【美国科学院报】中大发现M1天然病毒癌细胞有望精确杀灭

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doi: 10.1073/pnas.1408759111

Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers

Oncolytic virotherapy is a growing treatment modality that uses replicating viruses as selective antineoplastic agents. Safety and efficacy considerations dictate that an ideal oncolytic agent would discriminate between normal and cancer cells on the basis of common genetic abnormalities in human cancers. Here， we identify a naturally occurring alphavirus (M1) as a novel selective killer targeting zinc-finger antiviral protein (ZAP)-deficient cancer cells. In vitro， in vivo， and ex vivo studies showed potent oncolytic efficacy and high tumor tropism of M1. We showed that the selectivity depends on ZAP deficiency by systematic identification. A large-scale multicenter pathology study using tissue microarrays reveals that ZAP is commonly deficient in human cancers， suggesting extensive application prospects for M1. Additionally， M1 killed cancer cells by inducing endoplasmic reticulum stress-mediated apoptosis. Our report provides novel insights into potentially personalized cancer therapy using oncolytic viruses.

以下内容转自中山大学校园网：
“我校中山医学院颜光美教授课题组于2014年10月7日在国际期刊Proceedings of the National Academy of Sciences of the United States of America上发表了天然甲病毒M1具有选择性抗肿瘤作用的最新研究，林园、张海鹏、梁剑开为共同第一作者。
全球癌症发病率呈现快速增长态势，现有的治疗手段远远未能满足临床需求。颜光美教授课题组发现，M1病毒是一种从中国海南岛分离得到的天然病毒，能选择性地感染并杀伤包括肝癌、结直肠癌、膀胱癌、黑色素瘤在内的多种体外培养的癌细胞，而对正常细胞无毒副作用。整体动物实验表明，经尾静脉注射的M1病毒能显著富集在肿瘤组织并抑制肿瘤生长，正常器官则不受影响。除细胞水平及动物实验之外，课题组还使用临床标本离体活组织培养模型进一步证实了上述新型溶瘤病毒的有效性和特异性。
更为重要的是，研究工作还证明了M1病毒作用的分子遗传学机制，即锌指抗病毒蛋白（ZAP）在部分肿瘤中的低表达与M1病毒溶瘤效应相关。这个发现为精准的临床用药和实施个体化疗法提供了可靠的科学依据，也会极大地增加未来临床试验取得成功的机会。
该研究成果对阐明新型天然溶瘤病毒M1选择性杀伤肿瘤细胞的机制和研发新型靶向抗肿瘤药物都具有重要意义。