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The objective of this study is to evaluate the ability of dynamic contrast enhanced computed tomography (DCE-CT) to assess intratumor physiological heterogeneity in tumors with different angiogenic phenotypes. DCE-CT imaging was performed on athymic nude mice bearing xenograft wild type (MCF-7neo) and VEGF-transfected (MCF-7VEGF) tumors by using a clinical multislice CT, and compared to skeletal muscle. Parametrical maps of tumor physiology-perfusion (F), permeability-surface area (PS), fractional intravascular plasma (fp), and interstitial space ( fis)-were obtained by fitting the time-dependent contrast-enhanced curves to a two-compartmental kinetic model for each voxel (0.3 x 0.3 x 0.75 mm3). Mean physiological measurements were compared with positron emission tomography (PET) imaging, and the spatial distribution of tumor vasculature was compared with histology. No statistically significant difference was found in mean physiological values of F, PS, and fp in MCF-7neo and muscle, while fis of MCF-7neo was a factor of two higher (p<0.04). MCF-7neo tumors also showed a radial heterogeneity with significant higher physiological values in periphery than those in middle and core regions (p<0.01 for all physiological parameters). MCF-7VEGF tumors demonstrated significant increases in all physiological parameters compared with MCF-7neo tumors, and a distinct saccular heterogeneous pattern compared with MCF-7neo and muscle. Both PET imaging and histological results showed good correlation with the above results for this same mouse model. No statistically significant difference was found in the mean perfusion and intravascular volume measured by PET imaging and DCE-CT. Increases in cross-sectional area of blood vessels (p<0.002) were observed in MCF-7VEGF tumors than MCF-7neo, and their spatial d- stribution correlated well with the spatial distribution of fp obtained by DCE-CT. The results of this study demonstrated the feasibility of DCE-CT in quantification of spatial heterogeneity in tumor physiology in small animal models. Monitoring variations in the tumor environment using DCE-CT offers an in vivo tool for the evaluation and optimization of new therapeutic strategies.