Article
Cytomegalovirus stimulates angiogenesis and emerges as a druggable target 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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Carmela Passaro
- Brigham and Women's, Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
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Arun Rooj
- Brigham and Women's, Harvard Medical School, Dept. of Neurosurgery, Boston, MA, Vereinigte Staaten
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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
Text
Objective: Cytomegalovirus (CMV) has been linked to glioblastoma for over a decade. However, mechanisms how CMV affects tumour growth are poorly understood. Here we identify a novel regulatory mechanism involving the cross-talk between infected tumour cells and vascular pericytes to promote angiogenesis in glioblastoma. We demonstrate that treatment with the antiviral drug Cidofovir prolongs survival in a syngeneic mouse glioblastoma model in vivo.
Methods: In vitro CMV expression in mouse and human glioblastoma samples were analysed. RNAseq and functional assays were used to investigate tube formation and vascular development. In vivo treatment experiments are performed using a new CMV latent, orthotopic mouse (C57BL/6) glioblastoma model.
Results: Immunostaining of patient samples identified viral antigens expressed in multiple cellular compartments including the novel observation of co-localization with pericytes. RNAseq of human brain vascular pericytes (HBVPs) and glioblastoma stem-like cells (GSCs) revealed upregulation of proangiogenic cytokines after CMV infection. Conditioned medium derived from CMV infected GSCs/HBVPs led to the establishment of larger (160%, p<0.0001) and more complex (number of junctions 9.5 (control) vs. 21 (CMV), p<0.0001) tube formation in human brain microvascular endothelial cells (HBMEC). Platelet derived growth factor DD (PDGF-DD) secreted by GSCs after CMV infection, was identified as a driver of HBVP migration and angiogenesis. Orthotopic injection of Gl261fluc murine glioblastoma cells in C57BL/6 mice harbouring a latent CMV infection caused intratumoural virus reactivation and shortened survival rates (30d vs 43d, p=0.0004). Increased area (p=0.0004) and length (p=0.001) of tumour vessels was found in CMV latent mice. Furthermore, CMV infected tumours showed significantly higher numbers of infiltrating- and blood vessel-associated pericytes. Treatment with the antiviral drug Cidofovir reduced the tumour vasculature and increased the survival of CMV latent mice (mean: 36d, p = 0,0001).
Conclusion: In patient-derived tumour samples CMV co-localizes with the perivascular niche. Tumour growth is accelerated in CMV latent mice driven by pro-angiogenic paracrine signalling. Secretion of PDGF-DD is associated with increased pericyte recruitment and consecutive angiogenesis. Antiviral treatment prolonged survival after tumour injection in CMV latent mice and represents a novel therapeutic option in glioblastoma.
Figure 1 [Fig. 1]
