Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
Oncogene. 2013 May 23;32(21):2670-81. doi: 10.1038/onc.2012.280. Epub 2012 Jul 16.
Amplification and rearrangements of the epidermal growth factor receptor (EGFR) gene are frequently found in glioblastoma multiforme (GBM). The most common variant is EGFR variant III (EGFRvIII). Research suggests that EGFRvIII could be a marker for a cancer stem cell or tumor-initiating population. If amplification and rearrangement are early events in tumorigenesis, this implies that they should be preserved throughout the tumor. However, in primary GBM, EGFRvIII expression is focal and sporadic. Unexpectedly, we found EGFR amplification and rearrangement throughout the tumor, including regions with no EGFRvIII expression, suggesting that mechanisms exist to modulate EGFRvIII expression even in the presence of high gene amplification. To study this phenomenon, we characterized three GBM cell lines with endogenous EGFRvIII. EGFRvIII expression was heterogeneous, with both positive and negative populations maintaining the genetic alterations, akin to primary tumors. Furthermore, EGFRvIII defined a hierarchy where EGFRvIII-positive cells gave rise to additional positive and negative cells. Only cells that had recently lost EGFRvIII expression could re-express EGFRvIII, providing an important buffer for maintaining EGFRvIII-positive cell numbers. Epigenetic mechanisms had a role in maintaining heterogeneous EGFRvIII expression. Demethylation induced a 20-60% increase in the percentage of EGFRvIII-positive cells, indicating that some cells could re-express EGFRvIII. Surprisingly, inhibition of histone deacetylation resulted in a 50-80% reduction in EGFRvIII expression. Collectively, this data demonstrates that EGFR amplification and rearrangement are early events in tumorigenesis and EGFRvIII follows a model of hierarchical expression. Furthermore, EGFRvIII expression is restricted by epigenetic mechanisms, suggesting that drugs that modulate the epigenome might be used successfully in glioblastoma tumors.
表皮生长因子受体 (EGFR) 基因的扩增和重排在多形性胶质母细胞瘤 (GBM) 中经常发生。最常见的变体是 EGFR 变体 III (EGFRvIII)。研究表明，EGFRvIII 可能是癌症干细胞或肿瘤起始细胞群体的标志物。如果扩增和重排是肿瘤发生的早期事件，这意味着它们应该在整个肿瘤中得到保留。然而，在原发性 GBM 中，EGFRvIII 的表达是局灶性和散发性的。出乎意料的是，我们发现 EGFR 扩增和重排在整个肿瘤中都存在，包括没有 EGFRvIII 表达的区域，这表明即使存在高基因扩增，也存在调节 EGFRvIII 表达的机制。为了研究这一现象，我们对三种具有内源性 EGFRvIII 的 GBM 细胞系进行了特征描述。EGFRvIII 的表达具有异质性，阳性和阴性群体都维持着遗传改变，类似于原发性肿瘤。此外，EGFRvIII 定义了一个层次结构，其中 EGFRvIII 阳性细胞产生额外的阳性和阴性细胞。只有最近失去 EGFRvIII 表达的细胞才能重新表达 EGFRvIII，为维持 EGFRvIII 阳性细胞数量提供了重要的缓冲。表观遗传机制在维持 EGFRvIII 异质性表达中发挥作用。去甲基化诱导 EGFRvIII 阳性细胞的百分比增加 20-60%，表明一些细胞可以重新表达 EGFRvIII。令人惊讶的是，组蛋白去乙酰化抑制剂导致 EGFRvIII 表达减少 50-80%。总的来说，这些数据表明 EGFR 扩增和重排是肿瘤发生的早期事件，EGFRvIII 遵循分层表达的模型。此外，EGFRvIII 的表达受到表观遗传机制的限制，这表明调节表观基因组的药物可能在胶质母细胞瘤肿瘤中成功使用。
