title: EGFRvIII/integrin β3 interaction in hypoxic and vitronectinenriching microenvironment promote GBM progression and metastasis.
abstract: 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.
authors.affiliation: Department of Immunology, Harbin Medical University, Harbin 150081, China.
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Immunology, Harbin Medical University, Harbin 150081, China.
authors.forename: Yucui
authors.initials: Y
authors.lastname: Dong
authors.affiliation: College of Fundamental Medicine, Hebei University, Baoding 071000, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Tan
authors.affiliation: College of Bioinformatics, Harbin Medical University, Harbin 150081, China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, Harbin Medical University, Harbin 150081, China.
authors.forename: Manli
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Harbin Medical University, Harbin 150081, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Immunology, Harbin Medical University, Harbin 150081, China.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Ju
authors.affiliation: Department of Immunology, Harbin Medical University, Harbin 150081, China.
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Immunology, Harbin Medical University, Harbin 150081, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Harbin Medical University, Harbin 150081, China.
authors.forename: Qifan
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China.|Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China.
authors.forename: Qixue
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The Oncology Hospital affiliated to Harbin Medical University, Harbin 150081, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Neurosurgery, The Hospital affiliated to Hebei University, 071000 Baoding, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Fang
authors.affiliation: Laboratory of Medical Genetics, Department of Biology, Harbin Medical University, 150081 Harbin, China.
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Anesthesia, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Jiaren
authors.initials: J
authors.lastname: Liu
authors.affiliation: College of Bioinformatics, Harbin Medical University, Harbin 150081, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China.|Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, China.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Kang
authors.affiliation: Department of Immunology, Harbin Medical University, Harbin 150081, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Ren
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D019096:Vitronectin / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C061248:ITGB3 protein, human; D039661:Integrin beta3; D012333:RNA, Messenger; D019096:Vitronectin; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors
keywords: EGFRvIII; cilengitide®; glioblastoma; integrin β3; tumor microenvironment