus in congenitally infected infants. PLoS Pathog 7:e1001344

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Dziurzynski K et al (2012) Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol 14(3):246–255

    Article  PubMed Central  PubMed  Google Scholar 

  35. Huse JT, Aldape K (2014) CMV and glioma—are we there yet? Neuro Oncol 16(11):1433–1434

    Article  PubMed  Google Scholar 

  36. Cobbs C (2014) Response to “Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics”. Neuro Oncol 14(3):1435–1436

    Article  Google Scholar 

  37. Stragliotto G et al (2013) Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus positive glioblastoma: a randomized, double-bind, hypothesis generating study. Int J Cancer 133(5):1204–1213

    Article  CAS  PubMed  Google Scholar 

  38. Soderberg-Naucler C, Rahbar A, Stragliotto G (2013) Survival in patients with glioblastoma treated with valganciclovir. New Engl J Med 369(10):985–986

    Article  PubMed  Google Scholar 

  39. Wrensch M et al (2001) Prevalence of antibodies to four herpesviruses among adults with glioma and controls. Am J Epidemiol 154(2):161–165

    Article  CAS  PubMed  Google Scholar 

  40. Soderberg-Naucler C, Peredo I, Stragliotto G (2013) Valganciclovir in patients with glioblastoma. New Engl J Med 369(21):2066–2067

    Article  PubMed  Google Scholar 

  41. Liu C-J, Hu Y-W (2014) Immortal time bias in retrospective analysis: is there a survival benefit in patients with glioblastoma who received prolonged treatment of adjuvant valganciclovir? Int J Cancer 135(1):250–251

    Article  CAS  PubMed  Google Scholar 

  42. Soderberg-Naucler C et al (2014) Use of Cox regression with treatment status as a time-dependent covariate to re-analyze survival benefit excludes immortal time bias effect in patients with glioblastoma who received prolonged adjuvant treatment with valganciclovir. Int J Cancer 135(1):248–249

    Article  PubMed  Google Scholar 

  43. Wick W, Wick A, Platten M (2014) Good maths is needed to understand CMV data in glioblastoma. Int J Cancer 134(12):2991–2992

    Article  CAS  PubMed  Google Scholar 

  44. Weller M, Soffietti R, Brada M (2014) The legend of cytomegalovirus and glioblastoma lives on. Neuro Oncol 16(1):166

    Article  PubMed Central  PubMed  Google Scholar 

  45. Wick W, Platten M (2014) CMV infection and glioma, a highly controversial concept struggling in the clinical arena. Neuro Oncol 16(3):332–333

    Article  PubMed Central  PubMed  Google Scholar 

  46. Cobbs CS (2014) Does valganciclovir have a role in glioblastoma therapy? Neuro Oncol 16(3):330–331

    Article  PubMed Central  PubMed  Google Scholar 

  47. Hadaczek P et al (2013) Cidofovir: a novel antitumor agent for glioblastoma. Clin Cancer Res 19(23):6473–6483

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Schuessler A, Walker DG, Khanna R (2014) Cytomegalovirus as a novel target for immunotherapy of glioblastoma multiforme. Front Oncol 4:275

    Article  PubMed Central  PubMed  Google Scholar 

  49. Nair SK, Sampson JH, Mitchell DA (2014) Immunological targeting of cytomegalovirus for glioblastoma therapy. Oncoimmunology 3:e29289

    Article  PubMed Central  PubMed  Google Scholar 

  50. Nair SK et al (2014) Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells. Clin Cancer Res 20(X):2684–2694

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Prins RM, Cloughesy TF, Liau LM (2008) Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N Engl J Med 359(5):539–541

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Crough T et al (2012) Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus-specific T-cells in patients with glioblastoma multiforme. Immunol Cell Biol 90(9):872–880

    Article  CAS  PubMed  Google Scholar 

  53. Ghazi et al (2012) Generation of polyclonal CMV-specific T cells for the adoptive immunotherapy of glioblastoma. J Immunother 35(2):159–168

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Schuessler A et al (2014) Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res 74(13):3466–3476

    Article  CAS  PubMed  Google Scholar 

  55. Wadman M (2013) NIH mulls rules for validating key results. Nature 500(7560):14–16

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, 4 Blackfan Circle, HIM 930A, Boston, MA, 02115, USA

    Sean E. Lawler

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  1. Sean E. Lawler
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Correspondence to Sean E. Lawler.

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Lawler, S.E. Cytomegalovirus and glioblastoma; controversies and opportunities. J Neurooncol 123, 465–471 (2015). https://doi.org/10.1007/s11060-015-1734-0

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