Brain Tumor Center, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Clin Cancer Res. 2013 Aug 15;19(16):4392-403. doi: 10.1158/1078-0432.CCR-12-1557. Epub 2013 Jun 26.
Antiangiogenic therapy reduces vascular permeability and delays progression but may ultimately promote an aggressive treatment-resistant phenotype. The aim of the present study was to identify mechanisms responsible for glioblastoma resistance to antiangiogenic therapy.
Glioma stem cell (GSC) NSC11 and U87 cell lines with acquired resistance to bevacizumab were developed from orthotopic xenografts in nude mice treated with bevacizumab. Genome-wide analyses were used to identify changes in tumor subtype and specific factors associated with resistance.
Mice with established parental NSC11 and U87 cells responded to bevacizumab, whereas glioma cell lines derived at the time of acquired resistance to anti-VEGF therapy were resistant to bevacizumab and did not have prolongation of survival compared with untreated controls. Gene expression profiling comparing anti-VEGF therapy-resistant cell lines to untreated controls showed an increase in genes associated with a mesenchymal origin, cellular migration/invasion, and inflammation. Gene-set enrichment analysis showed that bevacizumab-treated tumors showed a highly significant correlation to published mesenchymal gene signatures. Mice bearing resistant tumors showed significantly greater infiltration of myeloid cells in NSC11- and U87-resistant tumors. Invasion-related genes were also upregulated in both NSC11 and U87 resistant cells which had higher invasion rates in vitro compared with their respective parental cell lines.
Our studies identify multiple proinflammatory factors associated with resistance and identify a proneural to mesenchymal transition in tumors resistant to antiangiogenic therapy.
抗血管生成治疗可降低血管通透性并延迟进展，但最终可能会促进侵袭性和耐药的表型。本研究旨在确定胶质母细胞瘤对抗血管生成治疗产生耐药性的机制。
从接受贝伐单抗治疗的裸鼠原位移植瘤中开发出对贝伐单抗具有获得性耐药的神经胶质瘤干细胞（GSC）NSC11 和 U87 细胞系。使用全基因组分析来鉴定肿瘤亚型和与耐药性相关的特定因素的变化。
具有已建立的亲本 NSC11 和 U87 细胞的小鼠对贝伐单抗有反应，而在获得抗 VEGF 治疗耐药时衍生的胶质瘤细胞系对贝伐单抗耐药，与未治疗的对照组相比，生存时间没有延长。将抗 VEGF 治疗耐药细胞系与未治疗的对照组进行基因表达谱比较显示，与间充质起源、细胞迁移/侵袭和炎症相关的基因增加。基因集富集分析显示，贝伐单抗治疗的肿瘤与已发表的间充质基因特征具有高度显著的相关性。携带耐药肿瘤的小鼠在 NSC11 和 U87 耐药肿瘤中的髓样细胞浸润明显增加。在 NSC11 和 U87 耐药细胞中，与侵袭相关的基因也上调，其体外侵袭率均高于各自的亲本细胞系。
我们的研究确定了与耐药相关的多种促炎因子，并确定了对抗血管生成治疗耐药的肿瘤中神经前体细胞向间充质转化。
