Article
Cytomegalovirus mediated shorted survival and resistance to temozolomide in glioblastoma can be antagonist by antiviral therapy
Virustatikatherapie zur Unterdrückung der CMV vermittelten Reduktion des mittleren Überlebens und TMZ-Resistenz beim Glioblastom
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Published: | May 8, 2019 |
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Objective: Cytomegalovirus (CMV) is detectable in most glioblastoma samples. The receptor tyrosine kinases c-MET and its co-receptor CD44 are associated with shorter survival time and poor treatment response to the standard of care drug temozolomide (TMZ) in glioblastoma.
Methods: Changes in c-MET and CD44 expression after CMV infection were measured using qPCR and Western blot analysis. TRegulatory pathway analysis was performed using RNAseq and siRNA techniques. Functional analysis was performed using different mouse models in vivo.
Results: Detection of the CMV major immediate-early gene 1 in patient-derived tumour samples correlates linear with c-MET receptor expression (n=15, p=0.0005, R2=0.748). CMV infection of patient derived glioma stem cells (GSCs) leads to upregulation of c-MET/CD44 complex on mRNA and protein level. This upregulation is more pronounced in low c-MET/CD44- expressing, proneural GSCs (95-fold -/+9.3), compared to those of the mesenchymal subtype (2-fold -/+0.16). An upregulation of the c-MET receptor phosphorylation is detected in western blot analysis. The knock-down of the NF-kB p65 subunit using siRNA prevents c-MET upregulation. Phenotypically, a stable overexpression of c-MET on proneural GSCs leads to increased migration in vitro and shortened survival time in an orthotopic mouse xenograft model in vivo (mean survival: 10d vs 60d, p<.0001). Latent CMV infection in a syngenic mouse glioblastoma model leads to c-MET overexpression in tumour cells, shortened survival (34d vs 40d, p=0.0004) and increased TMZ resistance (mean survival: 35d vs 48d, p=0.0023). Treatment with the antiviral drug ganciclovir partially reverse CMV induced TMZ resistance (40d vs 49d, p<0.0001) and leads to prolonged overall survival.
Conclusion: CMV increases glioblastoma progression by upregulation of growth and invasion mediating receptor c-MET/CD44 complex. In vivo, shortened survival times and increased resistance to TMZ can be antagonized by antiviral therapy. These findings argue in favour of a supportive antiviral in the treatment of glioblastoma patients.