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J Clin Invest. 2019 Mar 11;130:1671-1683. doi: 10.1172/JCI123375. eCollection 2019 Mar 11.

Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis.

Author information

1
Department of Neurosurgery, Brigham and Women's Hospital.
2
Division of Newborn Medicine, Boston Children's Hospital, and.
3
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
5
Program for Interdisciplinary Neuroscience, NeuroTechnology Studio, Brigham and Women's Hospital, Boston, Massachusetts, USA.
6
Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
7
Department of Neurosurgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
8
Swedish Neuroscience Institute, Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, Seattle, Washington, USA.

Abstract

Cytomegalovirus (CMV) has been implicated in glioblastoma (GBM); however, a mechanistic connection in vivo has not been established. The purpose of this study is to characterize the effects of murine CMV (MCMV) on GBM growth in murine models. Syngeneic GBM models were established in mice perinatally infected with MCMV. We found that tumor growth was markedly enhanced in MCMV+ mice, with a significant reduction in overall survival compared with that of controls (P < 0.001). We observed increased angiogenesis and tumor blood flow in MCMV+ mice. MCMV reactivation was observed in intratumoral perivascular pericytes and tumor cells in mouse and human GBM specimens, and pericyte coverage of tumor vasculature was strikingly augmented in MCMV+ mice. We identified PDGF-D as a CMV-induced factor essential for pericyte recruitment, angiogenesis, and tumor growth. The antiviral drug cidofovir improved survival in MCMV+ mice, inhibiting MCMV reactivation, PDGF-D expression, pericyte recruitment, and tumor angiogenesis. These data show that MCMV potentiates GBM growth in vivo by increased pericyte recruitment and angiogenesis due to alterations in the secretome of CMV-infected cells. Our model provides evidence for a role of CMV in GBM growth and supports the application of antiviral approaches for GBM therapy.

KEYWORDS:

Brain cancer; Mouse models; Oncology; Pericytes; Virology

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