Investigating the role of cytomegalovirus in the potentiation of glioblastoma growth using multiple murine models

Abstract

OBJECTIVES: To determine the effect of murine cytomegalovirus (MCMV) infection on the growth and proliferation of glioblastoma using murine models of differing genetic backgrounds, as well as to determine whether the observed effects are dependent on the mutational background of the glioblastoma models. METHODS: An experimental orthotopic murine glioblastoma model was established using latently MCMV infected C57BL/6 mice, with non-infected mice as controls. Mouse brains were harvested at the end-point and subject to histological analysis using immunostaining and visualization by confocal microscopy. Viral infectivity and protein expression levels were assayed using time-lapse microscopy and western blotting. RESULTS: Our results indicate that while the degree of viral infection may differ between experimental cell lines, MCMV-infected tumor-bearing mice consistently demonstrate accelerated tumor growth and worsened survival relative to the uninfected controls. Additionally, our results provide further evidence to support the previously reported findings implicating CMV as a driver of angiogenesis in vivo, as sections from MCMV-infected mice showed a greater density of blood vessels and more complete blood-brain barrier formation. Finally, our results show that the addition of antiviral agents as an adjunct therapy to first-line chemotherapeutics effectively reduced tumor sphere size and partially reversed viral infection by MCMV. CONCLUSIONS: Here we demonstrate the tumor-promoting effects of MCMV infection are consistently observed in different glioblastoma mouse models suggesting that these effects are independent of the tumor genetic background of our tested tumor models. Moreover, the success of preliminary in vitro studies using a combination treatment of antiviral and chemotherapy strengthen the case for targeting CMV therapeutically in the treatment of GBM.