Article
Cytomegalovirus infection leads to c-MET overexpression, adversely affecting survival and resistance to Temozolomide in glioblastoma
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Authors
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Harald Krenzlin
- Brigham and Women's, Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
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Magdalena Skubal
- Brigham and Women's, Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
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Franz Lennard Ricklefs
- Brigham and Women's, Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten; Universitätsklinikum Hamburg-Eppendorf, Neurosurgery, Hamburg, Deutschland
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Charles H. Cook
- Beth Israel Deaconess Hospital, Dept. Surgery, Boston, MA, Vereinigte Staaten
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E. Antonio Chiocca
- Brigham and Women's, Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
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Sean Lawler
- Brigham and Women's, Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
| Published: | June 18, 2018 |
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Outline
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Objective: Cytomegalovirus (CMV) is detectable in most, if not all human 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. While CMV can affect various oncomodulatory signalling pathways, its role in glioblastoma remains largely elusive. Here, we investigate the interrelation of CMV interference with the nuclear factor (NF)-kB pathway in the regulation c-MET/ CD44 complex and mediation of TMZ resistance.
Methods: Changes in c-MET and CD44 expression after CMV infection were measured using qPCR and Western blot analysis. The involvement of the NFkB pathway was determined using siRNA in GSCs. 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). Additionally, an upregulation of the c-MET receptor phosphorylation is detected in western blot analysis, suggesting an activation of the c-MET signalling pathway in these cells. 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).
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 antagonised by antiviral therapy. These findings further strengthen the importance of CMV infection glioblastoma and suggest a potential role for supportive antiviral therapy.
