PDF(Pubmed)
Abstract：
Viral modifications enabling syncytium formation in infected cells can augment lysis by oncolytic herpes simplex viruses (oHSVs) which selectively kill cancer cells. In the case of receptor-retargeted oHSVs (RR-oHSVs) that exclusively enter and spread to cancer cells, anti-tumor effects can be enhanced in a magnitude of >100,000-fold by modifying the virus to a syncytial type (RRsyn-oHSV). However, when syncytia containing non-cancerous cells are induced by conditionally replicating syncytial oHSV (CRsyn-oHSV), syncytial death occurs at an early stage. This results in limited anti-tumor effects of the CRsyn-oHSV. Here, we investigated whether necroptosis is involved in death of the syncytia formed by the fusion of cancer cells and non-cancerous cells. Mixed-lineage kinase domain-like (MLKL), a molecule executing necroptosis, was expressed in all murine cancer cell lines examined, while receptor-interacting protein kinase 3 (RIPK3), which phosphorylates MLKL, was absent from most cell lines. In contrast, RIPK3 was expressed in non-cancerous murine fibroblast cell lines. When a CRsyn-oHSV-infected RIPK3-deficient cancer cell line was co-cultured with the fibroblast cell line, but not with the cancer cells themselves, MLKL was phosphorylated and syncytial death was induced. These results indicate that early necroptosis is induced in multinucleated giant cells formed by CRsyn-oHSV when they also contain non-cancerous cells.
摘要：
能够在感染细胞中形成合胞体的病毒修饰可以增强溶瘤性单纯疱疹病毒（oHSV）的裂解，该病毒选择性地杀死癌细胞。在受体重新靶向的oHSV（RR-oHSV）的情况下，它只能进入并扩散到癌细胞，通过将病毒修饰为合胞体类型（RRsyn-oHSV），可以将抗肿瘤作用增强至>100,000倍。然而,当包含非癌细胞的合胞体通过条件复制合胞体oHSV（CRsyn-oHSV）诱导时，合胞体死亡发生在早期。这导致CRsyn-oHSV的抗肿瘤作用有限。这里,我们研究了坏死是否与癌细胞和非癌细胞融合形成的合胞体的死亡有关.混合谱系激酶结构域样（MLKL），执行坏死的分子，在所有被检查的鼠癌细胞系中表达，而受体相互作用蛋白激酶3（RIPK3），磷酸化MLKL，在大多数细胞系中都不存在。相比之下,RIPK3在非癌鼠成纤维细胞系中表达。当CRsyn-oHSV感染的RIPK3缺陷癌细胞系与成纤维细胞细胞系共培养时，但不是癌细胞本身，MLKL磷酸化并诱导合胞体死亡。这些结果表明，当CRsyn-oHSV还包含非癌细胞时，在由CRsyn-oHSV形成的多核巨细胞中诱导了早期坏死。
