Evaluation of diethylnitrosamine- or hepatitis B virus X gene-induced hepatocellular carcinoma with [sup.18]F-FDG PET/CT: a preclinical study

The aim of this study was to evaluate whether the development of hepatocellular carcinoma (HCC) in murine models resembles tumor progression in humans, using non-invasive molecular imaging methods. Murine HCC models were generated by treating mice with diethylnitrosamine (DEN) or by the transgenic expression of hepatitis B virus X (HBx) protein (HBx-Tg model). Tumor development was detected using [sup.18F]-fluoro-2-deoxyglucose ([sup.18F]-FDG) positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI). The histopathological changes and expression of glucose transporter 1 (Glut1) and hexokinase 2 (HK2) were evaluated using hematoxylin and eosin and immunohistochemical staining, respectively. Tumor lesions as small as 1 mm in diameter were detected by MRI. Tumor development was monitored using [sup.18F]-FDG PET/CT at 6.5-10 months after DEN treatment or 11-20 months after birth of the HBx-Tg model mice. A correlation study between the [sup.18F]-FDG uptake levels and expression levels of HK2 and Glut1 in developed HCC showed a high [sup.18F]-FDG uptake in poorly differentiated HCCs that expressed high levels of HK2, in contrast to that in well-differentiated tumors. The progression of primary HCCs resembling human HCC in murine models was detected and monitored by [sup.18F]-FDG PET/CT. The correlation between tumor size and [SUV.sub.max] was verified in the two HCC models. To the best of our knowledge, this is the first study to demonstrate that in vivo [sup.18F]-FDG uptake varies in HCCs according to differentiation grade in a preclinical study. Key words: diethylnitrosamine, hepatitis B virus X protein, hepatocellular carcinoma, [sup.18F]-FDG-PET/CT, tumor grading