MRI assessment of hemodynamic effects of angiopoietin-2 overexpression in a brain tumor model.
Despite treatment efforts, the median survival in patients with glioblastoma multiforme, the most aggressive form of glioma, does not extend beyond 12-15 months. One of the major pathophysiological characteristics of these tumors is their ability to induce active angiogenesis. Thus, based on the lack of efficient therapies, agents that inhibit angiogenesis are particularly attractive as a therapeutic option. However, it has been recently proposed that although specifically targeting vascular endothelial growth factor, the main angiogenic factor, certainly leads to significant tumor regression, it could also be followed by tumor relapses. In this case, angiogenesis is driven by alternate pathways that include other angiogenic factors. One possible strategy to overcome this therapeutic obstacle is to overexpress antivascular 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 ( approximately 86%) along with an increase in the survival median ( approximately 70%) but does not modify the tumor vascular area or cerebral blood volume. However, tumor Ang2-derived blood 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 MR image 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.
Valable
Samuel
S
CERVOxy Group, Centre CYCERON, Caen, France. valable@cyceron.fr
Eddi
Dauphou
D
Constans
Jean-Marc
JM
Guillamo
Jean-Sébastien
JS
Bernaudin
Myriam
M
Roussel
Simon
S
Petit
Edwige
E
D042702:Angiopoietin-2 / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005910:Glioma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D006439:Hemodynamics; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D015854:Up-Regulation
D042702:Angiopoietin-2