Quantification of antiangiogenic treatment effects on tissue heterogeneity in glioma tumour xenograft model using a combination of DCE-MRI and 3D-ultramicroscopy
This study aimed at assessing the effects of an anti-angiogenic treatment, which neutralises vascular endothelial growth factor (VEGF), on tumour heterogeneity.
Murine glioma cells have been inoculated into the right brain frontal lobe of 16 mice. Anti-VEGF antibody was administered to a first group (n = 8), while a second group (n = 8) received a placebo. Magnetic resonance acquisitions, performed at days 10, 12, 15 and 23 following the implantation, allowed the derivation of a three-dimensional features dataset characterising tumour heterogeneity. Three-dimensional ultramicroscopy and standard histochemistry analysis have been performed to verify in vivo results.
Placebo-treated mice displayed a highly-vascularised area at the tumour periphery, a monolithic necrotic core and a chaotic dense vasculature across the entire tumour. In contrast, the B20-treated group did not show any highly vascularised regions and presents a fragmented necrotic core. A significant reduction of the number of vessel segments smaller than 17 μm has been observed. There was no difference in overall tumour volume and growth rate between the two groups.
Region-specific analysis revealed that VEGF inhibition affects only: (1) highly angiogenic compartments expressing high levels of VEGF and characterised by small capillaries, and also (2) the formation and structure of necrotic regions. These effects appear to be transient and limited in time.
• VEGF inhibition affects only the highly angiogenic region and small capillaries network
• VEGF inhibition is transient in time
• Tumour volume is not affected by anti-angiogenic treatment
• VEGF inhibition also influences the architecture of necrotic regions
KeywordsTumour heterogeneity Anti-angiogenic treatment VEGF inhibition Glioma DCE-MRI
Epithelial growth factor
Fibroblast growth factor
Vascular endothelial growth factor
Mouse glioma cells 261
Vascular permeability (transfer constant)
Vascular leakage space
Murine anti-VEGF monoclonal antibody
Platelet-derived growth factor
Standard error of the mean
The scientific guarantor of this publication is Prof. Markus Rudin. The authors of this manuscript declare relationships with the following companies: F. Hoffmann-La Roche Ltd. The authors state that this work has not received any funding. One of the authors has significant statistical expertise. Approval from the institutional animal care committee was obtained. Methodology: prospective, observational/experimental, performed at two institutions.
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