Low levels of Human Cytomegalovirus Infection in Glioblastoma multiforme associates with patient survival; -a case-control study

Herpesviridae

Cecilia Söderberg-Naucler²  Jan Willems⁴  Chato Taher²  Inti Peredo¹  Abiel Orrego⁴  Giuseppe Stragliotto³  Afsar Rahbar² 

[1] Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden;Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, 171 76Stockholm, Sweden;Department of Neurology , Karolinska University Hospital, Stockholm, Sweden;Department of Pathology, Karolinska University Hospital, Stockholm, Sweden

关键词: Survival;    Glioblastoma;    HCMV;   

Others  :  801229
DOI  :  10.1186/2042-4280-3-3

 received in 2011-07-08, accepted in 2012-03-16,  发布年份 2012

【 摘 要 】

Background

Glioblastoma multiforme (GBM) represent the most aggressive brain tumor with a median overall survival of about 12-15 months. Over 90% of GBM tumors have recently been shown to be infected with human cytomegalovirus (HCMV). In this case-control study, we evaluated whether there was an association between the grade of HCMV infection and long-term survival (> 18 months) in GBM patients.

Material and methods

Brain tumor tissue sections from consecutive GBMs patients who survived more than 18 months (n = 40), and an equal number of GBM patients, matched to date of diagnosis and surgery, operated at Karolinska University Hospital in 2000-2005 were selected. HCMV infection grade was determined by estimation of the number of HCMV positive cells (scored negative or grade 1-4) in tumor tissue specimens. Using Chi-Square test and logistic regression analysis, we analyzed whether there was an association between long-term survival and HCMV low-grade infection or other clinical parameters known to be associated with prolonged survival of GBM patients; age under 50 years, radical surgery or low recursive partition analysis (RPA) subclass.

Results

HCMV infection was detected in tumor samples from 79 of 80 patients (99%). Among patients surviving > 18 months, HCMV infection grade 1 in the GBM tumor was predominant. A low grade HCMV infection was found in 19 patients, of these 16 survived > 18 months. Thus, 16 of 40 (40%) GBM patients who lived > 18 months had low-grade HCMV infection while only 3 of 40 (8%) GBM patients who lived < 18 months did (p .0006, Chi-Square test). Multiple logistic regression analyses yielded an odds ratio estimate of 6.604 with 95% confidence interval (1.36-32.1) (p .019) for low grade HCMV after adjustment for RPA class III and IV, radical surgery, age and gamma knife treatment.

Conclusion

In conclusion, we found that low-grade HCMV infection was strongly associated with long-term survival in GBM patients.

【 授权许可】

   
2012 Rahbar et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Bergenheim T, et al.: Registration on regional basis of patients with primary brain tumors. Regional differences disclosed. Lakartidningen 2007, 104(5):332-338. 340-1
• [2]Lantos PL VS, KP (Eds): Greenfield's neuropathology. 6th edition. London: Arnold; 1996.
• [3]Gupta M, Djalilvand A, Brat DJ: Clarifying the diffuse gliomas: an update on the morphologic features and markers that discriminate oligodendroglioma from astrocytoma. Am J Clin Pathol 2005, 124(5):755-768.
• [4]Affronti ML, et al.: Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy. Cancer 2009, 115(15):3501-3511.
• [5]Cobbs CS, et al.: Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 2002, 62(12):3347-3350.
• [6]Mitchell DA, et al.: Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol 2008, 10(1):10-18.
• [7]Lucas KG, et al.: The detection of CMV pp 65 and IE1 in glioblastoma multiforme. J Neurooncol 2011, 103(2):231-238.
• [8]Taylor-Wiedeman J, et al.: Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol 1991, 72(Pt 9):2059-2064.
• [9]Soderberg-Naucler C, Fish KN, Nelson JA: Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 1997, 91(1):119-126.
• [10]Sinclair J: Human cytomegalovirus: Latency and reactivation in the myeloid lineage. J Clin Virol: The Official Publication of the Pan American Society for Clinical Virology 2008, 41(3):180-185.
• [11]Cinatl J Jr, et al.: Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression. FEMS Microbiol Rev 2004, 28(1):59-77.
• [12]Boldogh I, AbuBakar S, Albrecht T: Activation of proto-oncogenes: an immediate early event in human cytomegalovirus infection. Science 1990, 247(4942):561-564.
• [13]Bresnahan WA, Albrecht T, Thompson EA: The cyclin E promoter is activated by human cytomegalovirus 86-kDa immediate early protein. J Biol Chem 1998, 273(34):22075-22082.
• [14]Hagemeier C, et al.: Functional interaction between the HCMV IE2 transactivator and the retinoblastoma protein. EMBO J 1994, 13(12):2897-2903.
• [15]Muganda P, Carrasco R, Qian Q: The human cytomegalovirus IE2 86 kDa protein elevates p53 levels and transactivates the p53 promoter in human fibroblasts. Cell Mol Biol (Noisy-le-Grand) 1998, 44(2):321-331.
• [16]Shen Y, Zhu H, Shenk T: Human cytomagalovirus IE1 and IE2 proteins are mutagenic and mediate "hit-and-run" oncogenic transformation in cooperation with the adenovirus E1A proteins. Proc Natl Acad Sci USA 1997, 94(7):3341-3345.
• [17]Maussang D, et al.: The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. Cancer Res 2009, 69(7):2861-2869.
• [18]Slinger E, et al.: HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis. Sci Signal 2010, 3(133):ra58.
• [19]Maussang D, et al.: Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc Natl Acad Sci USA 2006, 103(35):13068-13073.
• [20]Baryawno N, et al.: Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J Clin Invest 2011, 121(10):4043-4055.
• [21]Mirimanoff RO, et al.: Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 2006, 24(16):2563-2569.
• [22]Lachin JM: Introduction to sample size determination and power analysis for clinical trials. Control Clin Trials 1981, 2(2):93-113.
• [23]Stupp R, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005, 352(10):987-996.
• [24]Wen PY, Kesari S: Malignant gliomas in adults. N Engl J Med 2008, 359(5):492-507.
• [25]Shen YH, et al.: Human cytomegalovirus inhibits Akt-mediated eNOS activation through upregulating PTEN (phosphatase and tensin homolog deleted on chromosome 10). Cardiovasc Res 2006, 69(2):502-511.
• [26]Straat K, et al.: Activation of telomerase by human cytomegalovirus. J Natl Cancer Inst 2009, 101(7):488-497.
• [27]Qiu H, et al.: Human CMV infection induces 5-lipoxygenase expression and leukotriene B4 production in vascular smooth muscle cells. J Exp Med 2008, 205(1):19-24.
• [28]Chen Z, et al.: Degradation of p21cip1 in cells productively infected with human cytomegalovirus. J Virol 2001, 75(8):3613-3625.
• [29]Bongers G, et al.: The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice. J Clin Invest 2010, 120(11):3969-3978.
• [30]Soroceanu L, et al.: Human Cytomegalovirus US28 Found in Glioblastoma Promotes an Invasive and Angiogenic Phenotype. Cancer Res 2011.
• [31]Dziurzynski K, et al.: Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin Canc Res: An Official Journal of the American Association for Cancer Research 2011, 17(14):4642-4649.
• [32]Kortylewski M, et al.: Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 2005, 11(12):1314-1321.
• [33]O'Farrell AM, et al.: IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways. EMBO J 1998, 17(4):1006-1018.