Abstract
Malignant glioma cells associate with various microanatomical brain structures such as blood vessels, white matter tracts, and brain parenchyma as they spread throughout the brain. However, how these distinct brain tumor invasion patterns coordinate tumor growth and influence clinical outcomes remains unknown. We have investigated how perivascular growth affects glioma growth patterning and response to anti-angiogenic therapy within the highly vascularized brain. We show that orthotopically implanted rodent and human malignant glioma cells, as well as de-novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma, and peripheral cancer metastasis to the human brain each use brain perivascular space as a means for tissue invasion. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual gliomas cells use perivascular space as a conduit for tumor invasion. We generated an agent-based computational model, which recapitulated biologically observed perivascular glioma growth without the need for neoangiogenesis. This in-silico result prompted us to test whether neoangiogenesis is indeed required for tumor progression in perivascularly invading glioma by treating tumor-bearing 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 implanted orthotopically with gliomas from mouse or human origin, or mice subjected to sleeping-beauty generated endogenous gliomas; in all models tested anti-angiogenics exacerbated brain tumor invasion. Our results provide compelling experimental evidence for the recently described failure of clinically used anti-angiogenics to extend the survival of human glioma patients. Given that anti-angiogenics may be beneficial in some patients suffering from certain genetically identifiable glioma subtypes, whether there are mouse or human glioma cells whose growth in-vitro can be reduced by anti-angiogenic approaches remains to be determined.
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