Quantification of intra-tumor physiological heterogeneity and therapeutic response in xenograft MCF-7 breast tumor models by dynamic contrast enhanced computed tomography
Abstract
Purpose. The objective is to evaluate the ability of dynamic contrast enhanced computed tomography (DCE-CT) to assess intra-tumor physiological heterogeneity and monitor physiological response to anti-angiogenic therapy in xenograft tumor models. Materials and methods. DCE-CT imaging was performed on athymic nude mice bearing xenograft wild type (n=6) (MCF-7WT) and VEGF-transfected (n=13) (MCF-7VEGF) tumors by using a clinical multi-slice CT. 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 (0.3x0.3x0.75mm3) within a tumor. This was followed by monitoring the anti-angiogenic effects in three mice from the MCF-7 VEGF group. These mice were intravenously injected with a monoclonal antibody against VEGFR2 and their physiological changes were longitudinally monitored over 10-14 days including baseline scan, followed by scans 2-3 days and 7-14 days after treatment. Results. Mean physiological values for MCF-7 WT tumors (F=0.17±0.05mL/min/mL, fp=0.10±0.02) were statistically equivalent (p=0.17 for F and p=0.32 for fp) with those of muscle (F=0.23±0.08mL/min/mL, fp=0.09±0.02), but showed a significant variation in radial heterogeneity (p<0.0001). The measured physiology of MCF-7VEGF demonstrated significant increases in perfusion (2.12±0.96mL/min/mL, p<0.001) and f p (0.24±0.05, p<0.001) with a distinct saccular heterogeneous pattern. Both PET imaging and histological results showed good correlation with the above results for this same mouse model. Mean perfusion measured using PET imaging are in line with DCE-CT (p>0.05). Histological analysis showed good correlation with spatial distribution of fp obtained by DCE-CT. Finally, longitudinal changes in tumor physiology due to treatment showed a significant decrease in the mean fp (22.7±2.5%, p<0.03), and a narrowing of its histogram distribution after treatment (2-3 days) followed by a recovery and enhancement about 5-7 days after the treatment, which was not observed in the control group. Conclusion. This study demonstrated the feasibility of DCE-CT to quantify spatial and temporal physiology changes in tumor physiology in small animal models. A single-dose anti-angiogenic treatment show sings of vascular normalization followed by vascular expansion. Monitoring variations in the tumor environment using DCE-CT offers an in-vivo tool for the evaluation and optimization of anti-angiogenic therapy in combination with radiation and chemotherapies.
Degree
Ph.D.
Advisors
Liang, Purdue University.
Subject Area
Biomedical engineering|Medical imaging|Nuclear physics
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