Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes

ABSTRACT Glioblastoma multiforme (GBM) is the most common brain tumor in adults. Human cytomegalovirus (HCMV) genomes are present in GBM tumors, yielding hope that antiviral treatments could prove therapeutic and improve the poor prognosis of GBM patients. We discovered that GBM cells infected in vi...

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Autores principales:	Che Liu, Paul A. Clark, John S. Kuo, Robert F. Kalejta
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	brain cancer cancer chemoresistance chemotherapy herpesvirus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8cee44aa671943ee9a03558c9490e665
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spelling	oai:doaj.org-article:8cee44aa671943ee9a03558c9490e6652021-11-15T15:21:45ZHuman Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes10.1128/mSphere.00137-172379-5042https://doaj.org/article/8cee44aa671943ee9a03558c9490e6652017-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00137-17https://doaj.org/toc/2379-5042ABSTRACT Glioblastoma multiforme (GBM) is the most common brain tumor in adults. Human cytomegalovirus (HCMV) genomes are present in GBM tumors, yielding hope that antiviral treatments could prove therapeutic and improve the poor prognosis of GBM patients. We discovered that GBM cells infected in vitro with HCMV display properties of cancer stem cells. HCMV-infected GBM cells grow more slowly than mock-infected controls, demonstrate a higher capacity for self-renewal determined by a sphere formation assay, and display resistance to the chemotherapeutic drug temozolomide. Our data suggest that HCMV, while present in only a minority of the cells within a tumor, could contribute to the pathogenesis of GBMs by promoting or prolonging stem cell-like phenotypes, thereby perpetuating tumors in the face of chemotherapy. Importantly, we show that temozolomide sensitivity is restored by the antiviral drug ganciclovir, indicating a potential mechanism underlying the positive effects observed in GBM patients treated with antiviral therapy. IMPORTANCE A role for HCMV in GBMs remains controversial for several reasons. Some studies find HCMV in GBM tumors, while others do not. Few cells within a GBM may harbor HCMV, making it unclear how the virus could be contributing to the tumor phenotype without infecting every cell. Finally, HCMV does not overtly transform cells in vitro. However, tumors induced by other viruses can be treated with antiviral remedies, and initial results indicate that this may be true for anti-HCMV therapies and GBMs. With such a poor prognosis for GBM patients, any potential new intervention deserves exploration. Our work here describes an evidence-based model for how HCMV could contribute to GBM biology while infecting very few cells and without transforming them. It also illuminates why anti-HCMV treatments may be beneficial to GBM patients. Our observations provide blueprints for future in vitro studies examining how HCMV manipulates stem cell-specific pathways and future clinical studies of anti-HCMV measures as GBM therapeutics.Che LiuPaul A. ClarkJohn S. KuoRobert F. KalejtaAmerican Society for Microbiologyarticlebrain cancercancerchemoresistancechemotherapyherpesvirusMicrobiologyQR1-502ENmSphere, Vol 2, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	brain cancer cancer chemoresistance chemotherapy herpesvirus Microbiology QR1-502
spellingShingle	brain cancer cancer chemoresistance chemotherapy herpesvirus Microbiology QR1-502 Che Liu Paul A. Clark John S. Kuo Robert F. Kalejta Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes
description	ABSTRACT Glioblastoma multiforme (GBM) is the most common brain tumor in adults. Human cytomegalovirus (HCMV) genomes are present in GBM tumors, yielding hope that antiviral treatments could prove therapeutic and improve the poor prognosis of GBM patients. We discovered that GBM cells infected in vitro with HCMV display properties of cancer stem cells. HCMV-infected GBM cells grow more slowly than mock-infected controls, demonstrate a higher capacity for self-renewal determined by a sphere formation assay, and display resistance to the chemotherapeutic drug temozolomide. Our data suggest that HCMV, while present in only a minority of the cells within a tumor, could contribute to the pathogenesis of GBMs by promoting or prolonging stem cell-like phenotypes, thereby perpetuating tumors in the face of chemotherapy. Importantly, we show that temozolomide sensitivity is restored by the antiviral drug ganciclovir, indicating a potential mechanism underlying the positive effects observed in GBM patients treated with antiviral therapy. IMPORTANCE A role for HCMV in GBMs remains controversial for several reasons. Some studies find HCMV in GBM tumors, while others do not. Few cells within a GBM may harbor HCMV, making it unclear how the virus could be contributing to the tumor phenotype without infecting every cell. Finally, HCMV does not overtly transform cells in vitro. However, tumors induced by other viruses can be treated with antiviral remedies, and initial results indicate that this may be true for anti-HCMV therapies and GBMs. With such a poor prognosis for GBM patients, any potential new intervention deserves exploration. Our work here describes an evidence-based model for how HCMV could contribute to GBM biology while infecting very few cells and without transforming them. It also illuminates why anti-HCMV treatments may be beneficial to GBM patients. Our observations provide blueprints for future in vitro studies examining how HCMV manipulates stem cell-specific pathways and future clinical studies of anti-HCMV measures as GBM therapeutics.
format	article
author	Che Liu Paul A. Clark John S. Kuo Robert F. Kalejta
author_facet	Che Liu Paul A. Clark John S. Kuo Robert F. Kalejta
author_sort	Che Liu
title	Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes
title_short	Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes
title_full	Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes
title_fullStr	Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes
title_full_unstemmed	Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes
title_sort	human cytomegalovirus-infected glioblastoma cells display stem cell-like phenotypes
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/8cee44aa671943ee9a03558c9490e665
work_keys_str_mv	AT cheliu humancytomegalovirusinfectedglioblastomacellsdisplaystemcelllikephenotypes AT paulaclark humancytomegalovirusinfectedglioblastomacellsdisplaystemcelllikephenotypes AT johnskuo humancytomegalovirusinfectedglioblastomacellsdisplaystemcelllikephenotypes AT robertfkalejta humancytomegalovirusinfectedglioblastomacellsdisplaystemcelllikephenotypes
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Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes

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