Department of Neurological Surgery, Dardinger Neuro-oncology Center, Solid Tumor Program at the James Comprehensive Cancer Center, Center for Biostatistics, Departments of Pathology, Veterinary Biosciences, and Surgery, The Ohio State University Medical Center, Columbus, Ohio, USA.
Cancer Res. 2013 Jun 1;73(11):3441-50. doi: 10.1158/0008-5472.CAN-12-3846.
To study the controversial role of cytomegalovirus (CMV) in glioblastoma, we assessed the effects of murine CMV (MCMV) perinatal infection in a GFAP-cre; Nf1(loxP/+); Trp53(-/+) genetic mouse model of glioma (Mut3 mice). Early on after infection, MCMV antigen was predominantly localized in CD45+ lymphocytes in the brain with active viral replication and local areas of inflammation, but, by 7 weeks, there was a generalized loss of MCMV in brain, confirmed by bioluminescent imaging. MCMV-infected Mut3 mice exhibited a shorter survival time from their gliomas than control Mut3 mice perinatally infected with mock or with a different neurotropic virus. Animal survival was also significantly shortened when orthotopic gliomas were implanted in mice perinatally infected with MCMV versus controls. MCMV infection increased phosphorylated STAT3 (p-STAT3) levels in neural stem cells (NSC) harvested from Mut3 mice subventricular zone, and, in vivo, there was increased p-STAT3 in NSCs in MCMV-infected compared with control mice. Of relevance, human CMV (HCMV) also increased p-STAT3 and proliferation of patient-derived glioblastoma neurospheres, whereas a STAT3 inhibitor reversed this effect in vitro and in vivo. These findings thus associate CMV infection to a STAT3-dependent modulatory role in glioma formation/progression in the context of tumor suppressor mutations in mice and possibly in humans.
为了研究巨细胞病毒（CMV）在胶质母细胞瘤中的争议性作用，我们评估了鼠巨细胞病毒（MCMV）围产期感染在胶质母细胞瘤 GFAP-cre; Nf1(loxP/+); Trp53(-/-) 遗传小鼠模型（Mut3 小鼠）中的影响。感染后早期，MCMV 抗原主要定位于大脑中的 CD45+淋巴细胞中，存在活跃的病毒复制和局部炎症区域，但到第 7 周时，大脑中的 MCMV 普遍丢失，这通过生物发光成像得到了证实。与假感染或感染另一种神经营养性病毒的 Mut3 小鼠相比，感染 MCMV 的 Mut3 小鼠的生存期更短。与对照 Mut3 小鼠相比，将 Mut3 小鼠原位植入的胶质瘤在围产期感染 MCMV 的小鼠中，动物的存活时间也明显缩短。MCMV 感染增加了从 Mut3 小鼠侧脑室区采集的神经干细胞（NSC）中磷酸化 STAT3（p-STAT3）的水平，并且在体内，与对照小鼠相比，感染 MCMV 的小鼠中的 NSCs 中 p-STAT3 增加。相关地，人巨细胞病毒（HCMV）也增加了患者来源的胶质母细胞瘤神经球的 p-STAT3 和增殖，而 STAT3 抑制剂在体外和体内逆转了这种作用。这些发现因此将 CMV 感染与在小鼠和可能在人类中肿瘤抑制基因突变的情况下，在神经胶质瘤形成/进展中依赖 STAT3 的调节作用联系起来。
