Elsevier

Neoplasia

Volume 16, Issue 7, July 2014, Pages 543-561
Neoplasia

Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy1,2

https://doi.org/10.1016/j.neo.2014.06.003Get rights and content
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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.

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1

This article refers to supplementary materials, which are designated by Figures S1 to S7 and Movies S1 and S2 and are available online at www.neoplasia.com.

2

This work was supported by National Institutes of Health/National Institute of Neurological Disorders and Stroke grants 1RO1-NS 054193, 1RO1-NS 061107, and 1RO1-NS082311 to P.R.L. and grants 1UO1-NS052465, 1RO1-NS 057711, and 1RO1-NS074387 to M.G.C.