Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes
Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes
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DOI：
10.1128/msphere.00137-17
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发表时间：
2017-05-01
期刊：
影响因子：
4.8
通讯作者：
Kalejta, Robert F.
中科院分区：
文献类型：
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作者：
Liu, Che;Clark, Paul A.;Kalejta, Robert F.
多形性胶质母细胞瘤（GBM）是成人最常见的脑肿瘤。GBM肿瘤中存在人巨细胞病毒（HCMV）基因组，这给抗病毒治疗带来了希望，可以证明其具有治疗作用并改善GBM患者的不良预后。我们发现在体外用HCMV感染的GBM细胞显示癌症干细胞的特性。HCMV感染的GBM细胞比模拟感染的对照生长得更慢，通过球体形成测定显示出更高的自我更新能力，并显示出对化疗药物替莫唑胺的抗性。我们的数据表明，HCMV，虽然只存在于肿瘤内的少数细胞，可能有助于GBM的发病机制，通过促进或延长干细胞样表型，从而使肿瘤在化疗面前永存。重要的是，我们表明，替莫唑胺的敏感性恢复的抗病毒药物更昔洛韦，表明潜在的机制，观察到的积极影响GBM患者抗病毒therapy.IMPORTANCE HCMV在GBM中的作用仍然存在争议，有几个原因。一些研究在GBM肿瘤中发现了HCMV，而另一些则没有。GBM中很少有细胞可能携带HCMV，因此不清楚病毒如何在不感染每个细胞的情况下促成肿瘤表型。最后，HCMV在体外不明显转化细胞。然而，由其他病毒引起的肿瘤可以用抗病毒药物治疗，初步结果表明，这可能是真的抗HCMV治疗和GBM。由于GBM患者的预后如此差，任何潜在的新干预措施都值得探索。我们在这里的工作描述了一个基于证据的模型，说明HCMV如何在感染很少的细胞而不转化它们的情况下促进GBM生物学。它还阐明了为什么抗HCMV治疗可能对GBM患者有益。我们的观察结果提供了未来的体外研究，探讨HCMV如何操纵干细胞特异性途径和未来的临床研究抗HCMV措施GBM治疗的蓝图。
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.