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Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis
Harald Krenzlin, … , E. Antonio Chiocca, Sean E. Lawler
Harald Krenzlin, … , E. Antonio Chiocca, Sean E. Lawler
Published March 11, 2019
Citation Information: J Clin Invest. 2019;129(4):1671-1683. https://doi.org/10.1172/JCI123375.
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Research Article Oncology Virology

Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis

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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.

Authors

Harald Krenzlin, Prajna Behera, Viola Lorenz, Carmela Passaro, Mykola Zdioruk, Michal O. Nowicki, Korneel Grauwet, Hong Zhang, Magdalena Skubal, Hirotaka Ito, Rachel Zane, Michael Gutknecht, Marion B. Griessl, Franz Ricklefs, Lai Ding, Sharon Peled, Arun Rooj, C. David James, Charles S. Cobbs, Charles H. Cook, E. Antonio Chiocca, Sean E. Lawler

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Figure 1

MCMV infection accelerates GBM growth in mice.

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MCMV infection accelerates GBM growth in mice.
(A) Experimental overview...
(A) Experimental overview. (B) Kaplan-Meier curves of GL261Luc2 tumor-bearing mice. Uninfected, n = 20; MCMV+, n = 19. P < 0.0001, log-rank test. Median survival is indicated on plot and shown in parentheses. (C) BLI and (D) MRI analysis of tumor-bearing MCMV+ and control animals 30 days after tumor implantation. (D) Tumor volume rendering from MRI images (left), tumor volume over time (right). n = 3. Box extends from the 25th to 75th percentile, and the median is indicated by a horizontal line. The whiskers represent the maximum and minimum values. Statistical analysis was performed by 2-way ANOVA with Bonferroni’s correction. *P < 0.05; ***P < 0.005. (E) H&E staining of GL261Luc2 tumors at end points. Scale bars: 1 mm (left panels); 50 μm (right panels).
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