The reverse Warburg effect and 18F-FDG uptake in non-small cell lung cancer A549 in mice: a pilot study.

Abstract

UNLABELLED:

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.

CONCLUSION:

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.

• Authors: Guojian Zhang, Jianbo Li, Xuemei Wang, Yuanyuan Ma, Xindao Yin, Feng Wang, Huaiyu Zheng, Xiaoxian Duan, Gregory C Postel, Xiao-Feng Li
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 56 Issue 4 Pg. 607-12 (Apr 2015) ISSN: 1535-5667 [Electronic] United States
• PMID: 25722447 (Publication Type: Journal Article)
• Copyright: © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Chemical References

• Blood Glucose
• Nitroimidazoles
• Radiopharmaceuticals
• Fluorodeoxyglucose F18
• pimonidazole
• Glucose

Topics

• Animals
• Blood Glucose (analysis, metabolism)
• Body Weight
• Carcinoma, Non-Small-Cell Lung (diagnostic imaging)
• Cell Line, Tumor
• Diet
• Female
• Fluorodeoxyglucose F18
• Glucose (metabolism)
• Humans
• Hypoxia
• Lung Neoplasms (diagnostic imaging)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Nitroimidazoles (chemistry)
• Pilot Projects
• Positron-Emission Tomography
• Radiopharmaceuticals
• Tumor Microenvironment