Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death-Dependent Changes in Glycolysis
Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death-Dependent Changes in Glycolysis
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DOI：
10.1158/0008-5472.can-19-0182
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发表时间：
2019-07-15
期刊：
影响因子：
11.2
通讯作者：
Brindle, Kevin M.
中科院分区：
文献类型：
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作者：
Hesketh, Richard L.;Wang, Jiazheng;Brindle, Kevin M.
代谢成像已被广泛用于测量肿瘤对治疗的早期反应。在此，我们评估了PET测量[F-18] FDG摄取和MRI测量超极化[1-C-13]丙酮酸代谢的能力，以检测小鼠结肠直肠癌（Colo 205）和乳腺癌（MDA-MB-231）异种移植物治疗诱导细胞死亡后糖酵解的早期变化。一种与人细胞结合但不与小鼠细胞结合的TRAIL激动剂诱导肿瘤选择性细胞死亡。通过注射[1，6-（13）C2]葡萄糖并测量肿瘤提取物中的C-13标记代谢物来评估肿瘤糖酵解。注射超极化的[1-C-13]丙酮酸盐诱导乳酸标记快速减少。这种减少与细胞死亡的组织学标志物的增加相关，并且在肿瘤体积减少之前，反映了从葡萄糖到乳酸盐的通量减少和乳酸盐浓度降低。然而，[F-18] FDG摄取和磷酸化在治疗后得以维持，这先前已归因于浸润免疫细胞的[F-18] FDG摄取增加。流式分选肿瘤和来自解聚肿瘤的免疫细胞中[F-18] FDG摄取的定量确定了CD 11b（+）/CD 45（+）巨噬细胞是存在的最[F-18] FDG亲合的细胞类型，但它们占肿瘤中存在的细胞的< 5%，并且不能解释[F-18] FDG-PET检测治疗反应的失败。因此，与[F-18] FDG摄取的PET测量相比，超极化[1-C-13]丙酮酸代谢的MRI测量是细胞死亡后发生的糖酵解通量早期降低的更敏感的标志物。这些发现表明，MRI测量超极化[1-C-13]丙酮酸代谢上级灵敏度优于PET测量F-18，FDG摄取检测治疗诱导肿瘤细胞死亡后糖酵解的早期变化
Metabolic imaging has been widely used to measure the early responses of tumors to treatment. Here, we assess the abilities of PET measurement of [F-18] FDG uptake and MRI measurement of hyperpolarized [1-C-13] pyruvate metabolism to detect early changes in glycolysis following treatmentinduced cell death in human colorectal (Colo205) and breast adenocarcinoma (MDA-MB-231) xenografts in mice. A TRAIL agonist that binds to human but not mouse cells induced tumor-selective cell death. Tumor glycolysis was assessed by injecting [1,6-(13)C2] glucose and measuring C-13-labeled metabolites in tumor extracts. Injection of hyperpolarized [1-C-13] pyruvate induced rapid reduction in lactate labeling. This decrease, which correlated with an increase in histologic markers of cell death and preceded decrease in tumor volume, reflected reduced flux from glucose to lactate and decreased lactate concentration. However, [F-18] FDG uptake and phosphorylation were maintained following treatment, which has been attributed previously to increased [F-18] FDG uptake by infiltrating immune cells. Quantification of [F-18] FDG uptake in flow-sorted tumor and immune cells from disaggregated tumors identified CD11b(+)/CD45(+) macrophages as the most [F-18] FDG-avid cell type present, yet they represented < 5% of the cells present in the tumors and could not explain the failure of [F-18] FDG-PET to detect treatment response. MRI measurement of hyperpolarized [1-C-13] pyruvate metabolism is therefore a more sensitive marker of the early decreases in glycolytic flux that occur following cell death than PET measurements of [F-18] FDG uptake.Significance: These findings demonstrate superior sensitivity of MRI measurement of hyperpolarized [1-C-13] pyruvate metabolism versus PET measurement of F-18-FDG uptake for detecting early changes in glycolysis following treatmentinduced tumor cell death.