Bachoo Robert M, Maher Elizabeth A, Ligon Keith L, Sharpless Norman E, Chan Suzanne S, You Mingjian James, Tang Yi, DeFrances Jessica, Stover Elizabeth, Weissleder Ralph, Rowitch David H, Louis David N, DePinho Ronald A
Center for Neuro-Oncology, Boston, Massachusetts 02115, USA.
Cancer Cell. 2002 Apr;1(3):269-77. doi: 10.1016/s1535-6108(02)00046-6.
Ink4a/Arf inactivation and epidermal growth factor receptor (EGFR) activation are signature lesions in high-grade gliomas. How these mutations mediate the biological features of these tumors is poorly understood. Here, we demonstrate that combined loss of p16(INK4a) and p19(ARF), but not of p53, p16(INK4a), or p19(ARF), enables astrocyte dedifferentiation in response to EGFR activation. Moreover, transduction of Ink4a/Arf(-/-) neural stem cells (NSCs) or astrocytes with constitutively active EGFR induces a common high-grade glioma phenotype. These findings identify NSCs and astrocytes as equally permissive compartments for gliomagenesis and provide evidence that p16(INK4a) and p19(ARF) synergize to maintain terminal astrocyte differentiation. These data support the view that dysregulation of specific genetic pathways, rather than cell-of-origin, dictates the emergence and phenotype of high-grade gliomas.
Ink4a/Arf基因失活和表皮生长因子受体（EGFR）激活是高级别胶质瘤的标志性病变。这些突变如何介导这些肿瘤的生物学特性目前尚不清楚。在此，我们证明p16（INK4a）和p19（ARF）的联合缺失，而非p53、p16（INK4a）或p19（ARF）的单独缺失，可使星形胶质细胞在EGFR激活时发生去分化。此外，用组成型活性EGFR转导Ink4a/Arf（-/-）神经干细胞（NSCs）或星形胶质细胞可诱导出常见的高级别胶质瘤表型。这些发现确定神经干细胞和星形胶质细胞是胶质瘤发生的同等许可性细胞区室，并提供证据表明p16（INK4a）和p19（ARF）协同作用以维持星形胶质细胞的终末分化。这些数据支持这样一种观点，即特定遗传途径的失调而非细胞起源决定了高级别胶质瘤的发生和表型。
