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Biologic Correlates of Intratumoral Heterogeneity in ¹⁸F-FDG Distribution with Regional Expression of Glucose Transporters and Hexokinase-II in Experimental Tumor

¹ Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
² Department of Tracer Kinetics, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
³ Department of Radiology, Nikko Memorial Hospital, Muroran, Japan
⁴ Department of Pathology, Hokkaido Gastroenterology Hospital, Sapporo, Japan

The biologic mechanisms involved in the intratumoral heterogeneous distribution of ¹⁸F-FDG have not been fully investigated. To clarify factors inducing heterogeneous ¹⁸F-FDG distribution, we determined the intratumoral distribution of ¹⁸F-FDG by autoradiography (ARG) and compared it with the regional expression levels of glucose transporters Glut-1 and Glut-3 and hexokinase-II (HK-II) in a rat model of malignant tumor. Methods: Rats were inoculated with allogenic hepatoma cells (KDH-8) into the left calf muscle (n = 7). Tumor tissues were excised 1 h after the intravenous injection of ¹⁸F-FDG and sectioned to obtain 2 adjacent slices for ARG and histochemical studies. The regions of interest (ROIs) were placed on ARG images to cover mainly the central (CT) and peripheral (PT) regions of viable tumor tissues and necrotic/apoptotic (NA) regions. The radioactivity in each ROI was analyzed quantitatively using a computerized imaging analysis system. The expression levels of Glut-1, Glut-3, and HK-II were determined by immunostaining and semiquantitative evaluation. The hypoxia-inducible factor 1 (HIF-1) was also immunostained. Results: ARG images showed that intratumoral ¹⁸F-FDG distribution was heterogeneous. The accumulation of ¹⁸F-FDG in the CT region was the highest, which was 1.6 and 2.3 times higher than those in the PT and NA regions, respectively (P < 0.001). The expression levels of Glut-1, Glut-3, and HK-II were markedly higher in the CT region (P < 0.001) compared with those in the PT region. The intratumoral distribution of ¹⁸F-FDG significantly correlated with the expression levels of Glut-1, Glut-3, and HK-II (r = 0.923, P < 0.001 for Glut-1; r = 0.829, P < 0.001 for Glut-3; and r = 0.764, P < 0.01 for HK-II). The positive staining of HIF-1 was observed in the CT region. Conclusion: These results demonstrate that intratumoral ¹⁸F-FDG distribution corresponds well to the expression levels of Glut-1, Glut-3, and HK-II. The elevated expression levels of Glut-1, Glut-3, and HK-II, induced by hypoxia (HIF-1), may be contributing factors to the higher ¹⁸F-FDG accumulation in the CT region.

Key Words: ¹⁸F-FDG • glucose transporters • hexokinase • heterogeneity • tumor

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