Abstract
It has been reported that 18F-FDG uptake is higher in hypoxic cancer cells than in well-oxygenated cells. We demonstrated that 18F-FDG uptake in lung cancer would be affected by high concentration oxygen breathing. Methods. Overnight fasted non-small-cell lung cancer A549 subcutaneous (s.c.) xenografts bearing mice (n = 10) underwent 18F-FDG micro-PET scans, animals breathed room air on day 1, and same animals breathed carbogen (95% O2 + 5% CO2) on the subsequent day. In separated studies, autoradiography and immunohistochemical staining visualization of frozen section of A549 s.c. tumors were applied, and to compare between carbogen-breathing mice and those with air breathing, a combination of 18F-FDG and hypoxia marker pimonidazole was injected 1 h before animal sacrifice, and 18F-FDG accumulation was compared with pimonidazole binding and glucose transporter 1 (GLUT-1) expression. Results. PET studies revealed that tumor 18F-FDG uptake was significantly decreased in carbogen-breathing mice than those with air breathing (P < 0.05). Ex vivo studies confirmed that carbogen breathing significantly decreased hypoxic fraction detected by pimonidazole staining, referring to GLUT-1 expression, and significantly decreased 18F-FDG accumulation in tumors. Conclusions. High concentration of O2 breathing during 18F-FDG uptake phase significantly decreases 18F-FDG uptake in non-small-cell lung cancer A549 xenografts growing in mice.
Highlights
Warburg effect has been adapted to explain 18F-FDG accumulation in cancer cells; increase in glucose metabolism is considered as one of the fundamentals of cancer [10], and a recent observation has demonstrated that Warburg effect hypothesis may not fully explain the difference in 18F-FDG uptake between well-oxygenated cancer cells and hypoxic cancer cells logically [11,12,13]. 18F-FDG uptake in terms of glucose metabolism in hypoxic cancer cells has been extensively studied in cell cultures and in animal models of cancers, and it has been reported that hypoxic cancer cells or tissues frequently accumulate higher levels of 18F-FDG than welloxygenated tumor tissues or cells [14,15,16,17,18,19,20]
positron emission tomography (PET) studies were performed on subsequent day basis (Figure 1(a)). 18F-FDG uptake in A549 subcutaneous tumor in mice breathing carbogen was significantly lower than that in mice breathing air, and carbogen breathing little affected 18F-FDG uptake in normal organs (Figure 1(b))
In digital autoradiography, when 5 mice were treated with carbogen breathing, glucose demand in A549 tumors as measured by 18F-FDG uptake was 4.19 ± 1.32%, which was significantly lower than that in mice breathing air (9.67 ± 4.35, n 5 mice, P < 0.01), and pimonidazole binding decreased in high glucose transporter 1 (GLUT-1) expression regions when animals breathed carbogen (Figure 4)
Summary
Lung cancer is the leading cause of cancer death worldwide [1]. 18F-Fluorodeoxyglucose (18F-FDG) is an analog of glucose, and 118F-FDG positron emission tomography (PET) imaging has emerged as an important clinical tool for cancer detection, staging, and monitoring of response and is routinely used in the clinical management of lung cancer and several other cancer types [2,3,4,5,6,7,8,9].Warburg effect has been adapted to explain 18F-FDG accumulation in cancer cells; increase in glucose metabolism is considered as one of the fundamentals of cancer [10], and a recent observation has demonstrated that Warburg effect hypothesis may not fully explain the difference in 18F-FDG uptake between well-oxygenated cancer cells and hypoxic cancer cells logically [11,12,13]. 18F-FDG uptake in terms of glucose metabolism in hypoxic cancer cells has been extensively studied in cell cultures and in animal models of cancers, and it has been reported that hypoxic cancer cells or tissues frequently accumulate higher levels of 18F-FDG than welloxygenated tumor tissues or cells [14,15,16,17,18,19,20]. Tumor oxygen level may play a key role for 18F-FDG uptake in cancer. Ljungkvist et al reported a significant decrease in hypoxia fraction in head-neck cancer models in mice [25], and this finding was reproduced in cancer models from various cancer types by investigators from other laboratories. It is reported in head-neck cancer and colon cancer models growing in nude mice that carbogen breathing significantly decreased 18F-FDG uptake [22,23,24,25,26,27]
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