L-Glucose: Another Path to Cancer Cells

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.