Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma.
Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma.
复制标题
DOI：
10.18632/oncotarget.2910
复制
发表时间：
2015-10-13
期刊：
影响因子：
--
通讯作者：
Weiler M
中科院分区：
文献类型：
--
作者：
Kessler T;Sahm F;Blaes J;Osswald M;Rübmann P;Milford D;Urban S;Jestaedt L;Heiland S;Bendszus M;Hertenstein A;Pfenning PN;Ruiz de Almodóvar C;Wick A;Winkler F;von Deimling A;Platten M;Wick W;Weiler M
10号染色体上缺失的肿瘤抑制磷酸酶和张力蛋白同源物（PTEN）的缺失是胶质母细胞瘤中肿瘤细胞特异性表达血管内皮生长因子受体（VEGFR）-2的先决条件，胶质母细胞瘤定义了一个容易对抗血管生成治疗产生逃避抵抗的亚组。对人类肿瘤组织的免疫组织化学分析显示，19% 的检查标本中神经胶质瘤细胞表达 VEGFR-2，主要分布在浸润区。神经胶质瘤细胞 VEGFR-2 阳性仅限于 PTEN 缺陷的肿瘤标本。 PTEN 过表达会降低体外 VEGFR-2 表达，并敲低 raptor 或 rictor。对 VEGFR-2 的遗传干扰揭示了神经胶质瘤细胞中 VEGFR-2 的增殖、抗侵袭和化学保护功能。 VEGFR-2 依赖性细胞效应伴随着活化 B 细胞的“κ 轻链增强子”、蛋白激酶 B 和 N-myc 下游调节基因 1 的激活。双光子体内显微镜显示，神经胶质瘤细胞中 VEGFR-2 的表达阻碍了抗血管生成。贝伐单抗在 VEGFR-2 阳性神经胶质瘤细胞中诱导促侵袭反应。与 PTEN 阳性胶质母细胞瘤患者相比，PTEN 阴性胶质母细胞瘤患者在开始贝伐珠单抗治疗后生存期较短。总之，神经胶质瘤细胞中 VEGFR-2 的表达表明侵袭性胶质母细胞瘤亚群对替莫唑胺或贝伐珠单抗产生早期耐药性。 PTEN 的缺失可以作为通过常规神经病理学方法预先识别这些肿瘤的生物标志物。
Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer’ of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.