Cockle Julia V, Brüning-Richardson Anke, Scott Karen J, Thompson Jill, Kottke Timothy, Morrison Ewan, Ismail Azam, Carcaboso Angel M, Rose Ailsa, Selby Peter, Conner Joe, Picton Susan, Short Susan, Vile Richard, Melcher Alan, Ilett Elizabeth
Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
Yorkshire Regional Centre for Paediatric Oncology and Haematology, Leeds General Infirmary, Leeds LS1 3EX, UK.
Mol Ther Oncolytics. 2017 May 2;5:75-86. doi: 10.1016/j.omto.2017.04.002. eCollection 2017 Jun 16.
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.
小儿高级别胶质瘤（pHGG）和弥漫性脑桥内在型胶质瘤（DIPG）是侵袭性肿瘤，生存率低。溶瘤病毒疗法最初被设计为一种直接的细胞毒性治疗方法，现在也已知其通过免疫介导机制发挥作用。在此，我们研究一种此前未报道的作用机制：抑制小儿脑肿瘤的迁移和侵袭。我们使用二维（划痕试验、活细胞成像）和三维（胶原中的球体侵袭）试验在体外评估了溶瘤单纯疱疹病毒1716（HSV1716）对pHGG和DIPG迁移和侵袭的影响，并使用DIPG侵袭的原位异种移植模型在体内进行了评估。HSV1716抑制了pHGG和DIPG细胞系的迁移和侵袭。在有病毒存在的情况下，pHGG细胞表现出速度降低和形态改变。HSV1716通过稳定微管、抑制糖原合酶激酶-3以及阻止腺瘤性息肉病大肠杆菌（APC）在细胞前沿局部聚集来改变pHGG细胞骨架动态。HSV1716治疗还减少了小鼠原位异种移植DIPG模型中的肿瘤浸润。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）有潜力用作小儿脑肿瘤的一种新型抗侵袭治疗策略。
