Ono Koki, Takigawa Shota, Yamada Katsuya
Department of Physiology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
Department of Biochemistry and Molecular Biology, Faculty of Agriculture and Life Science, Hirosaki University, 3 Bunkyo-cho, Hirosaki, Aomori 036-8561, Japan.
Cancers (Basel). 2020 Apr 1;12(4):850. doi: 10.3390/cancers12040850.
Cancerous tumors comprise cells showing metabolic heterogeneity. Among numerous efforts to understand this property, little attention has been paid to the possibility that cancer cells take up and utilize otherwise unusable substrates as fuel. Here we discuss this issue by focusing on L-glucose, the mirror image isomer of naturally occurring D-glucose; L-glucose is an unmetabolizable sugar except in some bacteria. By combining relatively small fluorophores with L-glucose, we generated fluorescence-emitting L-glucose tracers (fLGs). To our surprise, 2-NBDLG, one of these fLGs, which we thought to be merely a control substrate for the fluorescent D-glucose tracer 2-NBDG, was specifically taken up into tumor cell aggregates (spheroids) that exhibited nuclear heterogeneity, a major cytological feature of malignancy in cancer diagnosis. Changes in mitochondrial activity were also associated with the spheroids taking up fLG. To better understand these phenomena, we review here the Warburg effect as well as key studies regarding glucose uptake. We also discuss tumor heterogeneity involving aberrant uptake of glucose and mitochondrial changes based on the data obtained by fLG. We then consider the use of fLGs as novel markers for visualization and characterization of malignant tumor cells.
癌性肿瘤由表现出代谢异质性的细胞组成。在众多理解这一特性的努力中，癌细胞摄取并利用原本无法利用的底物作为燃料的可能性却很少受到关注。在此，我们通过聚焦L-葡萄糖（天然存在的D-葡萄糖的镜像异构体）来探讨这个问题；L-葡萄糖是一种除了在某些细菌中外无法代谢的糖。通过将相对较小的荧光团与L-葡萄糖结合，我们生成了发射荧光的L-葡萄糖示踪剂（fLGs）。令我们惊讶的是，这些fLGs之一的2-NBDLG，我们原本认为它仅仅是荧光D-葡萄糖示踪剂2-NBDG的对照底物，却被特异性地摄取到表现出核异质性的肿瘤细胞聚集体（球体）中，核异质性是癌症诊断中恶性肿瘤的一个主要细胞学特征。线粒体活性的变化也与摄取fLG的球体相关。为了更好地理解这些现象，我们在此回顾了瓦伯格效应以及关于葡萄糖摄取的关键研究。我们还基于fLG获得的数据讨论了涉及葡萄糖异常摄取和线粒体变化的肿瘤异质性。然后，我们考虑将fLGs用作可视化和表征恶性肿瘤细胞的新型标志物。
