Aerobic glycolysis in cancers: Implications for the usability of oxygen-responsive genes and fluorodeoxyglucose-PET as markers of tissue hypoxia
Aerobic glycolysis in cancers: Implications for the usability of oxygen-responsive genes and fluorodeoxyglucose-PET as markers of tissue hypoxia
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DOI：
10.1002/ijc.23449
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发表时间：
2008-06-15
影响因子：
6.4
通讯作者：
Overgaard, Jens
中科院分区：
文献类型：
--
作者：
Busk, Morten;Horsman, Michael R.;Overgaard, Jens
糖酵解机制的缺氧反应性可能允许从HIF-1靶点（例如Glut-1）或[18F]-氟脱氧葡萄糖正电子发射断层扫描中预处理鉴定缺氧肿瘤，但结果好坏参半。我们假设这种差异是肿瘤中有氧糖酵解升高的必然结果（Warburg效应），因为主要糖酵解细胞的能量几乎不受缺氧的影响。因此，我们在常氧和缺氧细胞系中表征了糖酵解和线粒体ATP的产生。测量表明，大多数癌细胞主要依赖有氧糖酵解，因为它占其ATP预算的56-63%，但在宫颈癌SiHa中，ATP合成主要是线粒体。此外，缺氧对糖酵解通量的刺激作用与对有氧糖酵解的相对依赖呈负相关。接下来，在小鼠中培养具有Warburg表型或非糖酵解表型的肿瘤细胞，并在切片肿瘤上分析缺氧（吡莫硝唑染色）、Glut-1表达和（18）F-FDG摄取的空间模式。只有在SiHa肿瘤中，糖代谢升高的病灶与缺氧和Glut-1表达升高的区域一致地共定位。与此相反，Glut-1与吡莫硝唑染色在所有肿瘤中的空间格局相关性较好。综上所述，Glut-1作为缺氧标志物的价值不受有氧糖酵解的严重限制。相反，（18）F-FDG摄取和Glut-1表达分别作为区域缺氧和葡萄糖代谢的标志物，其特异性与Warburg效应的强度成反比。这种联系表明，结合FDG和缺氧特异性标志物的多示踪成像可能提供肿瘤能量表型的治疗相关信息。(C) 2008 Wiley-Liss, Inc。
The hypoxia-responsiveness of the glycolytic machinery may allow pretreatment identification of hypoxic tumors from HIF-1 targets (e.g., Glut-1) or [18F]-fluorodeoxyglucose positron emission tomography but results have been mixed. We hypothesized that this discrepancy is an inevitable consequence of elevated aerobic glycolysis in tumors (Warburg effect) as energetics in predominantly glycolytic cells is little affected by hypoxia. Accordingly, we characterized glycolytic and mitochondrial ATP generation in normoxic and anoxic cell lines. Measurements demonstrated that most cancer cells rely largely on aerobic glycolysis as it accounts for 56-63% of their ATP budget, but in the cervical carcinoma SiHa, ATP synthesis was mainly mitochondrial. Moreover, the stimulatory effect of anoxia on glycolytic flux was inversely correlated to the relative reliance on aerobic glycolysis. Next, tumor cells representing a Warburg or a nonglycolytic phenotype were grown in mice and spatial patterns of hypoxia (pimonidazole-stained), Glut-1 expression and (18)F-FDG uptake were analysed on sectioned tumors. Only in SiHa tumors did foci of elevated glucose metabolism consistently colocalize with regions of hypoxia and elevated Glut-1 expression. In contrast, spatial patterns of Glut-1 and pimonidazole staining correlated reasonably well in all tumors. In conclusion, Glut-1's value as a hypoxia marker is not severely restricted by aerobic glycolysis. In contrast, the specificity of (18)F-FDG uptake and Glut-1 expression as markers of regional hypoxia and glucose metabolism, respectively, scales inversely with the intensity of the Warburg effect. This linkage suggests that multi-tracer imaging combining FDG and hypoxia-specific markers may provide therapeutically relevant information on tumor energetic phenotypes. (C) 2008 Wiley-Liss, Inc.