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Antiangiogenic effects of dexamethasone in 9L gliosarcoma assessed by MRI cerebral blood volume maps
Michael A Badruddoja1, Hendrikus G J Krouwer, Scott D Rand
1Department of Neurology and Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. kathleen@mcw.edu
Abstract:
Depending on dose, dexamethasone has been shown to inhibit or stimulate growth of rat 9L gliosarcoma and decrease the expression of vascular endothelial growth factor (VEGF), an important mediator of tumor-associated angiogenesis. We demonstrate, by constructing relative cerebral blood volume (rCBV) maps with MRI, that dexamethasone also decreases total blood volume while increasing microvascular blood volume in Fischer rats bearing intracranial 9L gliosarcoma. Animals were inoculated with 1 x 10(5) 9L gliosarcoma tumor cells. On days 10-14 after tumor cell inoculation, animals were intra-peritoneally injected with dexamethasone (3 mg/kg) over 5 days. MRI-derived gradient echo (GE) and spin-echo (SE) rCBV maps were created to demonstrate total vasculature (GE) and microvasculature (SE). After MRI studies were performed, the rat's vasculature was perfused with a latex compound. Total vessel volume and diameters were assessed by microscopy. Dexamethasone decreased the tumor-enhancing area of postcontrast T1-weighted images (P < 0.0001) and total tumor volume(P = 0.0085). In addition, there was a greater than 50% decrease in GE rCBV (total vasculature) (P = 0.007) as well as a significant decrease in total fractional blood volume, as validated by histology (P = 0.0007). Conversely, there was an increase in SE rCBV signal (microvasculature) in animals treated with dexamethasone (P = 0.05), which was consistent with microscopy (P < 0.0001). These data demonstrate that (1) dexamethasone selectively treats tumor vasculature, suggesting a vessel-size selective effect and (2) MRI-derived rCBV is a noninvasive technique that can be used to evaluate changes in blood volume and vascular morphology.
Insights
Dexamethasone treatment in rats with 9L gliosarcoma reduced tumor size and altered tumor vasculature. Magnetic resonance imaging (MRI) revealed decreased total blood volume and increased microvascular volume, indicating selective vascular effects.
Area of Science:
- Neuro-oncology
- Vascular biology
- Medical imaging
Background:
- Dexamethasone's dose-dependent effects on 9L gliosarcoma growth and vascular endothelial growth factor (VEGF) expression are known.
- Tumor-associated angiogenesis is critical for gliosarcoma progression.
- Understanding dexamethasone's impact on tumor vasculature is crucial for treatment strategies.
Purpose of the Study:
- To investigate the effects of dexamethasone on tumor vasculature in a rat 9L gliosarcoma model.
- To assess changes in total and microvascular blood volume using MRI.
- To correlate MRI findings with histological assessments of tumor vascular morphology.
Main Methods:
- Fischer rats were inoculated with 9L gliosarcoma cells.
- Dexamethasone was administered intraperitoneally for 5 days.
- Relative cerebral blood volume (rCBV) maps were generated using MRI (gradient echo for total vasculature, spin echo for microvasculature).
- Tumor size and vascular morphology were assessed post-mortem via histology after latex perfusion.
Main Results:
- Dexamethasone significantly decreased tumor-enhancing areas and total tumor volume.
- MRI showed a >50% decrease in gradient echo rCBV (total vasculature) and reduced total fractional blood volume.
- Spin echo rCBV signal (microvasculature) increased, consistent with histological findings of altered vascular morphology.
- Histology confirmed a significant decrease in total vessel volume (P < 0.0001).
Conclusions:
- Dexamethasone selectively targets tumor vasculature, demonstrating a vessel-size selective effect.
- MRI-derived rCBV is a noninvasive tool for evaluating changes in tumor blood volume and vascular morphology.
- These findings provide insights into the anti-angiogenic mechanisms of dexamethasone in gliosarcoma.
