Hyperpolarized (13)C spectroscopy detects early changes in tumor vasculature and metabolism after VEGF neutralization.
Hyperpolarized (13)C spectroscopy detects early changes in tumor vasculature and metabolism after VEGF neutralization.
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DOI：
10.1158/0008-5472.can-11-2795
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发表时间：
2012-02-15
期刊：
影响因子：
11.2
通讯作者：
Brindle KM
中科院分区：
文献类型：
--
作者：
Bohndiek SE;Kettunen MI;Hu DE;Brindle KM
没有临床验证的生物标志物存在成像肿瘤对抗血管生成治疗的反应。在这里，我们报告的实用程序超极化13 C磁共振波谱（MRS）检测抗VEGF治疗的早期代谢作用。在两个结直肠癌异种移植模型显示不同的敏感性VEGF阻断，我们比较了超极化MRS与测量肿瘤灌注使用动态造影剂增强（DCE）-MRI和肿瘤细胞使用扩散加权MRI的表观扩散系数的组织水（ADC）。在对抗VEGF治疗敏感的肿瘤中，超极化[1- 13 C]丙酮酸和[1- 13 C]乳酸之间的13 C通量在抗VEGF治疗后降低，并与灌注减少相关。超极化[1，4 - 13 C2]富马酸盐产生的[1，4 - 13 C2]苹果酸与肿瘤细胞坏死平行增加，先于肿瘤ADC的任何变化。相反，对抗VEGF治疗不太敏感的肿瘤显示超极化[1- 13 C]丙酮酸盐的13 C通量增加，钆造影剂摄取增加，而肿瘤ADC降低。增加的标记通量可以通过VEGF阻断后血管正常化来解释，如观察到的，增加了超极化[1- 13 C]丙酮酸的递送。尽管这些肿瘤对治疗的反应最小，仅在组织学上观察到坏死轻微增加，但治疗耐药肿瘤中超极化[1，4 - 13 C2]富马酸盐的[1，4 - 13 C2]苹果酸产量也增加。总之，我们的研究结果表明，超极化13 C MRS检测抗VEGF治疗的早期反应，包括血管正常化或血管破坏和细胞死亡。
No clinically validated biomarkers exist to image tumor responses to anti-angiogenic therapy. Here we report the utility of hyperpolarized 13C magnetic resonance spectroscopy (MRS) to detect the early metabolic effects of anti-VEGF therapy. In two colorectal cancer xenograft models displaying differential sensitivity to VEGF blockade, we compared hyperpolarized MRS with measurements of tumor perfusion using dynamic contrast agent enhanced (DCE)-MRI and tumor cellularity using diffusion weighted MRI of the apparent diffusion coefficient of tissue water (ADC). In tumors sensitive to anti-VEGF therapy, 13C flux between hyperpolarized [1-13C]pyruvate and [1-13C]lactate decreased after anti-VEGF therapy and correlated with reduced perfusion. Production of [1,4-13C2]malate from hyperpolarized [1,4-13C2]fumarate increased in parallel with tumor cell necrosis, preceding any change in tumor ADC. In contrast, tumors that were less sensitive to anti-VEGF therapy showed an increase in 13C flux from hyperpolarized [1-13C]pyruvate and an increase in uptake of a gadolinium contrast agent, while tumor ADC decreased. Increased label flux could be explained by vascular normalization after VEGF blockade, increasing delivery of hyperpolarized [1-13C]pyruvate as observed. Despite the minimal response of these tumors to treatment, with only a minor increase in necrosis observed histologically, production of [1,4-13C2]malate from hyperpolarized [1,4-13C2]fumarate in therapy-resistant tumors also increased. Together, our findings demonstrate that hyperpolarized 13C MRS detects early responses to anti-VEGF therapy, including vascular normalization or vascular destruction and cell death.