In recent years, inherited and acquired mutations in the tricarboxylic acid (TCA) cycle enzymes have been reported in diverse cancers. Pheochromocytomas and paragangliomas often exhibit dysregulation of glucose metabolism, which is also driven by mutations in genes encoding the TCA cycle enzymes or by activation of hypoxia signaling. Pheochromocytomas and paragangliomas associated with succinate dehydrogenase (SDH) deficiency are characterized by high 18F-FDG avidity. This association is currently only partially explained. Therefore, we hypothesized that accumulation of succinate due to the TCA cycle defect could be the major connecting hub between SDH-mutated tumors and the 18F-FDG uptake profile. Methods: To test whether succinate modifies the 18F-FDG metabolic profile of tumors, we performed in vitro and in vivo (small-animal PET/CT imaging and autoradiography) experiments in the presence of succinate, fumarate, and phosphate-buffered saline (PBS) in different cell models. As a control, we also evaluated the impact of succinate on 18F-fluorocholine uptake and retention. Glucose transporter 1 (GLUT1) immunohistochemistry was performed to assess whether 18F-FDG uptake correlates with GLUT1 staining. Results: Intratumoral injection of succinate significantly increased 18F-FDG uptake at 24 h on small-animal PET/CT imaging and autoradiography. No effect of succinate was observed on cancer cells in vitro, but interestingly, we found that succinate caused increased 18F-FDG uptake by human umbilical vein endothelial cells in a concentration-dependent manner. No significant effect was observed after intratumoral injection of fumarate or PBS. Succinate, fumarate, and PBS have no effect on cell viability, regardless of cell lineage. Intramuscular injection of succinate also significantly increases 18F-FDG uptake by muscle when compared with either PBS or fumarate, highlighting the effect of succinate on connective tissues. No difference was observed between PBS and succinate on 18F-fluorocholine uptake in the tumor and muscle and on hind limb blood flow. GLUT1 expression quantification did not significantly differ between the study groups. Conclusion: The present study shows that succinate stimulates 18F-FDG uptake by endothelial cells, a finding that partially explains the 18F-FDG metabotype observed in tumors with SDH deficiency. Although this study is an 18F-FDG-based approach, it provides an impetus to better characterize the determinants of 18F-FDG uptake in various tumors and their surrounding microenvironment, with a special emphasis on the role of tumor-specific oncometabolites.

中文翻译：

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琥珀酸酯在肿瘤代谢中的进化作用：一项基于18F-FDG的研究。

近年来，已报道了三羧酸（TCA）循环酶中的遗传突变和获得性突变在多种癌症中得到报道。嗜铬细胞瘤和副神经节瘤通常表现出葡萄糖代谢失调，这也是由编码TCA循环酶的基因突变或缺氧信号激活引起的。与琥珀酸脱氢酶（SDH）缺乏症相关的嗜铬细胞瘤和副神经节瘤的特征是18F-FDG亲和力高。目前仅部分解释了这种关联。因此，我们假设由于TCA周期缺陷而导致的琥珀酸积累可能是SDH突变的肿瘤与18F-FDG摄取谱之间的主要连接枢纽。方法：为了检验琥珀酸酯是否会改变肿瘤的18F-FDG代谢谱，我们在琥珀酸盐，富马酸盐和磷酸盐缓冲盐水（PBS）存在下，在不同细胞模型中进行了体外和体内（小动物PET / CT成像和放射自显影）实验。作为对照，我们还评估了琥珀酸酯对18F-氟胆碱摄取和保留的影响。进行了葡萄糖转运蛋白1（GLUT1）免疫组织化学分析，以评估18F-FDG摄取是否与GLUT1染色相关。结果：在小动物PET / CT显像和放射自显影下，瘤内注射琥珀酸酯显着增加了24 h时18F-FDG的摄取。在体外未观察到琥珀酸酯对癌细胞的作用，但是有趣的是，我们发现琥珀酸酯以浓度依赖的方式引起人脐静脉内皮细胞对18F-FDG摄取的增加。瘤内注射富马酸酯或PBS后未观察到明显的作用。无论细胞谱系如何，琥珀酸酯，富马酸酯和PBS对细胞活力均无影响。与PBS或富马酸酯相比，肌内注射琥珀酸酯还可以显着增加肌肉对18F-FDG的摄取，从而突出了琥珀酸酯对结缔组织的作用。在肿瘤和肌肉中18 F-氟胆碱的摄取以及后肢的血流方面，PBS和琥珀酸酯之间没有观察到差异。研究组之间的GLUT1表达定量没有显着差异。结论：本研究表明琥珀酸酯刺激内皮细胞摄取18F-FDG，这一发现部分解释了在SDH缺乏症肿瘤中观察到的18F-FDG代谢型。尽管此研究是基于18F-FDG的方法，