Oncotarget

Research Papers:

EGFRvIII/integrin β3 interaction in hypoxic and vitronectinenriching microenvironment promote GBM progression and metastasis

Zhaoyu Liu, Lei Han, Yucui Dong, Yanli Tan, Yongsheng Li, Manli Zhao, Hui Xie, Huanyu Ju, He Wang, Yu Zhao, Qifan Zheng, Qixue Wang, Jun Su, Chuan Fang, Songbin Fu, Tao Jiang, Jiaren Liu, Xia Li, Chunsheng Kang and Huan Ren _

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Oncotarget. 2016; 7:4680-4694. https://doi.org/10.18632/oncotarget.6730

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Abstract

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

Correspondence to:

Huan Ren, e-mail: huanren2009@126.com and renhuan@ems.hrbmu.edu.cn

Chunsheng Kang, e-mail: kang97061@163.com

Xia Li, e-mail: lixia@hrbmu.edu.cn

Keywords: tumor microenvironment, EGFRvIII, integrin β3, glioblastoma, cilengitide®

Received: July 12, 2015     Accepted: November 25, 2015     Published: December 22, 2015

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.


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