Epidermal growth factor receptor and Ink4a/Arf:: Convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis

被引：515

作者：

Bachoo, RM

Maher, EA

Ligon, KL

Sharpless, NE

Chan, SS

You, MJJ

Tang, Y

DeFrances, J

Stover, E

Weissleder, R

Rowitch, DH

Louis, DN

DePinho, RA

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol,Div Neuropathol, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Ctr Mol Imaging Res, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

来源：

CANCER CELL | 2002年 / 1卷 / 03期

关键词：

D O I：

10.1016/S1535-6108(02)00046-6

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：269 / 277

页数：9

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