Abstract
Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is now a widely-used modality for glioblastoma (GBM) treatment. However, intratumoral heterogeneity of fluorescence intensity may reflect different onco-metabolic programs. Here, we investigated the metabolic mechanism underlying the heterogeneity of 5-ALA fluorescence in GBM. Using an in-house developed fluorescence quantification system for tumor tissues, we collected 3 types of GBM tissues on the basis of their fluorescence intensity, which was characterized as strong, weak, and none. Expression profiling by RNA-sequencing revealed 77 genes with a proportional relationship and 509 genes with an inverse relationship between gene expression and fluorescence intensity. Functional analysis and in vitro experiments confirmed glutaminase 2 (GLS2) as a key gene associated with the fluorescence heterogeneity. Subsequent metabolite profiling discovered that insufficient NADPH due to GLS2 underexpression was responsible for the delayed metabolism of 5-ALA and accumulation of protoporphyrin IX (PpIX) in the high fluorescence area. The expression level of GLS2 and related NADPH production capacity is associated with the regional heterogeneity of 5-ALA fluorescence in GBM.
Highlights
Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is a widely-used modality for glioblastoma (GBM) treatment
We have previously shown that mutation of isocitrate dehydrogenase 1 (IDH1), one of the tricarboxylic acid (TCA) cycle isozymes commonly mutated in lower grade gliomas, is related to the enhancement of protoporphyrin IX (PpIX) accumulation and fluorescence by exogenous 5-ALA in malignant glioma cells[18]
Because 5-ALA fluorescence is the result of the temporary intracellular accumulation of PpIX in cancer cells, we focused on gene sets related to cell metabolism as well as the neuronal system
Summary
Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is a widely-used modality for glioblastoma (GBM) treatment. Sporadic reports on alterations in heme biosynthetic enzymes and porphyrin transporters have been proposed for the mechanism of the preferential accumulation of PpIX in cancer cells, but the evidences were inconsistent among the tumor types[10]. Among the altered porphyrin transporters in cancer cells, ATP-binding cassette sub-family B member 6 (ABCB6) shows higher expression in glioma tissue than in normal brain tissue and is correlated with 5-ALA/PpIX fluorescence[12]. Considering the nature of the temporary accumulation of PpIX after 5-ALA administration in cancer cells, focusing on metabolic reprogramming in cancer may be a more reasonable way to investigate the mechanism of selective fluorescence. A novel hypothesis for the metabolic mechanism is needed to explain the selective 5-ALA-induced fluorescence in GBM tissue, because most GBM tissues express wild-type TCA enzymes[20]
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