Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy

Abstract

As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients.

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

“…A previous study from our lab showed that antibodies successfully cross the blood-brain barrier (BBB) and penetrate into the TME; the loss of BBB integrity associated with GBM growth may further support this process. [59][60][61][62][63] A preliminary analysis of Gr-1 antibody-treated mice showed that the efficacy of depletion lasted for approximately 4 days. Therefore, to ensure the maintenance of TK/Flt3L-induced tumor-specific T cell proliferation, we administered the antibody so that MDSCs would be eliminated from the GBM TME around the peak of the T cell response, which occurs 7 days after the administration of gene therapy.…”

Awake craniotomy versus craniotomy under general anesthesia for the surgical treatment of insular glioma: choices and outcomes

“…GA was also preferred for grade 4 gliomas, which more often present perivascularly and with adhesions to the M2 and M3 branches of the middle cerebral artery [21]. Pressure on these branches is painful for AC patients, so GA is typically used for grade 4 gliomas.…”

Mesenchymal/proangiogenic factor YKL-40 related to glioblastomas and its relationship with the subventricular zone

“…Growing evidence indicates that nuclear accumulation of HIF results in transcriptional activation of the vascular endothelial growth factor (VEGF) whose pathway is modulated by reactive oxygen species (ROS), and demonstrating VEGF downregulation following HIF1a gene deletion and that HIF1/2 determined VEGF levels [4,28,44]. Francescone et al identified that YKL-40 (CHI3L1) closely upregulates VEGF expression, and YKL-40-induced tumor vasculogenesis is at least partially dependent on VEGF [21].…”

“…Baker et al [4] studied the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. In their work, the authors explained that perivascular invasion give rise to neoangiogenesis by digesting normal brain tissue in a VEGF-independent way that leads to tumor invasion.…”