Department of Neurology, University of California, San Francisco, San Francisco, California.
Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany.
Cancer Res. 2018 Dec 15;78(24):6785-6794. doi: 10.1158/0008-5472.CAN-17-3551. Epub 2018 Nov 6.
: Amplification of the gene and its truncation mutant are hallmarks of glioblastoma. Although coexpression of EGFR and EGFRvIII confers a growth advantage, how EGFR and EGFRvIII influence the tumor microenvironment remains incompletely understood. Here, we show that EGFR and EGFRvIII cooperate to induce macrophage infiltration via upregulation of the chemokine CCL2. EGFRvIII was significantly enriched in glioblastoma patient samples with high CCL2, and knockout of CCL2 in tumors coexpressing EGFR and EGFRvIII led to decreased infiltration of macrophages. KRAS was a critical signaling intermediate for EGFR- and EGFRvIII-induced expression of CCL2. Our results illustrate how EGFR and EGFRvIII direct the microenvironment in glioblastoma. SIGNIFICANCE: Full-length EGFR and truncated EGFRvIII work through KRAS to upregulate the chemokine CCL2 and drive macrophage infiltration in glioblastoma.
:基因扩增及其截断突变是神经胶质瘤的特征。虽然 EGFR 和 EGFRvIII 的共表达赋予了生长优势，但 EGFR 和 EGFRvIII 如何影响肿瘤微环境仍不完全清楚。在这里，我们表明 EGFR 和 EGFRvIII 通过上调趋化因子 CCL2 合作诱导巨噬细胞浸润。CCL2 水平高的胶质母细胞瘤患者样本中 EGFRvIII 明显富集，并且在共表达 EGFR 和 EGFRvIII 的肿瘤中敲除 CCL2 导致巨噬细胞浸润减少。KRAS 是 EGFR 和 EGFRvIII 诱导 CCL2 表达的关键信号中间物。我们的结果说明了 EGFR 和 EGFRvIII 如何指导神经胶质瘤的微环境。意义：全长 EGFR 和截断的 EGFRvIII 通过 KRAS 上调趋化因子 CCL2，驱动神经胶质瘤中的巨噬细胞浸润。
