title: Histopathological characteristics of glutamine synthetase-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse).
abstract: We previously reported that Tsumura-Suzuki obese diabetic (TSOD) mice, a polygenic model of spontaneous type 2 diabetes, is a valuable model of hepatic carcinogenesis via non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). One of the characteristics of tumors in these mice is the diffuse expression of glutamine synthetase (GS), which is a diagnostic marker for hepatocellular carcinoma (HCC). In this study, we performed detailed histopathological examinations and found that GS expression was diffusely positive in >70% of the hepatic tumors from 15-month-old male TSOD mice. Translocation of β-catenin into nuclei with enhanced membranous expression also occurred in GS-positive tumors. Small lesions (<1 mm) in GS-positive cases exhibited dysplastic nodules, with severe nuclear atypia, whereas large lesions (>3 mm) bore the characteristics of human HCC, exhibiting nuclear and structural atypia with invasive growth. By contrast, the majority of GS-negative tumors were hepatocellular adenomas with advanced fatty change and low nuclear grade. In GS-negative tumors, loss of liver fatty acid-binding protein expression was observed. These results suggest that the histological characteristics of GS-positive hepatic tumors in TSOD mice resemble human HCC; thus, this model may be a useful tool in translational research targeting the NAFLD/NASH-HCC sequence.
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishida
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Baba
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hatta
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194, Japan.
authors.forename: Johji
authors.initials: J
authors.lastname: Imura
authors.affiliation: Institute for Animal Reproduction, Kasumigaura, Ibaraki 300-0134, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Sutoh
authors.affiliation: Institute for Animal Reproduction, Kasumigaura, Ibaraki 300-0134, Japan.
authors.forename: Syunji
authors.initials: S
authors.lastname: Toyohara
authors.affiliation: Institute for Animal Reproduction, Kasumigaura, Ibaraki 300-0134, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hokao
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
keywords: Tsumura-Suzuki obese diabetic mice; animal model; glutamine synthetase; hepatocellular carcinoma; metabolic syndrome