Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice

Abstract

Patients with recurrent malignant glioma treated with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan have had impressive reductions in MRI contrast enhancement and vasogenic edema. Responses to this regimen, as defined by a decrease in contrast enhancement, have led to significant improvements in progression-free survival rates but not in overall survival duration. Some patients for whom this treatment regimen fails have an uncharacteristic pattern of tumor progression, which can be observed radiographically as an increase in hyperintensity on T2-weighted or fluid-attenuated inverse recovery (FLAIR) MRI. To date, there have been no reports of paired correlations between radiographic results and histopathologic findings describing the features of this aggressive tumor phenotype. In this study, we correlate such findings for 3 illustrative cases of gliomas that demonstrated an apparent phenotypic shift to a predominantly infiltrative pattern of tumor progression after treatment with bevacizumab. Pathologic examination of abnormal FLAIR areas on MRI revealed infiltrative tumor with areas of thin-walled blood vessels, suggesting vascular “normalization,” which was uncharacteristically adjacent to regions of necrosis. High levels of insulin-like growth factor binding protein-2 and matrix metalloprotease-2 expression were seen within the infiltrating tumor. In an attempt to better understand this infiltrative phenotype associated with anti-VEGF therapy, we forced a highly angiogenic, noninvasive orthotopic U87 xenograft tumor to become infiltrative by treating the mice with bevacizumab. This model mimicked many of the histopathologic findings from the human cases and will augment the discovery of alternative or additive therapies to prevent this type of tumor recurrence in clinical practice.

Improved Treatment Efficacy of Antiangiogenic Therapy when Combined with Picornavirus Vaccination in the GL261 Glioma Model

“…However, histological analysis revealed a pattern of increased infiltration, with the formation of numerous satellite tumors [29]. These results were consistently reproduced in orthotopic mouse models, where xenografted human gliomas displayed inhibited tumor growth but significantly increased migration of tumor cells into the brain parenchyma and satellite tumor development [27,[30][31][32].…”

“…However, upon recurrence, tumors treated with antiangiogenic therapies display an increasingly invasive phenotype [11,17,[26][27][28]. Given this phenotypic alteration observed in human patients, tumor borders following treatment of GL261 gliomas with aflibercept were analyzed.…”

“…The GL261-Quad cell line is engineered to express the model antigens human gp100 [25][26][27][28][29][30][31][32][33] , chicken OVA 257-264 , chicken OVA [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339] , and mouse alloantigen I-Ea [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] . Female 6-8-week-old C57BL/6 mice (The Jackson Laboratory, Bar Harbor, ME, USA) were inoculated by stereotactic injection of 6.0×10 4 -1.0×10 5 GL261 or GL261-Quad cells into the right striatum.…”

“…An important caveat to the use of anti-VEGF therapy for the treatment of GBM is the frequent transition to an increasingly invasive phenotype that occurs following the development of bevacizumab resistance [26,27]. Incidence of diffuse or distant tumor progression as visualized by T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) magnetic resonance imaging (MRI) has been reported to be as high as 60 % in some patient cohorts, often in the absence of contrastenhancing lesions [17,28].…”

“…Incidence of diffuse or distant tumor progression as visualized by T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) magnetic resonance imaging (MRI) has been reported to be as high as 60 % in some patient cohorts, often in the absence of contrastenhancing lesions [17,28]. Additionally, a detailed histological analysis of nonenhancing tumor specimens exhibiting FLAIR abnormalities revealed abundant tumor cell infiltration into neuropil [27]. Studies in a variety of animal models using human GBM cell lines have recapitulated these clinical findings.…”