© Copyright 2009 by the Society for Neuro-Oncology
Received February 25, 2008
Accepted December 5, 2008
Basic and Translational Investigations
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MRI assessment of hemodynamic effects of an angiopoietin-2 overexpression on a brain
tumor model
Samuel Valable 1*,
Dauphou Eddi 1,
Jean-Marc Constans 2,
Jean-Sébastien Guillamo 3,
Myriam Bernaudin 1,
Simon Roussel 1,
Edwige Petit 1
1 Centre CYCERON; Caen, France
2 Centre CYCERON; Unité IRM Pôle Imagerie,
Centre Hospitalier Universitaire Côte de Nacre; Caen, France
3 Centre CYCERON; Department of Neurology, Centre
Hospitalier Universitaire Côte de Nacre; Caen, France
* To whom correspondence should be addressed. E-mail: valable{at}cyceron.fr or samvalable@caramail.com.
 |
Abstract |
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Despite treatment efforts, the survival median in patients with glioblastoma multiform, does not
extend over 12–15 months, the most aggressive form of glioma. One of the major
pathophysiological characteristics of these tumors is their ability to induce active angiogenesis.
Thus, based on the lack of efficient therapeutic, agents that inhibit angiogenesis are particularly
attractive as a therapeutic option. However, it has been recently proposed that although
specifically targeting VEGF, the main angiogenic factor, certainly leads to significant tumor
regression, it could be also followed by tumor relapses. In this case, angiogenesis is driven by
alternate pathways which include other angiogenic factors. One possible strategy to overcome
this therapeutic obstacle is to overexpress anti-vascular factors such as Angiopoietin-2 (Ang2).
Here, by using MRI and histological analysis, we studied the vascular events involved in glioma
growth impairment induced by Ang2 overexpression. Our results show that an increase in Ang2
expression, during the tumor growth, leads to a significant decrease in tumor growth (around
86%) along with an increase in the survival median (around 70%), but does not modify the tumor
vascular area and cerebral blood volume. However, tumor Ang2–derived vessels display an
abnormal, enlarged morphology. We show that the presence of Ang2 leads to an enhancement of
tumor perfusion and a decrease in tumor vessel permeability. Based on our MRI evaluations of
hemodynamic tumor vessel changes, we propose that Ang2–derived tumor vessels lead to an
inadequate oxygenation of the tumor tissue leading to impairment in tumor growth.
Key Words:
Angiopoietin-2, glioma, angiogenesis, MRI, CBV
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