Aerobic glycolysis in cancers: Implications for the usability of oxygen-responsive genes and fluorodeoxyglucose-PET as markers of tissue hypoxia

被引:98
作者
Busk, Morten [1 ]
Horsman, Michael R. [1 ]
Kristjansen, Paul E. G. [2 ]
van der Kogel, Albert J. [3 ]
Bussink, Johan [3 ]
Overgaard, Jens [1 ]
机构
[1] Aarhus Univ Hosp, Dept Expt Clin Oncol, DK-8000 Aarhus C, Denmark
[2] Univ Copenhagen, Expt Oncol Lab, Inst Mol Pathol, DK-1168 Copenhagen, Denmark
[3] Radboud Univ Nijmegen, Med Ctr, Dept Radiat Oncol, NL-6525 ED Nijmegen, Netherlands
关键词
hypoxia; Warburg; Pasteur; fluorodeoxyglucose; Glut-1;
D O I
10.1002/ijc.23449
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:2726 / 2734
页数:9
相关论文
共 43 条
  • [1] GLUT-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: Relationship to pimonidazole binding
    Airley, RE
    Loncaster, J
    Raleigh, JA
    Harris, AL
    Davidson, SE
    Hunter, RD
    West, CML
    Stratford, IJ
    [J]. INTERNATIONAL JOURNAL OF CANCER, 2003, 104 (01) : 85 - 91
  • [2] Prediction of outcome in head-and-neck cancer patients using the standardized uptake value of 2-[18F]fluoro-2-deoxy-D-glucose
    Allal, AS
    Slosman, DO
    Kebdani, T
    Allaoua, M
    Lehmann, W
    Dulguerov, P
    [J]. INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2004, 59 (05): : 1295 - 1300
  • [3] Aloj L, 1999, CANCER RES, V59, P4709
  • [4] Feasibility of detecting hypoxia in experimental mouse tumours with 18F-fluorinated tracers and positron emission tomography -: A study evaluating [18F]fluoromisonidazole and [18F]fluoro-2-deoxy-D-glucose
    Bentzen, L
    Keiding, S
    Horsman, MR
    Falborg, L
    Hansen, SB
    Overgaard, J
    [J]. ACTA ONCOLOGICA, 2000, 39 (05) : 629 - 637
  • [5] Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours
    Bentzen, L
    Keiding, S
    Nordsmark, M
    Falborg, L
    Hansen, SB
    Keller, J
    Nielsen, OS
    Overgaard, J
    [J]. RADIOTHERAPY AND ONCOLOGY, 2003, 67 (03) : 339 - 344
  • [6] Assessment of hypoxia in experimental mice tumours by [18F]fluoromisonidazole PET and pO2 electrode measurements -: Infuence of tumour volume and carbogen breathing
    Bentzen, L
    Keiding, S
    Horsman, MR
    Grönroos, T
    Hansen, SB
    Overgaard, J
    [J]. ACTA ONCOLOGICA, 2002, 41 (03) : 304 - 312
  • [7] Effect of oncogene transformation of rat embryo cells on cellular oxygen consumption and glycolysis
    Biaglow, JE
    Cerniglia, G
    Tuttle, S
    Bakanauskas, V
    Stevens, C
    McKenna, G
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 235 (03) : 739 - 742
  • [8] Glucose deprivation and hypoxia increase the expression of the GLUT1 glucose transporter via a specific mRNA cis-acting regulatory element
    Boado, RJ
    Pardridge, WM
    [J]. JOURNAL OF NEUROCHEMISTRY, 2002, 80 (03) : 552 - 554
  • [9] Cher LM, 2006, J NUCL MED, V47, P410
  • [10] Cherk MH, 2006, J NUCL MED, V47, P1921