Systemic vesicular stomatitis virus selectively destroys multifocal glioma and metastatic carcinoma in brain
Systemic vesicular stomatitis virus selectively destroys multifocal glioma and metastatic carcinoma in brain
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DOI：
10.1523/jneurosci.4905-07.2008
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发表时间：
2008-02-20
影响因子：
5.3
通讯作者：
Van den Pol, Anthony N.
中科院分区：
文献类型：
--
作者：
Ozduman, Koray;Wollmann, Guido;Van den Pol, Anthony N.
转移性肿瘤和恶性神经胶质瘤构成脑中癌症的大多数。它们总是致命的，目前没有治愈方法。从体外对许多病毒的比较中，我们选择了一种在选择性杀死胶质母细胞瘤细胞方面表现最好的病毒。这种有复制能力的病毒，神经胶质瘤适应性水疱性气孔病毒株VSVrp30a，用于体内试验，其基本观点是，肿瘤细胞的感染将导致随后释放的病毒数量增加，以杀死额外的肿瘤细胞。静脉注射表达绿色荧光蛋白报告基因的VSVrp30 a，快速靶向并破坏植入小鼠脑中的多种类型的人和小鼠肿瘤，包括胶质母细胞瘤和乳腺肿瘤。当肿瘤被植入大脑和周围时，模拟全身性癌症转移，大脑内外的肿瘤同时被感染。鼻内接种，导致嗅神经运输病毒进入大脑，选择性地感染和杀死嗅球肿瘤。无论是对照皮质伤口还是移植的正常小鼠或人细胞都没有被靶向，表明病毒肿瘤选择性。对照病毒，包括伪狂犬病病毒，腺相关病毒，或复制缺陷型VSV，没有感染脑肿瘤。通过颅窗的共聚焦激光延时成像显示，静脉注射VSV在多个部位感染肿瘤并杀死迁移的肿瘤细胞。通过染料泄漏提示肿瘤血管系统破裂，可能是静脉内输送VSV的入口。定量PCR分析VSVrp30 a如何选择性感染肿瘤细胞，提出了多种机制，包括细胞表面结合和内化。
Metastatic tumors and malignant gliomas make up the majority of cancers in the brain. They are invariably fatal and there is currently no cure. From in vitro comparisons of a number of viruses, we selected one that appeared the best in selectively killing glioblastoma cells. This replication-competent virus, the glioma-adapted vesicular stomatis virus strain VSVrp30a, was used for in vivo tests with the underlying view that infection of tumor cells will lead to an increase in the number of viruses subsequently released to kill additional tumor cells. Intravenous injection of VSVrp30a expressing a green fluorescent protein reporter, rapidly targeted and destroyed multiple types of human and mouse tumors implanted in the mouse brain, including glioblastoma and mammary tumors. When tumors were implanted both in the brain and peripherally, emulating systemic cancer metastasis, tumors inside and outside the brain were simultaneously infected. Intranasal inoculation, leading to olfactory nerve transport of the virus into the brain, selectively infected and killed olfactory bulb tumors. Neither control cortical wounds nor transplanted normal mouse or human cells were targeted, indicating viral tumor selectivity. Control viruses, including pseudorabies, adeno-associated, or replication-deficient VSV, did not infect the brain tumor. Confocal laser time-lapse imaging through a cranial window showed that intravenous VSV infects the tumor at multiple sites and kills migrating tumor cells. Disrupted tumor vasculature, suggested by dye leakage, may be the port of entry for intravenously delivered VSV. Quantitative PCR analysis of how VSVrp30a selectively infected tumor cells suggested multiple mechanisms, including cell surface binding and internalization.