P03.08 Pathological Analysis of Xenografts with Malignant Glioma After Anti-angiogenic Therapy

Introduction: Malignant gliomas are known to secrete high levels of vascular endothelial growth factor (VEGF). Bevacizumab, which is a monoclonal antibody to VEGF, has demonstrated convincing therapeutic benefits in patients with glioblastoma. However, several reports have shown that anti-VEGF therapy induced invasive proliferation. Materials and Methods: We examined the effects of bevacizumab-induced invasive changes in glioma xenografts. U87ΔEGFR and Gli36Δ5 cells were stereotactically injected into the brain of nude mice or rats. Five days after tumor cell implantation, bevacizumab was administered intraperitoneally three times a week. At 18 days after tumor implantation, the brains were removed and observed histopathologically by an immunohistochemical assay and a transmission electron microscope. We analyzed the pathological changes which were treated with bevacizumab compared to the untreated group. Results: The bevacizumab treatment led to increased tumor cell invasion in spite of decreased angiogenesis and tumor size. Both immunohistochemical staining by collagen type I and transmission electron microscopic analysis demonstrated the remarkable increase of extracellular components in contrast to the decrease of angiogenesis. Conclusions: This study showed that the anti-angiogenic treatment with bevacizumab was effective to decrease vessels and tumor mass of malignant glioma, however it changed the microenvironment, including extracellular components around malignant glioma. The elucidation of this mechanism might contribute to the treatment of bevacizumab - refractory glioma.