Department of Neuropathology, Hospital of the Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
Clin Cancer Res. 2011 Jul 1;17(13):4367-77. doi: 10.1158/1078-0432.CCR-10-2811. Epub 2011 May 11.
Constitutive Wnt signaling caused by mutations in the β-catenin gene is a molecular hallmark of adamantinomatous craniopharyngiomas (adaCP) and promotes infiltration into adjacent brain tissue. Herein, we studied the pathogenic role of epidermal growth factor receptor (EGFR) activation in adaCP and whether tumor cell migration can be inhibited by the tyrosine kinase inhibitor gefitinib.
EGFR expression and activation [phosphorylated EGFR (EGFR-P)] was examined in a cohort of 25 surgical adaCP samples by PCR and Western blotting. Regional and cellular localization patterns of EGFR-P, β-catenin, and its target gene product Fascin were determined by immunofluorescence microscopy. Mutation analysis and gene copy number assay were carried out to examine genetic alterations in the EGFR gene. The impact of EGFR signaling on tumor cell migration was studied in vitro by using 11 primary human adaCP cultures treated with the EGFR ligand EGF and its inhibitor gefitinib.
Neither mutations nor amplifications in the EGFR gene were detected in our adaCP series. However, EGFR-P was detectable in tumor cell clusters located at the brain infiltration border and colocalized with nuclear β-catenin and Fascin. Activated EGFR significantly promoted tumor cell migration in vitro, whereas gefitinib reduced both tumor cell motility and Fascin expression.
Our data suggest EGFR signaling to play a role in cell migration and brain infiltration of adaCP. Targeting the EGFR signaling pathway by gefitinib may present a promising pharmacologic option in the treatment of this challenging tumor disease.
β-连环蛋白基因突变导致的组成型 Wnt 信号是造釉细胞瘤型颅咽管瘤（adamantinomatous craniopharyngiomas，adaCP）的分子特征，并促进肿瘤细胞浸润至邻近脑组织。在此，我们研究了表皮生长因子受体（epidermal growth factor receptor，EGFR）激活在 adaCP 中的致病作用，以及酪氨酸激酶抑制剂吉非替尼是否可以抑制肿瘤细胞迁移。
通过 PCR 和 Western blot 检测 25 例手术 adaCP 样本中 EGFR 的表达和激活[磷酸化 EGFR（phosphorylated EGFR，EGFR-P）]。通过免疫荧光显微镜检测 EGFR-P、β-连环蛋白及其靶基因产物 Fascin 的区域和细胞定位模式。进行突变分析和基因拷贝数检测以检查 EGFR 基因的遗传改变。通过使用 11 例原发性人 adaCP 培养物，用 EGFR 配体 EGF 和其抑制剂吉非替尼处理，研究 EGFR 信号对肿瘤细胞迁移的影响。
在我们的 adaCP 系列中未检测到 EGFR 基因的突变或扩增。然而，在位于脑浸润边界的肿瘤细胞簇中可检测到 EGFR-P，并且与核内 β-连环蛋白和 Fascin 共定位。激活的 EGFR 显著促进了体外肿瘤细胞的迁移，而吉非替尼降低了肿瘤细胞的迁移能力和 Fascin 表达。
我们的数据表明 EGFR 信号在 adaCP 的细胞迁移和脑浸润中发挥作用。通过吉非替尼靶向 EGFR 信号通路可能是治疗这种具有挑战性的肿瘤疾病的有前途的药物选择。
