Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis
| Autor: | Michał Nowicki, Hong Zhang, Franz Ricklefs, Michael Gutknecht, Charles Cobbs, Arun K. Rooj, Prajna Behera, Carmela Passaro, Hirotaka Ito, Sean E. Lawler, Rachel Zane, Lai Ding, Marion Griessl, E. Antonio Chiocca, C. David James, Mykola Zdioruk, Magdalena Skubal, Harald Krenzlin, Sharon Peled, Charles H. Cook, Korneel Grauwet, Viola Lorenz |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.drug_class Angiogenesis viruses Congenital cytomegalovirus infection Cytomegalovirus Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine stomatognathic system In vivo Cell Line Tumor medicine Animals Humans Platelet-Derived Growth Factor Lymphokines Neovascularization Pathologic biology virus diseases Neoplasms Experimental General Medicine medicine.disease Neoplasm Proteins 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Cytomegalovirus Infections NIH 3T3 Cells Cancer research biology.protein Pericyte Antiviral drug Glioblastoma Pericytes Platelet-derived growth factor receptor Research Article Cidofovir |
| Zdroj: | Journal of Clinical Investigation. 129:1671-1683 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci123375 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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