Molecular Characterization of EGFR and EGFRvIII Signaling Networks in Human Glioblastoma Tumor Xenografts
Molecular Characterization of EGFR and EGFRvIII Signaling Networks in Human Glioblastoma Tumor Xenografts
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DOI：
10.1074/mcp.m112.019984
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发表时间：
2012-12-01
影响因子：
7
通讯作者：
White, Forest M.
中科院分区：
文献类型：
--
作者：
Johnson, Hannah;Del Rosario, Amanda M.;White, Forest M.
多形性胶质母细胞瘤 (GBM) 是一种恶性原发性脑肿瘤，按照目前的护理标准，平均生存期为 15 个月。基因分析工作已经在大约 50% 的 GBM 患者中发现了野生型 (wt) 表皮生长因子受体酪氨酸激酶 (EGFR) 的扩增、过度表达和突变。 wtEGFR 的遗传畸变经常伴随着称为 EGFR 变体 III（EGFRvIII、de2-7EGFR、Delta EGFR）的突变型 EGFR 的过度表达，该突变型 EGFR 在 30% 的 GBM 肿瘤中表达。人类肿瘤中 EGFRvIII 过表达驱动的肿瘤发生的分子机制尚未完全阐明。为了确定 EGFRvIII 驱动的肿瘤的特异性治疗靶点，广泛了解 EGFRvIII 特异性信号传导非常重要。在这里，我们通过对一组胶质母细胞瘤异种移植物的蛋白质表达和酪氨酸磷酸化进行定量分析来表征信号传导，这些移植物是由表达 wtEGFR 或过表达 wtEGFR (wtEGFR+) 或 EGFRvIII (EGFRvIII+) 的患者手术标本建立的。与 wtEGFR 异种移植肿瘤相比，S100A10 (p11)、主要穹窿蛋白、鸟苷酸结合蛋白 1 (GBP1) 和碳酸酐酶 III (CAIII) 在表达 EGFRvIII 的异种移植肿瘤中的表达显着增加。研究发现，这四种蛋白的表达增加与 GBM 患者的生存率较低有关。这四种蛋白质的组合代表了神经胶质瘤生存不良的预后特征。蛋白质表达和磷酸化数据的整合揭示了各种肿瘤之间的显着异质性，并强调了在胶质母细胞瘤中激活的与 EGFR 运输相关的几种新途径。在这些肿瘤异种移植物中鉴定的途径和蛋白质代表了这种疾病的潜在治疗靶点。分子与细胞蛋白质组学 11: 10.1074/mcp.M112.019984, 1724-1740, 2012。
Glioblastoma multiforme (GBM) is a malignant primary brain tumor with a mean survival of 15 months with the current standard of care. Genetic profiling efforts have identified the amplification, overexpression, and mutation of the wild-type (wt) epidermal growth factor receptor tyrosine kinase (EGFR) in similar to 50% of GBM patients. The genetic aberration of wtEGFR is frequently accompanied by the overexpression of a mutant EGFR known as EGFR variant III (EGFRvIII, de2-7EGFR, Delta EGFR), which is expressed in 30% of GBM tumors. The molecular mechanisms of tumorigenesis driven by EGFRvIII overexpression in human tumors have not been fully elucidated. To identify specific therapeutic targets for EGFRvIII driven tumors, it is important to gather a broad understanding of EGFRvIII specific signaling. Here, we have characterized signaling through the quantitative analysis of protein expression and tyrosine phosphorylation across a panel of glioblastoma tumor xenografts established from patient surgical specimens expressing wtEGFR or overexpressing wtEGFR (wtEGFR+) or EGFRvIII (EGFRvIII+). S100A10 (p11), major vault protein, guanylate-binding protein 1(GBP1), and carbonic anhydrase III (CAIII) were identified to have significantly increased expression in EGFRvIII expressing xenograft tumors relative to wtEGFR xenograft tumors. Increased expression of these four individual proteins was found to be correlated with poor survival in patients with GBM; the combination of these four proteins represents a prognostic signature for poor survival in gliomas. Integration of protein expression and phosphorylation data has uncovered significant heterogeneity among the various tumors and has highlighted several novel pathways, related to EGFR trafficking, activated in glioblastoma. The pathways and proteins identified in these tumor xenografts represent potential therapeutic targets for this disease. Molecular & Cellular Proteomics 11: 10.1074/mcp.M112.019984, 1724-1740, 2012.