Cancer cell death enhances the penetration and efficacy of oncolytic herpes simplex virus in tumors
Cancer cell death enhances the penetration and efficacy of oncolytic herpes simplex virus in tumors
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DOI：
10.1158/0008-5472.can-07-6193
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发表时间：
2008-05-15
期刊：
影响因子：
11.2
通讯作者：
Boucher, Yves
中科院分区：
文献类型：
--
作者：
Nagano, Satoshi;Perentes, Jean Yannis;Boucher, Yves
肿瘤溶瘤病毒治疗的成功受到病毒在肿瘤中渗透性差的限制。间质胶原纤维和癌细胞之间的狭窄间隔是阻碍大病毒颗粒移动的主要障碍。为了绕过细胞屏障，我们测试了癌细胞凋亡产生的空隙空间增强溶瘤性单纯疱疹病毒（HSV）的初始传播和功效的假设。在患有乳腺肿瘤的小鼠中，通过多西环素调节的CD 8/半胱天冬酶-8、紫杉醇或紫杉醇加肿瘤坏死因子相关凋亡诱导配体（TRAIL）的表达/活化来诱导细胞凋亡。在缺乏胶原和富含胶原的肿瘤中，细胞凋亡或坏死增加了HSV的初始瘤内扩散。与HSV感染的孤立模式相比，HSV感染通常位于对照肿瘤的中心，细胞凋亡诱导和单次i. t.注射病毒产生了一种相互联系的和弥漫性的感染模式，从肿瘤中心延伸到周围。这种相互关联的病毒感染模式与富肿瘤区域中空隙空间和通道样结构的形成相关。我们还表明，信息技术。在半胱天冬酶-8活化或紫杉醇-TRAIL预处理后注射HSV延缓肿瘤生长，而在肿瘤细胞死亡诱导前施用HSV不能提高治疗功效。因此，我们的发现表明，在注射溶瘤HSV之前诱导癌细胞死亡增强了瘤内病毒递送/渗透和抗肿瘤功效。
The success of tumor oncolytic virotherapy is limited by the poor penetration of virus in tumors. Interstitial collagen fibers and the narrow spacing between cancer cells are major barriers hindering the movement of large viral particles. To bypass the cellular barrier, we tested the hypothesis that the void space produced by cancer cell apoptosis enhances the initial spread and efficacy of oncolytic herpes simplex virus (HSV). In mice with mammary tumors, apoptosis was induced by doxycycline-regulated expression/activation of CD8/caspase-8, paclitaxel, or paclitaxel plus tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In both collagen-poor and collagen-rich tumors, apoptosis or necrosis increased the initial intratumoral spread of HSV. Compared with the isolated pattern of HSV infection generally located in the center of control tumors, apoptosis induction and a single i.t. injection of virus produced an interconnected and diffuse pattern of infection, which extended from the tumor center to the periphery. This interconnected pattern of viral infection correlated with the formation of void spaces and channel-like structures in apoptosis-rich tumor areas. We also show that the i.t. injection of HSV after caspase-8 activation or paclitaxel-TRAIL pretreatment retards tumor growth, whereas HSV administration before tumor cell death induction did not improve therapeutic efficacy. Hence, our findings show that the induction of cancer cell death before the injection of oncolytic HSV enhances intratumoral virus delivery/penetration and antitumor efficacy.