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Abstract
Tumor heterogeneity is an important concept when assessing intratumoral variety in vascular phenotypes and responses to antiangiogenic treatment. This study explored spatiotemporal heterogeneity of vascular alterations in C6 glioma mice during tumor growth and antiangiogenic treatment on serial MR examinations (days 0, 4, and 7 from initiation of vehicle or multireceptor tyrosine kinase inhibitor administration). Transvascular permeability (TP) was quantified on dynamic‐contrast‐enhanced MRI (DCE‐MRI) using extravascular extracellular agent (Gd‐DOTA); blood volume (BV) was estimated using intravascular T2 agent (SPION). With regard to region‐dependent variability in vascular phenotypes, the control group demonstrated higher TP in the tumor center than in the periphery, and greater BV in the tumor periphery than in the center. This distribution pattern became more apparent with tumor growth. Antiangiogenic treatment effect was regionally heterogeneous: in the tumor center, treatment significantly suppressed the increase in TP and decrease in BV (ie, typical temporal change in the control group); in the tumor periphery, treatment‐induced vascular alterations were insignificant and BV remained high. On histopathological examination, the control group showed greater CD31, VEGFR2, Ki67, and NG2 expression in the tumor periphery than in the center. After treatment, CD31 and Ki67 expression was significantly suppressed only in the tumor center, whereas VEGFR2 and α‐caspase 3 expression was decreased and NG2 expression was increased in the entire tumor. These results demonstrate that MRI can reliably depict spatial heterogeneity in tumor vascular phenotypes and antiangiogenic treatment effects. Preserved angiogenic activity (high BV on MRI and high CD31) and proliferation (high Ki67) in the tumor periphery after treatment may provide insights into the mechanism of tumor resistance to antiangiogenic treatment.
Highlights
Since neoangiogenesis was identified as a fundamental factor in tumor growth, many antiangiogenic agents have been developed.[1,2,3,4,5,6]
Sorafenib is a multireceptor tyrosine kinase inhibitor (TKI), and it has been applied in clinical trials for treating glioblastoma.[8]
The initial magnetic resonance imaging (MRI) on day 0 demonstrated significant spatial heterogeneity in the distribution of Transvascular permeability (TP) and blood volume (BV) while all vascular parameters were similar between the control and treatment groups (P > .05 in all intergroup comparisons)
Summary
Since neoangiogenesis was identified as a fundamental factor in tumor growth, many antiangiogenic agents have been developed.[1,2,3,4,5,6] Despite an early expectation that these therapeutic agents would successfully increase survival time in patients with solid tumors, validation of meaningful survival benefits has failed in a considerable number of clinical trials. To explain such unsatisfactory treatment results, a variety of molecular and histologic theories have been suggested. Magnetic resonance imaging (MRI) is useful for providing quantitative information on the spatiotemporal heterogeneity of tumor vasculature over a series of repeated examinations
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