Integrin Inhibitor Suppresses Bevacizumab-Induced Glioma Invasion

Abstract

Glioblastoma is known to secrete high levels of vascular endothelial growth factor (VEGF), and clinical studies with bevacizumab, a monoclonal antibody to VEGF, have demonstrated convincing therapeutic benefits in glioblastoma patients. However, its induction of invasive proliferation has also been reported. We examined the effects of treatment with cilengitide, an integrin inhibitor, on bevacizumab-induced invasive changes in glioma. U87ΔEGFR cells were stereotactically injected into the brain of nude mice or rats. Five days after tumor implantation, cilengitide and bevacizumab were administered intraperitoneally three times a week. At 18 days after tumor implantation, the brains were removed and observed histopathologically. Next, the bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis. Bevacizumab treatment led to increased cell invasion in spite of decreased angiogenesis. When the rats were treated with a combination of bevacizumab and cilengitide, the depth of tumor invasion was significantly less than with only bevacizumab. Pathway analysis demonstrated the inhibition of invasion-associated genes such as the integrin-mediated cell adhesion pathway in the combination group. This study showed that the combination of bevacizumab with cilengitide exerted its anti-invasive effect. The elucidation of this mechanism might contribute to the treatment of bevacizumab-refractory glioma.

Periostin (POSTN) Regulates Tumor Resistance to Antiangiogenic Therapy in Glioma Models

“…Ishida et al (44) reported that an antagonist of integrin αvβ3 and integrin αvβ5 prevented bevacizumab-induced invasion in orthotopic glioma models that express these integrins at high levels. We found that GSC11 cells expressed the POSTN receptors integrin β1 and integrin β3 and that GSC272 cells expressed integrin β1 more highly than integrin β3.…”

Anti-high mobility group box-1 (HMGB1) antibody attenuates delayed cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats

“…Quantitative reverse transcription-polymerase chain reaction (quantitative RT-PCR) was performed as described previously2047. The expression of GAPDH was used to normalize the amount of cDNA.…”

Evaluation of extracellular matrix protein CCN1 as a prognostic factor for glioblastoma

“…CCN1 is known to interact with integrins, such as avb3, a6b1, avb5, and aIIb3, which leads to a variety of biological activities, including cell adhesion, migration, and invasion [10] [39]. We have previously shown that the inhibition of these integrins contributed to anti-glioma effects such as in combination with anti-VEGF therapy and viral therapy [40][41][42]. Recently, integrin avb3/5 inhibitors, such as cilengitide [cyclic RGD peptide (cRGD)], have been focused on the treatment of glioma.…”