Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis
Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis
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DOI：
10.1073/pnas.0813314106
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发表时间：
2009-02-24
影响因子：
11.1
通讯作者：
Charesta, Al
中科院分区：
文献类型：
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作者：
Zhu, Haihao;Acquaviva, Jaime;Charesta, Al
多形性胶质母细胞瘤(GBM)是一种高度致命的脑瘤，几乎没有治疗方法。表皮生长因子受体(EGFR)信号通路被认为在GBM的发病机制中起着至关重要的作用，它启动了肿瘤的早期发展，维持了肿瘤的生长，促进了肿瘤的侵袭，并介导了对治疗的抵抗。在超过50%的GBM肿瘤中，EGFR被突变激活，这一事实突显了这一途径的重要性。与此一致，我们在这里表明，成年小鼠中枢神经系统中野生型和/或突变型()表皮生长因子受体的激活，以及INK4A/ARF和PTEN抑癌基因功能的去除，产生了一种完全穿透性的、快速发病的高级别恶性胶质瘤表型，其病理和分子特征与人类胶质瘤显著相似。对这些GBM肿瘤细胞中信号事件激活的研究表明，野生型和VIII型EGFR表达细胞之间存在显著差异。我们发现野生型EGF受体通过其典型的途径传递信号，而由突变的EGFRvIII表达产生的肿瘤不使用这些相同的途径。我们的发现为突变的EGFR信号功能在GBM肿瘤生物学中的作用提供了重要的见解，并为在本文描述的临床前模型中测试靶向治疗药物奠定了基础。
Glioblastoma multiforme (GBM) is a highly lethal brain tumor for which little treatment is available. The epidermal growth factor receptor (EGFR) signaling pathway is thought to play a crucial role in GBM pathogenesis, initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. The importance of this pathway is highlighted in the fact that EGFR is mutationally activated in over 50% of GBM tumors. Consistent with this, we show here that concomitant activation of wild-type and/or mutant (vIII) EGFR and ablation of Ink4A/Arf and PTEN tumor suppressor gene function in the adult mouse central nervous system generates a fully penetrant, rapid-onset high-grade malignant glioma phenotype with prominent pathological and molecular resemblance to GBM in humans. Studies of the activation of signaling events in these GBM tumor cells revealed notable differences between wild-type and vIII EGFR-expressing cells. We show that wild-type EGF receptor signals through its canonical pathways, whereas tumors arising from expression of mutant EGFRvIII do not use these same pathways. Our findings provide critical insights into the role of mutant EGFR signaling function in GBM tumor biology and set the stage for testing of targeted therapeutic agents in the preclinical models described herein.