Neuro-Oncology Branch, National Cancer Institute, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Cancer Res. 2012 Nov 15;72(22):6065-75. doi: 10.1158/0008-5472.CAN-12-2594. Epub 2012 Sep 17.
Glioblastoma multiforme is the most common type of primary malignant brain tumor and may arise from a cell with neural stem-like properties. Deregulation of the retinoblastoma, phosphoinositide-3 kinase (PI3K), and p53 pathways are molecular hallmarks of this disease. Recent work has shown that p53(-/-)Pten(-/-) mice form gliomas in a c-Myc-dependent manner. To explore the role of the INK4A/ARF locus and Pten deletions in gliomagenesis, we generated Pten(-/-)Ink4a/Arf(-/-) mouse neural stem cells (mNSC) and such cells were highly proliferative, self-renewing, relatively refractory to differentiation, and induced both low- and high-grade glioma formation in vivo. In contrast to p53(-/-) Pten(-/-) mNSCs, however, Pten(-/-)Ink4a/Arf(-/-) mNSCs do not express appreciable levels of c-Myc in vitro, although glioma stem cells derived from thesecells did. Sequencing of Pten(-/-)Ink4a/Arf(-/-) mNSC-derived tumors revealed spontaneous mutations in Tp53 in vivo with subsequent downregulation of Fbxw7. Expression of p53 mutants in Pten(-/-)Ink4a/Arf(-/-) mNSC or knockdown of Fbxw7 resulted in reexpression of c-Myc with enhanced Pten(-/-)Ink4a/Arf(-/-) mNSC tumorigenecity. We propose that p53 mutations contribute to gliomagenesis by both allowing the overexpression of c-Myc through downregulation of Fbxw7 and by protecting against c-Myc-induced apoptosis.
多形性胶质母细胞瘤是最常见的原发性恶性脑肿瘤，可能起源于具有神经干细胞样特性的细胞。视网膜母细胞瘤、磷酸肌醇-3 激酶 (PI3K) 和 p53 途径的失调是这种疾病的分子标志。最近的研究表明，p53(-/-)Pten(-/-) 小鼠以 c-Myc 依赖性方式形成神经胶质瘤。为了探索 INK4A/ARF 基因座和 Pten 缺失在神经胶质瘤发生中的作用，我们生成了 Pten(-/-)Ink4a/Arf(-/-) 小鼠神经干细胞 (mNSC)，这些细胞具有高度增殖、自我更新、相对不易分化的特点，并在体内诱导低级别和高级别神经胶质瘤的形成。然而，与 p53(-/-)Pten(-/-) mNSC 不同的是，Pten(-/-)Ink4a/Arf(-/-) mNSC 在体外并不表达可观水平的 c-Myc，尽管从这些细胞衍生的神经胶质瘤干细胞确实表达 c-Myc。对 Pten(-/-)Ink4a/Arf(-/-) mNSC 衍生肿瘤的测序显示，体内 Tp53 自发突变，随后 Fbxw7 下调。在 Pten(-/-)Ink4a/Arf(-/-) mNSC 中表达 p53 突变体或敲低 Fbxw7 导致 c-Myc 的重新表达，并增强了 Pten(-/-)Ink4a/Arf(-/-) mNSC 的致瘤性。我们提出，p53 突变通过下调 Fbxw7 允许 c-Myc 的过表达，并通过保护免受 c-Myc 诱导的细胞凋亡，从而促进神经胶质瘤的发生。
