Study on the regulatory mechanism of vascular abnormality in glioblastoma

Abstract

Glioblastoma multiform (GBM) is the most aggressive and incurable brain tumor due to unclear pathogenesis and therapeutic mechanisms. Despite the active treatment combining surgery, chemotherapy, and radiation therapy, most of patients with GBM undergo recurrence and their median overall survival is about fifteen months. Tumor angiogenesis, a representative characteristics of GBM, has been investigated and anti-angiogenic treatment emerged as one of therapeutic strategies for GBM. Though FDA approved bevacizumab, which is known to be an anti-angiogenesis drug by blocking VEGF, for the treatment of patients with recurrent GBM, this anti-VEGF antibody failed to extend the overall survival. Therefore, new regulatory mechanisms underlying GBM vasculatures remain to be identified for better therapeutic strategy for GBM treatment.

Using somatic oncogenic mutations, we established a novel GBM mouse model with histopathological and vascular characteristics of human GBM such as tumor necrosis, microvascular proliferation, and invasion. In addition, we established tumor monitoring systems ex vivo and in vivo to evaluate drug efficacy. Employing these advanced GBM mouse models, we revealed morphological, functional, and molecular characteristics of GBM vasculature. Specifically, GBM vessels undergo dynamic remodeling consisting of tumor vasodilation and tumor vasoconstriction rather than tumor angiogenesis. Unlike previous glioma models, our new GBM models having invasion zone were useful to study the dynamic vascular changes from normal brain vessels toward tumor vessels at the tumor periphery.

We found that GBM vessels are normalized morphologically and functionally by VEGFR2 inhibition and Tie2 activation. In particular, Tie2 activation effectively inhibited vascular leakage by rescuing tight junction and inhibiting transcytosis, leading to remarkable vascular recovery. Therefore, we identified VEGFR2 and Tie2 as key players in vascular remodeling in GBM and provide a strategic insight into vascular regulation for GBM treatment instead of anti-angiogenic therapy.