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European Radiology

, Volume 27, Issue 7, pp 2894–2902 | Cite as

Quantification of antiangiogenic treatment effects on tissue heterogeneity in glioma tumour xenograft model using a combination of DCE-MRI and 3D-ultramicroscopy

  • Marco Dominietto
  • Michael Dobosz
  • Sandra Bürgi
  • Anja Renner
  • Gudrun Zahlmann
  • Werner Scheuer
  • Markus Rudin
Oncology

Abstract

Objectives

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.

Key Points

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

Keywords

Tumour heterogeneity Anti-angiogenic treatment VEGF inhibition Glioma DCE-MRI 

Abbreviations

EGF

Epithelial growth factor

FGF

Fibroblast growth factor

VEGF

Vascular endothelial growth factor

GL261

Mouse glioma cells 261

Ktrans

Vascular permeability (transfer constant)

Ve

Vascular leakage space

Λ(r)

Lacunarity

B20

Murine anti-VEGF monoclonal antibody

PDGF

Platelet-derived growth factor

SEM

Standard error of the mean

Notes

Acknowledgments

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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Copyright information

© European Society of Radiology 2016

Authors and Affiliations

  1. 1.Institute for Biomedical EngineeringUniversity and ETH ZurichZurichSwitzerland
  2. 2.Biomaterials Science CenterUniversity of BaselAllschwilSwitzerland
  3. 3.Discovery Oncology, Pharmaceutical Research and Early Development (pRED)Roche Innovation Center PenzbergPenzbergGermany
  4. 4.pRED, Oncology DTA, Innovation Center Basel, F. Hoffmann-La Roche LtdBaselSwitzerland

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