Garrigue Philippe, Bodin-Hullin Aurore, Balasse Laure, Fernandez Samantha, Essamet Wassim, Dignat-George Françoise, Pacak Karel, Guillet Benjamin, Taïeb David
Aix-Marseille University, INSERM, UMR-S 1076, Marseille, France.
Aix-Marseille University, CERIMED, Marseille, France.
J Nucl Med. 2017 Nov;58(11):1749-1755. doi: 10.2967/jnumed.117.192674. Epub 2017 Jun 15.
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 F-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 F-FDG uptake profile. To test whether succinate modifies the F-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 F-fluorocholine uptake and retention. Glucose transporter 1 (GLUT1) immunohistochemistry was performed to assess whether F-FDG uptake correlates with GLUT1 staining. Intratumoral injection of succinate significantly increased F-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 F-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 F-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 F-fluorocholine uptake in the tumor and muscle and on hind limb blood flow. GLUT1 expression quantification did not significantly differ between the study groups. The present study shows that succinate stimulates F-FDG uptake by endothelial cells, a finding that partially explains the F-FDG metabotype observed in tumors with SDH deficiency. Although this study is an F-FDG-based approach, it provides an impetus to better characterize the determinants of F-FDG uptake in various tumors and their surrounding microenvironment, with a special emphasis on the role of tumor-specific oncometabolites.
近年来，三羧酸（TCA）循环酶的遗传性和获得性突变在多种癌症中均有报道。嗜铬细胞瘤和副神经节瘤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所驱动的。与琥珀酸脱氢酶（SDH）缺乏相关的嗜铬细胞瘤和副神经节瘤的特征是具有高F-FDG摄取率。目前这种关联仅得到部分解释。因此，我们推测由于TCA循环缺陷导致的琥珀酸积累可能是SDH突变肿瘤与F-FDG摄取特征之间的主要连接枢纽。为了测试琥珀酸是否会改变肿瘤的F-FDG代谢特征，我们在不同细胞模型中，分别在存在琥珀酸、富马酸和磷酸盐缓冲盐水（PBS）的情况下进行了体外和体内（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对F-氟胆碱摄取和潴留的影响。进行葡萄糖转运蛋白1（GLUT1）免疫组织化学检测，以评估F-FDG摄取是否与GLUT1染色相关。在小动物PET/CT成像和放射自显影中，瘤内注射琥珀酸在24小时时显著增加了F-FDG摄取。在体外未观察到琥珀酸对癌细胞有影响，但有趣的是，我们发现琥珀酸以浓度依赖的方式导致人脐静脉内皮细胞的F-FDG摄取增加。瘤内注射富马酸或PBS后未观察到显著影响。无论细胞谱系如何，琥珀酸、富马酸和PBS对细胞活力均无影响。与PBS或富马酸相比，肌肉内注射琥珀酸也显著增加了肌肉的F-FDG摄取，突出了琥珀酸对结缔组织的作用。在肿瘤和肌肉中，PBS和琥珀酸对F-氟胆碱摄取以及后肢血流方面未观察到差异。研究组之间GLUT1表达定量无显著差异。本研究表明，琥珀酸刺激内皮细胞摄取F-FDG，这一发现部分解释了在SDH缺乏的肿瘤中观察到的F-FDG代谢型。尽管本研究是基于F-FDG的方法，但它为更好地表征各种肿瘤及其周围微环境中F-FDG摄取的决定因素提供了动力，特别强调了肿瘤特异性肿瘤代谢物的作用。
