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Introduction
Tsumura-Suzuki obese diabetic (TSOD) mice are an inbred ddY strain that displays spontaneous metabolic syndrome and type 2 diabetes mellitus. At the age of ≥8 weeks, this strain develops apparent obesity, glycosuria, hyperglycemia and hyperinsulinemia (1–3). Due to its characteristics, the pathophysiology of TSOD mice is also considered to be reflected in metabolic syndrome, which is a severe risk factor for the development of incurable diseases that affect the entire body. From 4 months of age onwards, the liver of TSOD mice starts to exhibit fatty degeneration, hepatocellular ballooning, Mallory bodies and neutrophil infiltration, which are markers of non-alcoholic fatty liver disease (NAFLD) and subsequent non-alcoholic steatohepatitis (NASH). Furthermore, after 10 months of age, spontaneous hepatic tumors also start to develop in TSOD mice (4).
NAFLD and NASH are associated with metabolic syndrome, obesity, type 2 diabetes and dyslipidemia. NASH is involved in a multistep process that begins with the accumulation of lipids in the liver and additional factors, such as oxidative stress and cytokines (5). It has been reported that NAFLD and NASH may lead to cirrhosis and the development of hepatic tumors, as well as hepatitis B virus (HBV) and hepatitis C virus (HCV) infections (6,7). It is widely believed that the incidence of NAFLD/NASH as a cause of hepatic tumors will increase with the improvement in anti-HBV and anti-HCV strategies over time. Hence, thorough understanding of the pathological sequence from NAFLD/NASH to hepatic tumorigenesis is required.
A variety of diagnostic markers for hepatocellular carcinoma (HCC) have been recently identified. Glutamine synthetase (GS) is one of the markers involved in nitrogen homeostasis in the liver (8–10). GS is a target of Wnt/β-catenin signaling, which is activated in HCC, and accounts for the association between GS expression and the growth of HCC (11,12). We previously reported that GS-positive lesions were also found in tumors in TSOD mice (4); however, the detailed characteristics of GS-positive and -negative tumors in TSOD mice have not yet been elucidated. The aim of this study was to clarify the histopathological characteristics of hepatic tumors derived from TSOD mice in GS-positive and -negative legions.
Materials and methods
TSOD mice
A total of 40 7-week old male TSOD mice were purchased from the Institute for Animal Reproduction (Kasumigaura, Ibaraki, Japan)....