The reverse Warburg effect and 18F-FDG uptake in non-small cell lung cancer A549 in mice: a pilot study.
The purpose of this study was to observe the effect of fasting and feeding on (18)F-FDG uptake in a mouse model of human non-small cell lung cancer.


METHODS
In in vivo studies, (18)F-FDG small-animal PET scans were acquired in 5 mice bearing non-small cell lung cancer A549 xenografts on each flank with continuous feeding and after overnight fasting to observe the changes in intratumoral distribution of (18)F-FDG and tumor (18)F-FDG standardized uptake value (SUV). In ex vivo studies, intratumoral spatial (18)F-FDG distribution assessed by autoradiography was compared with the tumor microenvironment (including hypoxia by pimonidazole and stroma by hematoxylin and eosin stain). Five overnight-fasted mice and 5 fed mice with A549 tumors were observed.


RESULTS
Small-animal PET scans were obtained in fed animals on day 1 and in the same animals after overnight fasting; the lapse was approximately 14 h. Blood glucose concentration after overnight fasting was not different from fed mice (P = 0.42), but body weight loss was significant after overnight fasting (P = 0.001). Intratumoral distribution of (18)F-FDG was highly heterogeneous in all tumors examined, and change in spatial intratumoral distribution of (18)F-FDG between 2 sets of PET images from the same mouse was remarkably different in all mice. Tumor (18)F-FDG mean SUV and maximum SUV were not significantly different between fed and fasted animals (all P > 0.05, n = 10). Only tumor mean SUV weakly correlated with blood glucose concentration (R(2) = 0.17, P = 0.03). In ex vivo studies, in fasted mice, there was spatial colocalization between high levels of (18)F-FDG uptake and pimonidazole-binding hypoxic cancer cells; in contrast, pimonidazole-negative normoxic cancer cells and noncancerous stroma were associated with low (18)F-FDG uptake. However, high (18)F-FDG uptake was frequently observed in noncancerous stroma of tumors but rarely in viable cancer cells of the tumors in fed animals.


CONCLUSIONS
Host dietary status may play a key role in intratumoral distribution of (18)F-FDG. In the fed animals, (18)F-FDG accumulated predominantly in noncancerous stroma in the tumors, that is, reverse Warburg effect. In contrast, in fasted status, (18)F-FDG uptake was found in hypoxic cancer cells component (Pasteur effect). Our findings may provide a better understanding of competing cancer glucose metabolism hypotheses: the Warburg effect, reverse Warburg effect, and Pasteur effect.
Department of Nuclear Medicine, Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, China Department of Diagnostic Radiology, University of Louisville, Louisville, Kentucky.
Guojian
G
Zhang
Department of Nuclear Medicine, Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, China Department of Diagnostic Radiology, University of Louisville, Louisville, Kentucky.
Jianbo
J
Li
Department of Nuclear Medicine, Inner Mongolia Medical University Affiliated Hospital, Hohhot, Inner Mongolia, China linucmed@gmail.com wangxuemei201010@163.com.
Xuemei
X
Wang
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York; and.
Yuanyuan
Y
Ma
Department of Diagnostic Radiology, University of Louisville, Louisville, Kentucky Department of Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
Xindao
X
Yin
Department of Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
Feng
F
Wang
Department of Diagnostic Radiology, University of Louisville, Louisville, Kentucky.
Huaiyu
H
Zheng
Department of Diagnostic Radiology, University of Louisville, Louisville, Kentucky.
Xiaoxian
X
Duan
Department of Diagnostic Radiology, University of Louisville, Louisville, Kentucky.
Gregory C
GC
Postel
Department of Diagnostic Radiology, University of Louisville, Louisville, Kentucky linucmed@gmail.com wangxuemei201010@163.com.
Xiao-Feng
XF
Li
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D001835:Body Weight; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging*; D045744:Cell Line, Tumor; D004032:Diet; D005260:Female; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D008175:Lung Neoplasms / Q000000981:diagnostic imaging*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009593:Nitroimidazoles / Q000737:chemistry; D010865:Pilot Projects; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D059016:Tumor Microenvironment
D001786:Blood Glucose; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C033815:pimonidazole; D005947:Glucose
18F-fluorodeoxyglucose; PET; Pasteur effect; non–small cell lung cancer; reverse Warburg effect