EGFRvIII/integrin β3 interaction in hypoxic and vitronectinenriching microenvironment promote GBM progression and metastasis
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Zhaoyu Liu1,*, Lei Han2,*, Yucui Dong1,*, Yanli Tan3,*, Yongsheng Li4, Manli Zhao1, Hui Xie1, Huanyu Ju1, He Wang1, Yu Zhao1, Qifan Zheng1, Qixue Wang2,5, Jun Su6, Chuan Fang7, Songbin Fu8, Tao Jiang9, Jiaren Liu10, Xia Li4, Chunsheng Kang2,5, Huan Ren1
1Department of Immunology, Harbin Medical University, Harbin 150081, China
2Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China
3College of Fundamental Medicine, Hebei University, Baoding 071000, China
4College of Bioinformatics, Harbin Medical University, Harbin 150081, China
5Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China
6Department of Neurosurgery, The Oncology Hospital affiliated to Harbin Medical University, Harbin 150081, China
7Department of Neurosurgery, The Hospital affiliated to Hebei University, 071000 Baoding, China
8Laboratory of Medical Genetics, Department of Biology, Harbin Medical University, 150081 Harbin, China
9Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China
10Department of Anesthesia, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA
*These authors contributed equally to this work
Huan Ren, e-mail: [email protected] and [email protected]
Chunsheng Kang, e-mail: [email protected]
Xia Li, e-mail: [email protected]
Keywords: tumor microenvironment, EGFRvIII, integrin β3, glioblastoma, cilengitide®
Received: July 12, 2015 Accepted: November 25, 2015 Published: December 22, 2015
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.
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