Abstract
Glioblastoma (GBM) is a highly angiogenic malignancy, and its abundant, aberrant neovascularization is closely related to the proliferation and invasion of tumor cells. However, anti-angiogenesis combined with standard radio-/chemo-therapy produces little improvement in treatment outcomes. Determining the reason for treatment failure is pivotal for GBM treatment. Here, histopathological analysis and dynamic contrast-enhanced MRI (DCE-MRI) were used to explore the effects of temozolomide (TMZ) and bevacizumab (BEV) on GBM neovascularization patterns in an orthotopic U87MG mouse model at 1, 3 and 6 days after treatment. We found that the amount of vascular mimicry (VM) significantly increased 6 days after BEV treatment. TMZ inhibited neovascularization at an early stage, but the microvessel density (MVD) and transfer coefficient (Ktrans) derived from DCE-MRI increased 6 days after treatment. TMZ and BEV combination therapy slightly prolonged the inhibitory effect on tumor microvessels. Sprouting angiogenesis was positively correlated with Ktrans in all treatment groups. The increase in VM after BEV administration and the increase in MVD and Ktrans after TMZ administration may be responsible for treatment resistance. Ktrans holds great potential as an imaging biomarker for indicating the variation in sprouting angiogenesis during drug treatment for GBM.
Highlights
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults
We demonstrated that neovascularization patterns varied along with tumor development and that dynamic contrast-enhanced MRI (DCE-MRI) can be used to evaluate neovascularization patterns in a glioma model[19]
DCE-MRI measures the MR signal to determine the change in concentration of the contrast agent over time within a field of view (FOV), and its quantitative parameters can be obtained through different pharmacokinetic models
Summary
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite advances in tumor therapy, such as maximum surgical resection followed by radio-/chemo-therapy and immune/gene therapy[1], the prognosis of GBM patients is still poor, consisting of a median survival time of 14.6 months and a five-year survival rate lower than 10%2,3. GBM is characterized by abundant and abnormal neovascularization, including vascular co-option, angiogenesis, vasculogenesis, mosaic vessel formation, vascular mimicry, and glioblastoma-endothelial cell transdifferentiation[4,5,6,7]. Using orthotopic rat C6 glioma models, our group discovered a new mosaic pattern of glioma vascularization[5] and confirmed vascular co-option, sprouting angiogenesis, intussusceptive microvascular growth (IMG) and vascular mimicry in the tumor region. We demonstrated that neovascularization patterns varied along with tumor development and that dynamic contrast-enhanced MRI (DCE-MRI) can be used to evaluate neovascularization patterns in a glioma model[19]. Dynamic susceptibility contrast MRI (DSC-MRI) can assess tumor vessel perfusion, and DCE-MRI can be used to evaluate vascular permeability[20]. Ktrans has been reported to be strongly correlated with glioma vascular permeability and microvessel density (MVD) after anti-angiogenesis therapy[22,23]. We used DCE-MRI to monitor the effect of anti-angiogenesis therapy in this study
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