Weiss William A, Burns Michael J, Hackett Christopher, Aldape Ken, Hill John R, Kuriyama Hiroko, Kuriyama Nagato, Milshteyn Nadezhda, Roberts Tim, Wendland Michael F, DePinho Ron, Israel Mark A
Department of Neurology, University of California, San Francisco, California 94143-0663, USA.
Cancer Res. 2003 Apr 1;63(7):1589-95.
Oligodendrogliomas of all grades overexpress epidermal growth factor receptor (EGFR), whereas deletion of ink4a/arf is found only in high-grade tumors. We used the S100 beta promoter to generate transgenic mice expressing v-erbB, a transforming allele of EGFR. These mice developed low-grade oligodendroglioma. Transgenic animals heterozygous for ink4a/arf or p53 developed high-grade tumors. Comparative genomic hybridization revealed loss of distal mouse chromosome 4, a region orthologous with human chromosome 1p, which is commonly lost in oligodendroglioma. Our results demonstrate that overexpression of EGFR, an epigenetic observation of uncertain significance in human oligodendroglioma, can initiate oligodendroglioma in the mouse. Furthermore, p53 pathway mutations can mediate the transition from low to high grade. These models hold promise for studying tumor lineage, identifying contributing genetic alterations and evaluating preclinical therapies in this important neoplasm.
所有级别的少突胶质细胞瘤均过度表达表皮生长因子受体（EGFR），而仅在高级别肿瘤中发现ink4a/arf缺失。我们使用S100β启动子来生成表达v-erbB（EGFR的一个转化等位基因）的转基因小鼠。这些小鼠发生了低级别少突胶质细胞瘤。ink4a/arf或p53杂合的转基因动物发生了高级别肿瘤。比较基因组杂交显示小鼠4号远端染色体缺失，该区域与人类1号染色体同源，在少突胶质细胞瘤中通常会缺失。我们的结果表明，EGFR的过度表达（这一在人类少突胶质细胞瘤中意义不确定的表观遗传学观察结果）可在小鼠中引发少突胶质细胞瘤。此外，p53通路突变可介导从低级别到高级别的转变。这些模型有望用于研究肿瘤谱系、确定相关的基因改变以及评估这种重要肿瘤的临床前治疗。
