NKX2.2 Suppresses Self-Renewal of Glioma-Initiating Cells
NKX2.2 Suppresses Self-Renewal of Glioma-Initiating Cells
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DOI：
10.1158/0008-5472.can-10-2304
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Hirao, Atsushi
中科院分区：
文献类型：
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作者：
Muraguchi, Teruyuki;Tanaka, Shingo;Hirao, Atsushi
胶质母细胞瘤（GBM）是最具侵略性和破坏性的脑癌形式。为了开发合理有效的分子治疗方法，需要能够阐明其进展机制的动物模型。在这项研究中，我们报告了自发性神经胶质瘤小鼠模型的发展，这些模型代表了由定义的遗传改变控制的疾病的不同进展阶段。神经干/祖细胞（NPC）特异性的Ras组成性激活加上p53缺陷导致主要间变性星形细胞瘤（III级）的发展，而p53加上p16（Ink 4a）/p19（Arf）的联合缺失导致6周内100%无突变的GBM（IV级）的发展。这些胶质瘤模型显示出增强的干细胞特性（干性）伴随恶性进展。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，这是少突胶质细胞分化所必需的，与肿瘤恶性程度的增加。GBM源性胶质瘤起始细胞（GIC）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，小鼠NPC中Nkx2.2的下调加速了GBM的形成。重要的是，NXK2.2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病理生物学上的显著优势，并为开发新的基于机制的治疗方法提供了更好的机会。Cancer Res; 71（3）; 1135-45. (C)2010年AACR。
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. Cancer Res; 71(3); 1135-45. (C) 2010 AACR.