Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion.
Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion.
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DOI：
10.1016/j.omto.2017.04.002
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发表时间：
2017-06-16
期刊：
影响因子：
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通讯作者：
Ilett E
中科院分区：
文献类型：
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作者：
Cockle JV;Brüning-Richardson A;Scott KJ;Thompson J;Kottke T;Morrison E;Ismail A;Carcaboso AM;Rose A;Selby P;Conner J;Picton S;Short S;Vile R;Melcher A;Ilett E
儿童高级别胶质瘤(PHGG)和弥漫性固有桥脑胶质瘤(DIPG)均为侵袭性肿瘤，生存率较低。溶瘤病毒疗法最初被设计为一种直接的细胞毒治疗，现在也已知通过免疫中介机制发挥作用。在这里，我们研究了一个以前未报道的作用机制：抑制儿童脑肿瘤的迁移和侵袭。我们通过2D(划痕试验，活细胞成像)和3D(胶原球体侵袭)实验，以及体内DIPG侵袭原位异种移植模型，评价了溶瘤单纯疱疹病毒1716(HSV1716)对PHGG和DIPG体外迁移和侵袭的影响。HSV1716可抑制PHGG和DIPG细胞的迁移和侵袭。PHGG细胞在病毒存在下表现出速度减慢和形态改变。HSV1716通过稳定微管，抑制糖原合成酶激酶-3，阻止腺瘤性息肉病(APC)向细胞前沿聚集，改变了PHGG细胞骨架动力学。HSV1716治疗也减少了小鼠原位异种移植DIPG模型中的肿瘤浸润率。我们的结果表明HSV1716靶向PHGG和DIPG的迁移和侵袭，并表明溶瘤病毒(OV)作为一种新的抗侵袭治疗策略用于儿童脑肿瘤的潜力。
Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are invasive tumors with poor survival. Oncolytic virotherapy, initially devised as a direct cytotoxic treatment, is now also known to act via immune-mediated mechanisms. Here we investigate a previously unreported mechanism of action: the inhibition of migration and invasion in pediatric brain tumors. We evaluated the effect of oncolytic herpes simplex virus 1716 (HSV1716) on the migration and invasion of pHGG and DIPG both in vitro using 2D (scratch assay, live cell imaging) and 3D (spheroid invasion in collagen) assays and in vivo using an orthotopic xenograft model of DIPG invasion. HSV1716 inhibited migration and invasion in pHGG and DIPG cell lines. pHGG cells demonstrated reduced velocity and changed morphology in the presence of virus. HSV1716 altered pHGG cytoskeletal dynamics by stabilizing microtubules, inhibiting glycogen synthase kinase-3, and preventing localized clustering of adenomatous polyposis coli (APC) to the leading edge of cells. HSV1716 treatment also reduced tumor infiltration in a mouse orthotopic xenograft DIPG model. Our results demonstrate that HSV1716 targets the migration and invasion of pHGG and DIPG and indicates the potential of an oncolytic virus (OV) to be used as a novel anti-invasive treatment strategy for pediatric brain tumors.