Liu Zhaoyu, Han Lei, Dong Yucui, Tan Yanli, Li Yongsheng, Zhao Manli, Xie Hui, Ju Huanyu, Wang He, Zhao Yu, Zheng Qifan, Wang Qixue, Su Jun, Fang Chuan, Fu Songbin, Jiang Tao, Liu Jiaren, Li Xia, Kang Chunsheng, Ren Huan
Department of Immunology, Harbin Medical University, Harbin 150081, China.
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
Oncotarget. 2016 Jan 26;7(4):4680-94. doi: 10.18632/oncotarget.6730.
Glioblastoma (GBM) is one of the most lethal brain tumors with a short survival time. EGFR amplification and mutation is the most significant genetic signature in GBM. About half of the GBMs with EGFR amplification express a constitutively autophosphorylated variant of EGFR, known as EGFRvIII. Our in vitro data demonstrated further enhanced EGFRvIII activity and tumor cell invasion in the tumor microenvironment of hypoxia plus extracellular matrix (ECM) vitronectin, in which EGFRvIII and integrin β3 tended to form complexes. The treatment with ITGB3 siRNA or the integrin antagonist cilengetide preferentially interrupted the EGFRvIII/integrin β3 complex, effectively reduced tumor cell invasion and activation of downstream signaling effectors. Cilengitide is recently failed in Phase III CENTRIC trial in unselected patients with GBM. However, we found that cilengitide demonstrated efficacious tumor regression via inhibition of tumor growth and angiogenesis in EGFRvIII orthotopic xenografts. Bioinformatics analysis emphasized key roles of integrin β3, hypoxia and vitronectin and their strong correlations with EGFRvIII expression in malignant glioma patient samples in vivo. In conclusion, we demonstrate that EGFRvIII/integrin β3 complexes promote GBM progression and metastasis in the environment of hypoxia and vitronectin-enrichment, and cilengitide may serve as a promising therapeutics for EGFRvIII-positive GBMs.
胶质母细胞瘤（GBM）是最致命的脑肿瘤之一，生存时间短。表皮生长因子受体（EGFR）扩增和突变是GBM中最显著的基因特征。约一半具有EGFR扩增的GBM表达一种组成型自磷酸化的EGFR变体，称为EGFRvIII。我们的体外数据表明，在缺氧加细胞外基质（ECM）玻连蛋白的肿瘤微环境中，EGFRvIII活性和肿瘤细胞侵袭进一步增强，其中EGFRvIII和整合素β3倾向于形成复合物。用整合素β3小干扰RNA（siRNA）或整合素拮抗剂西仑吉肽治疗优先中断EGFRvIII/整合素β3复合物，有效降低肿瘤细胞侵袭和下游信号效应器的激活。西仑吉肽最近在未选择的GBM患者的III期CENTRIC试验中失败。然而，我们发现西仑吉肽在EGFRvIII原位异种移植中通过抑制肿瘤生长和血管生成表现出有效的肿瘤消退。生物信息学分析强调了整合素β3、缺氧和玻连蛋白的关键作用以及它们与体内恶性胶质瘤患者样本中EGFRvIII表达的强相关性。总之，我们证明EGFRvIII/整合素β3复合物在缺氧和玻连蛋白富集的环境中促进GBM进展和转移，西仑吉肽可能是EGFRvIII阳性GBM的一种有前景的治疗方法。
