Quantification of antiangiogenic treatment effects on tissue heterogeneity in glioma tumour xenograft model using a combination of DCE-MRI and 3D-ultramicroscopy.
OBJECTIVE
This study aimed at assessing the effects of an anti-angiogenic treatment, which neutralises vascular endothelial growth factor (VEGF), on tumour heterogeneity.


METHODS
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.


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.


CONCLUSIONS
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.


CONCLUSIONS
• 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.
Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland. marcodiego.dominietto@unibas.ch.|Biomaterials Science Center, University of Basel, Allschwil, Switzerland. marcodiego.dominietto@unibas.ch.
Marco
http://orcid.org/0000-0002-6926-2629
M
Dominietto
Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Penzberg, Nonnenwald 2, 82377, Penzberg, Germany.
Michael
M
Dobosz
Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland.
Sandra
S
Bürgi
Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Penzberg, Nonnenwald 2, 82377, Penzberg, Germany.
Anja
A
Renner
pRED, Oncology DTA, Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Gudrun
G
Zahlmann
Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Penzberg, Nonnenwald 2, 82377, Penzberg, Germany.
Werner
W
Scheuer
Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland.
Markus
M
Rudin
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D005625:Frontal Lobe; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008853:Microscopy / Q000379:methods*; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A
Anti-angiogenic treatment; DCE-MRI; Glioma; Tumour heterogeneity; VEGF inhibition