High CD46 receptor density determines preferential killing of tumor cells by oncolytic measles virus
High CD46 receptor density determines preferential killing of tumor cells by oncolytic measles virus
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DOI：
10.1158/0008-5472.can-04-0884
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发表时间：
2004-07-15
期刊：
影响因子：
11.2
通讯作者：
Peng, KW
中科院分区：
文献类型：
--
作者：
Anderson, BD;Nakamura, T;Peng, KW
麻疹病毒Edmonston B减毒活毒株（MV-Edm）是一种有效的特异性溶瘤剂，但其肿瘤选择性机制尚不清楚。该病毒在肿瘤细胞中引起广泛的合胞体形成的细胞病变效应（CPE），但在正常细胞中引起最小的损伤或细胞杀伤。CPE依赖于病毒蛋白的表达和MV-Edm的主要细胞受体CD 46的存在。使用病毒编码的可溶性标记肽来提供病毒基因表达水平的定量读数，我们确定肿瘤细胞和正常细胞表达相当水平的病毒蛋白。CD 46介导病毒附着、进入和病毒诱导的细胞间融合。使用表达一系列CD 46密度的工程化细胞，我们确定，尽管病毒进入随着CD 46密度逐渐增加，但细胞融合在低受体密度下最小，但在高于CD 46受体的阈值密度时显著增加。众所周知，与正常细胞相比，肿瘤细胞在其表面上表达丰富的CD 46受体。因此，在正常细胞典型的低CD 46密度下，发生感染，但细胞间融合可忽略不计。在肿瘤细胞典型的较高密度下，感染导致广泛的细胞融合。细胞间融合还通过募集邻近未感染的细胞进入合胞体而导致病毒基因表达的增强，从而进一步放大CPE。高和低CD 46受体密度之间的区分为MV-Edm的溶瘤特异性提供了令人信服的基础，并确立MV-Edm作为有希望的CD 46靶向癌症治疗剂。
Live attenuated Edmonston B strain of measles virus (MV-Edm) is a potent and specific oncolytic agent, but the mechanism underlying its tumor selectivity is unknown. The virus causes cytopathic effects (CPEs) of extensive syncytial formation in tumor cells but minimal damage or cell killing in normal cells. The CPE is dependent on expression of viral proteins and the presence of CD46, the major cellular receptor of MV-Edm. Using a virally encoded soluble marker peptide to provide a quantitative readout of the level of viral gene expression, we determined that tumor cells and normal cells expressed comparable levels of viral proteins. CD46 mediates virus attachment, entry, and virus-induced cell-to-cell fusion. Using engineered cells expressing a range of CD46 densities, we determined that whereas virus entry increased progressively with CD46 density, cell fusion was minimal at low receptor densities but increased dramatically above a threshold density of CD46 receptors. It is well established that tumor cells express abundant CD46 receptors on their surfaces compared with their normal counterparts. Thus, at low CD46 densities typical of normal cells, infection occurs, but intercellular fusion is negligible. At higher densities typical of tumor cells, infection leads to extensive cell fusion. Intercellular fusion also results in enhancement of viral gene expression through recruitment of neighboring uninfected cells into the syncytium, further amplifying the CPE. Discrimination between high and low CD46 receptor density provides a compelling basis for the oncolytic specificity of MV-Edm and establishes MV-Edm as a promising CD46-targeted cancer therapeutic agent.