Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
Brain Pathol. 2013 May;23(3):244-53. doi: 10.1111/j.1750-3639.2012.00633.x. Epub 2012 Oct 11.
Pediatric high-grade astrocytomas (HGAs) account for 15-20% of all pediatric central nervous system tumors. These neoplasms predominantly involve the supratentorial hemispheres or the pons--diffuse intrinsic pontine gliomas (DIPG). Assumptions that pediatric HGAs are biologically similar to adult HGAs have recently been challenged, and the development of effective therapeutic modalities for DIPG and supratentorial HGA hinges on a better understanding of their biological properties. Here, 20 pediatric HGAs (9 DIPGs and 11 supratentorial HGAs) were subject to gene expression profiling following approval by the research ethics board at our institution. Many of these tumors showed expression signatures composed of genes that promote G1/S and G2/M cell cycle progression. In particular, Aurora kinase B (AURKB) was consistently and highly overexpressed in 6/9 DIPGs and 8/11 HGAs. Array data were validated using quantitative real-time PCR and immunohistochemistry, as well as cross-validation of our data set with previously published series. Inhibition of Aurora B activity in DIPG and in pediatric HGA cell lines resulted in growth arrest accompanied by morphological changes, cell cycle aberrations, nuclear fractionation and polyploidy as well as a reduction in colony formation. Our data highlight Aurora B as a potential therapeutic target in DIPG.
儿童高级别星形细胞瘤（HGAs）占所有儿童中枢神经系统肿瘤的 15-20%。这些肿瘤主要累及大脑半球或脑桥——弥漫性内在脑桥胶质瘤（DIPG）。最近，人们对儿童 HGAs 在生物学上与成人 HGAs 相似的假设提出了质疑，而 DIPG 和大脑半球 HGAs 的有效治疗方法的发展取决于对其生物学特性的更好理解。在这里，经过我们机构的研究伦理委员会的批准，对 20 例儿童 HGAs（9 例 DIPG 和 11 例大脑半球 HGAs）进行了基因表达谱分析。这些肿瘤中的许多都表现出由促进 G1/S 和 G2/M 细胞周期进程的基因组成的表达特征。特别是，Aurora 激酶 B（AURKB）在 6/9 例 DIPG 和 8/11 例 HGAs 中始终高度过表达。使用定量实时 PCR 和免疫组织化学以及与先前发表的系列数据集的交叉验证来验证阵列数据。在 DIPG 和儿科 HGA 细胞系中抑制 Aurora B 活性会导致生长停滞，同时伴有形态变化、细胞周期异常、核分裂和多倍体形成以及集落形成减少。我们的数据强调了 Aurora B 作为 DIPG 潜在治疗靶点的重要性。
