Neuroscience Center, Shantou University Medical College, Shantou 515041, China.
Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, China.
Brain. 2021 Mar 3;144(2):615-635. doi: 10.1093/brain/awaa404.
The molecular pathogenesis of glioblastoma indicates that RTK/Ras/PI3K, RB and TP53 pathways are critical for human gliomagenesis. Here, several transgenic zebrafish lines with single or multiple deletions of nf1, tp53 and rb1 in astrocytes, were established to genetically induce gliomagenesis in zebrafish. In the mutant with a single deletion, we found only the nf1 mutation low-efficiently induced tumour incidence, suggesting that the Nf1 pathway is critical for the initiation of gliomagenesis in zebrafish. Combination of mutations, nf1;tp53 and rb1;tp53 combined knockout fish, showed much higher tumour incidences, high-grade histology, increased invasiveness, and shortened survival time. Further bioinformatics analyses demonstrated the alterations in RTK/Ras/PI3K, cell cycle, and focal adhesion pathways, induced by abrogated nf1, tp53, or rb1, were probably the critical stepwise biological events for the initiation and development of gliomagenesis in zebrafish. Gene expression profiling and histological analyses showed the tumours derived from zebrafish have significant similarities to the subgroups of human gliomas. Furthermore, temozolomide treatment effectively suppressed gliomagenesis in these glioma zebrafish models, and the histological responses in temozolomide-treated zebrafish were similar to those observed in clinically treated glioma patients. Thus, our findings will offer a potential tool for genetically investigating gliomagenesis and screening potential targeted anti-tumour compounds for glioma treatment.
胶质母细胞瘤的分子发病机制表明，RTK/Ras/PI3K、RB 和 TP53 通路对于人类神经胶质瘤的发生至关重要。在这里，我们建立了几种在星形胶质细胞中单个或多个缺失 nf1、tp53 和 rb1 的转基因斑马鱼系，以在斑马鱼中遗传诱导神经胶质瘤发生。在单个缺失的突变体中，我们仅发现 nf1 突变低效率地诱导肿瘤发生率，这表明 Nf1 通路对于斑马鱼神经胶质瘤发生的起始至关重要。nf1;tp53 和 rb1;tp53 组合敲除鱼的突变组合显示出更高的肿瘤发生率、高级别的组织学、增加的侵袭性和缩短的生存时间。进一步的生物信息学分析表明，由 nf1、tp53 或 rb1 缺失引起的 RTK/Ras/PI3K、细胞周期和焦点黏附途径的改变，可能是斑马鱼神经胶质瘤发生和发展的关键逐步生物学事件。基因表达谱和组织学分析表明，源自斑马鱼的肿瘤与人类神经胶质瘤的亚组具有显著的相似性。此外，替莫唑胺治疗有效地抑制了这些神经胶质瘤斑马鱼模型中的神经胶质瘤发生，并且替莫唑胺治疗的斑马鱼中的组织学反应与临床上治疗的神经胶质瘤患者中观察到的反应相似。因此，我们的发现将为遗传研究神经胶质瘤发生和筛选潜在的针对神经胶质瘤治疗的靶向抗肿瘤化合物提供一种潜在的工具。
