Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
Cancer Res. 2011 Feb 1;71(3):1135-45. doi: 10.1158/0008-5472.CAN-10-2304. Epub 2010 Dec 17.
Glioblastoma (GBM) is the most aggressive and destructive form of brain cancer. Animal models that can unravel the mechanisms underlying its progression are needed to develop rational and effective molecular therapeutic approaches. In this study, we report the development of mouse models for spontaneous gliomas representing distinct progressive stages of disease that are governed by defined genetic alterations. Neural stem/progenitor cell (NPC)-specific constitutive Ras activation in vivo plus p53 deficiency led to development of primarily anaplastic astrocytoma (grade III), whereas combined loss of p53 plus p16(Ink4a)/p19(Arf) led to development of GBM (grade IV) at 100% penetrance within 6 weeks. These glioma models showed enhanced stem cell properties (stemness) accompanied by malignant progression. Notably, we determined that, in our models and in human specimens, downregulation of the homeodomain transcription factor NKX2.2, which is essential for oligodendroglial differentiation, was correlated with increased tumor malignancy. NKX2.2 overexpression by GBM-derived glioma-initiating cells (GIC) induced oligodendroglial differentiation and suppressed self-renewal capacity. By contrast, Nkx2.2 downregulation in mouse NPCs accelerated GBM formation. Importantly, the inhibitory effects of NXK2.2 on GIC self-renewal were conserved in human cells. Thus, our mouse models offer pathobiologically significant advantages to investigate the nature of brain tumors, with improved opportunities to develop novel mechanism-based therapeutic approaches.
胶质母细胞瘤（GBM）是最具侵袭性和破坏性的脑癌。为了开发合理有效的分子治疗方法，需要开发能够揭示其进展背后机制的动物模型。在这项研究中，我们报告了自发胶质瘤小鼠模型的开发，这些模型代表了疾病不同的进展阶段，这些阶段由明确的遗传改变控制。体内神经干细胞/祖细胞（NPC）特异性组成型 Ras 激活加上 p53 缺失导致主要是间变性星形细胞瘤（III 级）的发展，而 p53 缺失加上 p16（Ink4a）/p19（Arf）缺失导致 100%穿透性的 GBM（IV 级）在 6 周内发展。这些神经胶质瘤模型显示出增强的干细胞特性（干性）伴随着恶性进展。值得注意的是，我们确定，在我们的模型和人类标本中，同源域转录因子 NKX2.2 的下调与肿瘤恶性程度的增加有关，NKX2.2 对于少突胶质细胞分化是必需的。GBM 源性神经胶质瘤起始细胞（GIC）中的 NKX2.2 过表达诱导少突胶质细胞分化并抑制自我更新能力。相比之下，在小鼠 NPC 中下调 Nkx2.2 加速了 GBM 的形成。重要的是，NKX2.2 对 GIC 自我更新的抑制作用在人类细胞中是保守的。因此，我们的小鼠模型为研究脑肿瘤的性质提供了具有重要病理生物学意义的优势，并为开发新的基于机制的治疗方法提供了更好的机会。
