Authors' Affiliations: Comprehensive Cancer Imaging Centre; and Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom; and Children's Medical Center Research Institute, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas.
Cancer Res. 2014 Mar 1;74(5):1319-28. doi: 10.1158/0008-5472.CAN-13-2768.
The high rate of glucose uptake to fuel the bioenergetic and anabolic demands of proliferating cancer cells is well recognized and is exploited with (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography ((18)F-FDG-PET) to image tumors clinically. In contrast, enhanced glucose storage as glycogen (glycogenesis) in cancer is less well understood and the availability of a noninvasive method to image glycogen in vivo could provide important biologic insights. Here, we demonstrate that (18)F-N-(methyl-(2-fluoroethyl)-1H-[1,2,3]triazole-4-yl)glucosamine ((18)F-NFTG) annotates glycogenesis in cancer cells and tumors in vivo, measured by PET. Specificity of glycogen labeling was demonstrated by isolating (18)F-NFTG-associated glycogen and with stable knockdown of glycogen synthase 1, which inhibited (18)F-NFTG uptake, whereas oncogene (Rab25) activation-associated glycogen synthesis led to increased uptake. We further show that the rate of glycogenesis is cell-cycle regulated, enhanced during the nonproliferative state of cancer cells. We demonstrate that glycogen levels, (18)F-NFTG, but not (18)F-FDG uptake, increase proportionally with cell density and G1-G0 arrest, with potential application in the assessment of activation of oncogenic pathways related to glycogenesis and the detection of posttreatment tumor quiescence.
高葡萄糖摄取率为增殖癌细胞的生物能量和合成代谢需求提供燃料，这一点已得到广泛认可，并通过（18）F-2-氟-2-脱氧-d-葡萄糖正电子发射断层扫描（（18）F-FDG-PET）用于临床肿瘤成像。相比之下，癌症中增强的葡萄糖储存为糖原（糖原生成）则不太为人所知，而能够无创地在体内成像糖原的方法可能会提供重要的生物学见解。在这里，我们证明（18）F-N-（甲基-（2-氟乙基）-1H-[1,2,3]三唑-4-基）葡萄糖胺（（18）F-NFTG）可以通过 PET 测量来注释癌细胞和体内肿瘤中的糖原生成。通过分离（18）F-NFTG 相关的糖原和稳定敲低糖原合酶 1，证明了糖原标记的特异性，这抑制了（18）F-NFTG 的摄取，而癌基因（Rab25）激活相关的糖原合成导致摄取增加。我们进一步表明，糖原生成的速度受细胞周期调控，在癌细胞的非增殖状态下增强。我们证明糖原水平、（18）F-NFTG，但不是（18）F-FDG 的摄取，与细胞密度和 G1-G0 阻滞呈比例增加，这可能应用于评估与糖原生成相关的致癌途径的激活以及检测治疗后肿瘤静止状态。
