Intravenous injections of the oncolytic virus M1 as a novel therapy for muscle-invasive bladder cancer.
Intravenous injections of the oncolytic virus M1 as a novel therapy for muscle-invasive bladder cancer.
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DOI：
10.1038/s41419-018-0325-3
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发表时间：
2018-02-15
影响因子：
9
通讯作者：
Gao X
中科院分区：
文献类型：
--
作者：
Hu C;Liu Y;Lin Y;Liang JK;Zhong WW;Li K;Huang WT;Wang DJ;Yan GM;Zhu WB;Qiu JG;Gao X
肌肉浸润性膀胱癌（MIBC）与低生存率和高复发率相关，即使在患者接受系统治疗（如手术和化疗）的情况下也是如此。在这里，我们发现一种天然存在的甲病毒，即M1，选择性地杀死膀胱癌细胞，但不杀死正常细胞，我们对病毒复制和MIBC以及患者来源的MIBC细胞凋亡变化的观察结果支持了这一发现。转录组分析显示，干扰素刺激基因（ISG）在敏感的膀胱癌细胞中表达水平低，在耐药细胞中表达水平高。敲低ZC 3 HAV 1（ZAP），ISG中的一种抗病毒因子，恢复M1病毒在抗性细胞中的反应性，并且过表达ZAP部分逆转了M1病毒诱导的敏感细胞中细胞活力的降低。在原位MIBC小鼠中，尾静脉注射M1显著抑制肿瘤生长并延长生存期，M1的抗肿瘤作用强于一线化疗药物顺铂（CDDP）。经治疗的肿瘤显示增强的裂解半胱天冬酶-3信号，其代表细胞凋亡，和降低的Ki-67信号，其代表细胞增殖。此外，临床肿瘤标本的组织微阵列（TMA）分析显示，高达45.6%的MIBC病例表现出低ZAP表达，这一发现在晚期MIBC中普遍存在。我们的研究结果表明，溶瘤病毒M1是一种新的药物，能够作为一个精确和有效的治疗MIBC。
Muscle-invasive bladder cancer (MIBC) is associated with low survival and high recurrence rates even in cases in which patients receive systemic treatments, such as surgery and chemotherapy. Here, we found that a naturally existing alphavirus, namely, M1, selectively kills bladder cancer cells but not normal cells, findings supported by our observations of changes in viral replication and MIBC and patient-derived MIBC cell apoptosis. Transcriptome analysis revealed that interferon-stimulated genes (ISGs) are expressed at low levels in sensitive bladder cancer cells and high levels in resistant cells. Knocking down ZC3HAV1 (ZAP), an antiviral factor in ISGs, restores M1 virus reactivity in resistant cells, and overexpressing ZAP partially reverses M1 virus-induced decreases in cell viability in sensitive cells. In orthotopic MIBC mice, tail vein injections of M1 significant inhibit tumor growth and prolong survival period, antitumor effects of M1 are stronger than those of the first-line chemotherapy agent cisplatin (CDDP). Treated tumors display enhanced cleaved-caspase-3 signals, which are representative of cell apoptosis, and decreased Ki-67 signals, which are representative of cell proliferation. Moreover, tissue microarray (TMA) analyses of clinical tumor specimens revealed that up to 45.6% of cases of MIBC presented with low ZAP expression, a finding that is prevalent in advanced MIBC. Our results indicate that the oncolytic virus M1 is a novel agent capable of functioning as a precise and effective therapy for MIBC.
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影响因子：
16.6
作者：
Todorova T;Bock FJ;Chang P
通讯作者：
Chang P
影响因子：
2.6
作者：
Abdollah, Firas;Gandaglia, Giorgio;Sun, Maxine
通讯作者：
Sun, Maxine
影响因子：
6.2
作者：
Cote, RJ;Datar, RH
通讯作者：
Datar, RH
干扰素α通过刺激抗病毒免疫来拮抗溶瘤病毒M1的抗肝癌活性
影响因子：
--
作者：
Ying, Liu;Cheng, Hu;Liang, Peng
通讯作者：
Liang, Peng
影响因子：
4.5
作者：
Zehnder, Pascal;Studer, Urs E.;Gill, Inderbir S.
通讯作者：
Gill, Inderbir S.