Oncolytic reovirus-mediated killing of mouse cancer-associated fibroblasts
Oncolytic reovirus-mediated killing of mouse cancer-associated fibroblasts
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DOI：
10.1016/j.ijpharm.2021.121269
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发表时间：
2021-11-13
影响因子：
5.8
通讯作者：
Sakurai, Fuminori
中科院分区：
文献类型：
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作者：
Kurisu, Nozomi;Kaminade, Tadataka;Sakurai, Fuminori
溶瘤病毒作为一类新型的抗癌生物药物，能够介导肿瘤细胞的特异性感染，产生高效的肿瘤细胞杀伤作用，引起了人们的广泛关注。肿瘤相关成纤维细胞(CAF)是肿瘤微环境的重要组成部分，对肿瘤细胞的生长、存活和转移具有重要的支持作用，提示CAF对溶瘤病毒的抗肿瘤作用有影响，但溶瘤病毒治疗后是否影响CAF的存活率和性质仍有待充分研究。溶瘤呼肠孤病毒是一种非包膜病毒，含有10个节段的双链RNA基因组，具有高效的肿瘤细胞裂解作用，对正常细胞没有明显的细胞毒性，已在全球范围内进行了各种类型肿瘤的临床试验。在这项研究中，我们证明了呼肠孤病毒对从皮下肿瘤分离的小鼠原代CAF具有细胞毒性，但对尾端成纤维细胞不具有细胞毒性。呼肠孤病毒感染后，caspase 3激活，凋亡相关基因表达上调，提示呼肠孤病毒可诱导原代培养的小鼠CAF发生凋亡。呼肠孤病毒瘤内注射诱导肿瘤内小鼠CAF凋亡。综上所述，这些结果表明，呼肠孤病毒不仅可以杀死癌细胞，还可以杀死CAF，从而具有介导抗肿瘤作用的潜力。
Oncolytic viruses, which mediate tumor cell-specific infection, resulting in efficient tumor cell killing, have attracted much attention as a novel class of anti-cancer biopharmaceutical agents. Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment that strongly supports the growth, survival, and metastasis of tumor cells, suggesting that CAFs would have influence to the antitumor effects of oncolytic viruses; however, it remains to be fully evaluated whether oncolytic viruses affect the viabilities and properties of CAFs following treatment. Oncolytic reovirus, which is a non-enveloped virus that contains 10-segmented double-stranded RNA genome, shows efficient tumor cell lysis without apparent cytotoxicity to normal cells and has been tested worldwide in clinical trials against various types of tumors. In this study, we demonstrated that reovirus exhibited cytotoxicity against mouse primary CAFs isolated from subcutaneous tumors, but not against tail-tip fibroblasts. Infection with reovirus resulted in activation of caspase 3 and up-regulation of apoptosis-related gene expression, indicating that reovirus induced apoptosis of mouse primary CAFs. Intratumoral administration of reovirus induced apoptosis of mouse CAFs in the tumor. Taken together, these results indicate that reovirus has the potential to mediate antitumor effects by killing not only cancer cells but also CAFs.