Early detection of antiangiogenic treatment responses in a mouse xenograft tumor model using quantitative perfusion MRI

Abstract

Angiogenesis plays a major role in tumor growth and metastasis, with tumor perfusion regarded as a marker for angiogenesis. To evaluate antiangiogenic treatment response in vivo, we investigated arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure tumor perfusion quantitatively. Chronic and 24-h acute treatment responses to bevacizumab were assessed by ASL and dynamic-contrast-enhanced (DCE) MRI in the A498 xenograft mouse model. After the MRI, tumor vasculature was assessed by CD34 staining. After 39 days of chronic treatment, tumor perfusion decreased to 44.8 ± 16.1 mL/100 g/min (P < 0.05), compared to 92.6 ± 42.9 mL/100 g/min in the control group. In the acute treatment study, tumor perfusion in the treated group decreased from 107.2 ± 32.7 to 73.7 ± 27.8 mL/100 g/min (P < 0.01; two-way analysis of variance), as well as compared with control group post dosing. A significant reduction in vessel density and vessel size was observed after the chronic treatment, while only vessel size was reduced 24 h after acute treatment. The tumor perfusion correlated with vessel size (r = 0.66; P < 0.005) after chronic, but not after acute treatment. The results from DCE-MRI also detected a significant change between treated and control groups in both chronic and acute treatment studies, but not between 0 and 24 h in the acute treatment group. These results indicate that tumor perfusion measured by MRI can detect early vascular responses to antiangiogenic treatment. With its noninvasive and quantitative nature, ASL MRI would be valuable for longitudinal assessment of tumor perfusion and in translation from animal models to human.

Optimization of arterial spin labeling MRI for quantitative tumor perfusion in a mouse xenograft model

“…Studies with anti‐angiogenic treatments have shown reduction of perfusion and microvascular density in mice . In our study, perfusion was not correlated with vessel density or area ratio over the entire tumor.…”

“…It was found that SNR efficiency generally peaked between 5 and 20 pairs of averages and then gradually decreased with more averaging. Therefore, 20 pairs of averages were used in our later tumor studies to optimize the scan time, SNR and quantification accuracy.…”

Bevacizumab-Induced Inhibition of Angiogenesis Promotes a More Homogeneous Intratumoral Distribution of Paclitaxel, Improving the Antitumor Response

“…Decreased tumor perfusion, with only reductions in vessel size/ area has been reported in xenograft cancer models after acute treatment with bevacizumab, whereas vessel density decreased after chronic treatment (42). The doses of the angiogenesis inhibitors-we used a low clinically relevant dose of bevacizumab-and duration of the treatment are likely to account for the different results, in the different experimental settings (13,42,43). Inadequate vasculature and decreased permeability due to wrong timing or too high dose of an antiangiogenics may in Figure 3.…”

Renal Arterial Spin Labeling Magnetic Resonance Imaging

“…Perfusion measurements by ASL were able to differentiate renal masses with different histological findings [45] and cellularity [46,47]. In animal models, ASL could follow the response to anti-angiogenic treatments [43,48] and reflected cell viability in tumors responding to sorafenib [49]. In patients, ASL measurements were proposed for evaluating the completeness of tumor ablation and the extent of coagulation regions in RF ablation of RCC [50].…”