Abstract
BackgroundThis study demonstrates that a dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) perfusion parameter may indicate vascular abnormality in a brain tumor model and reflects an effect of dexamethasone treatment. In addition, X-ray computed tomography (CT) measurements of vascular tortuosity and tissue markers of vascular morphology were performed to investigate the underpinnings of tumor response to dexamethasone.Methodology/Principal FindingsOne cohort of Fisher 344 rats (N = 13), inoculated intracerebrally with 9L gliosarcoma cells, was treated with dexamethasone (i.p. 3 mg/kg/day) for five consecutive days, and another cohort (N = 11) was treated with equal volume of saline. Longitudinal DSC-MRI studies were performed at the first (baseline), third and fifth day of treatments. Relative cerebral blood volume (rCBV) was significantly reduced on the third day of dexamethasone treatment (0.65±.13) as compared to the fifth day during treatment (1.26±.19, p<0.05). In saline treated rats, relative CBV gradually increased during treatment (0.89±.13, 1.00±.21, 1.13±.23) with no significant difference on the third day of treatment (p>0.05). In separate serial studies, microfocal X-ray CT of ex vivo brain specimens (N = 9) and immunohistochemistry for endothelial cell marker anti-CD31 (N = 8) were performed. Vascular morphology of ex vivo rat brains from micro-CT analysis showed hypervascular characteristics in tumors, and both vessel density (41.32±2.34 branches/mm3, p<0.001) and vessel tortuosity (p<0.05) were significantly reduced in tumors of rats treated with dexamethasone compared to saline (74.29±3.51 branches/mm3). The vascular architecture of rat brain tissue was examined with anti-CD31 antibody, and dexamethasone treated tumor regions showed reduced vessel area (16.45±1.36 µm2) as compared to saline treated tumor regions (30.83±4.31 µm2, p<0.001) and non-tumor regions (22.80±1.11 µm2, p<0.01).Conclusions/SignificanceIncreased vascular density and tortuosity are culprit to abnormal perfusion, which is transiently reduced during dexamethasone treatment.
Highlights
Blood vessels have critical role in tumor growth to deliver nutrients and remove wastes from the tumor microenvironment
Longitudinal changes of tumor blood volume are clearly conspicuous within the same rat. From these maps regions-of-interests were defined in tumor and non-tumor regions for a cohort of rats treated with dexamethasone (N = 13) and another cohort of rats treated with saline (N = 11)
The present study sought to investigate the underpinnings of abnormal perfusion parametric measures obtained from dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) in a rat brain tumor model and to assess vascular changes after dexamethasone treatment
Summary
Blood vessels have critical role in tumor growth to deliver nutrients and remove wastes from the tumor microenvironment. As a result of abnormal organization of tumor vessels, the blood flow in tumor vessels is abnormal and permeability of vessel is increased [3,4]. It has been proposed, with some evidence, that abnormal blood vessels could be pruned by eliminating excess endothelial cells, thereby resulting to a somewhat ‘normal’ vessel state that both functionally and morphologically can provide better delivery of nutrients and therapeutics [2,5]. Inhibition of VEGF or its receptor leads to apoptosis of endothelial cells and a decrease in vessel diameter, density and permeability [1,6] and increases oxygen tension [7]. X-ray computed tomography (CT) measurements of vascular tortuosity and tissue markers of vascular morphology were performed to investigate the underpinnings of tumor response to dexamethasone
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