The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 1L7.
Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14378-83. doi: 10.1073/pnas.1303504110. Epub 2013 Aug 13.
Gliomas represent the most common type of brain tumor, but show considerable variability in histologic appearance and clinical outcome. The phenotypic differences between types and grades of gliomas have not been explained solely on the grounds of differing oncogenic stimuli. Several studies have demonstrated that some phenotypic differences may be attributed to regional differences in the neural stem cells from which tumors arise. We hypothesized that temporal differences may also play a role, with tumor phenotypic variability reflecting intrinsic differences in neural stem cells at distinct developmental stages. To determine how the tumorigenic potential of lineally related stem cells changes over time, we used a conditional transgenic system that integrates Cre-Lox-mediated and Tet-regulated expression to drive K-ras(G12D) expression in neuro-glial progenitor populations at different developmental time points. Using this model, we demonstrate that K-ras(G12D)-induced transformation is dependent on the developmental stage at which it is introduced. Diffuse malignant brain tumors develop during early embryogenesis but not when K-ras(G12D) expression is induced during late embryogenesis or early postnatal life. We show that differential expression of cell-cycle regulators during development may be responsible for this differing susceptibility to malignant transformation and that loss of p53 can overcome the transformation resistance seen at later developmental stages. These results highlight the interplay between genetic alterations and the molecular changes that accompany specific developmental stages; early progenitors may lack the regulatory mechanisms present at later, more lineage-restrictive, developmental time points, making them more susceptible to transformation.
神经胶质瘤是最常见的脑肿瘤类型，但在组织学表现和临床结果方面存在很大的可变性。不同类型和级别的神经胶质瘤之间的表型差异不能仅仅归因于不同的致癌刺激。几项研究表明，一些表型差异可能归因于肿瘤起源的神经干细胞在区域上的差异。我们假设，时间上的差异也可能起作用，肿瘤表型的可变性反映了不同发育阶段神经干细胞的内在差异。为了确定线性相关的干细胞的肿瘤发生潜力随时间如何变化，我们使用了一种条件性转基因系统，该系统整合了 Cre-Lox 介导和 Tet 调节表达，以在不同的发育时间点驱动神经胶质祖细胞群体中的 K-ras(G12D)表达。使用这种模型，我们证明 K-ras(G12D)诱导的转化依赖于引入它的发育阶段。弥漫性恶性脑肿瘤在胚胎早期发育过程中发展，但不在胚胎晚期或新生儿期诱导 K-ras(G12D)表达时发展。我们表明，细胞周期调节剂在发育过程中的差异表达可能是导致这种对恶性转化的不同易感性的原因，并且 p53 的缺失可以克服在后期发育阶段观察到的转化抵抗。这些结果强调了遗传改变与伴随特定发育阶段的分子变化之间的相互作用；早期祖细胞可能缺乏在后期更具谱系限制性的发育时间点存在的调节机制，使它们更容易发生转化。
