Helaine Charly, Ferré Aurélie E, Leblond Marine M, Pérès Elodie A, Bernaudin Myriam, Valable Samuel, Petit Edwige
UNICAEN, CNRS, CEA, ISTCT/CERVOxy Group, GIP Cyceron, Normandie University, 14000 Caen, France.
Cancers (Basel). 2020 Nov 30;12(12):3585. doi: 10.3390/cancers12123585.
(1) We wanted to assess the impact of Ang2 in RCT-induced changes in the environment of glioblastoma. (2) The effect of Ang2 overexpression in tumor cells was studied in the GL261 syngeneic immunocompetent model of GB in response to fractionated RCT. (3) We showed that RCT combined with Ang2 led to tumor clearance for the GL261-Ang2 group by acting on the tumor cells as well as on both vascular and immune compartments. (4) In vitro, Ang2 overexpression in GL261 cells exposed to RCT promoted senescence and induced robust genomic instability, leading to mitotic death. (5) Coculture experiments of GL261-Ang2 cells with RAW 264.7 cells resulted in a significant increase in macrophage migration, which was abrogated by the addition of soluble Tie2 receptor. (6) Together, these preclinical results showed that, combined with RCT, Ang2 acted in an autocrine manner by increasing GB cell senescence and in a paracrine manner by acting on the innate immune system while modulating the vascular tumor compartment. On this preclinical model, we found that an ectopic expression of Ang2 combined with RCT impedes tumor recurrence.
(1)我们想要评估血管生成素2（Ang2）在放射治疗（RCT）诱导的胶质母细胞瘤环境变化中的影响。(2)在GL261同基因免疫活性胶质母细胞瘤模型中，研究了肿瘤细胞中Ang2过表达对分次RCT的反应。(3)我们发现，RCT联合Ang2通过作用于肿瘤细胞以及血管和免疫区室，使GL261 - Ang2组的肿瘤清除。(4)在体外，暴露于RCT的GL261细胞中Ang2过表达促进衰老并诱导强烈的基因组不稳定，导致有丝分裂死亡。(5)GL261 - Ang2细胞与RAW 264.7细胞的共培养实验导致巨噬细胞迁移显著增加，添加可溶性Tie2受体可消除这种增加。(6)总之，这些临床前结果表明，与RCT联合使用时，Ang2通过增加胶质母细胞瘤细胞衰老以自分泌方式起作用，并通过作用于先天免疫系统以旁分泌方式起作用，同时调节肿瘤血管区室。在这个临床前模型中，我们发现Ang2的异位表达与RCT联合可阻碍肿瘤复发。
