BACKGROUND/AIMS: It is well known that N-nitrosobis(2-oxopropyl)amine(BOP)-induced pancreas cancer and cholangiocarcinoma in Syrian hamster is similar to that of humans in morphological, biological and immunological aspects. The cyclic administration of BOP and ethionine, choline-deficient diet and methionine is known to rapidly induce the ductal type of carcinoma in pancreas and bile duct. Authors studied whether the rapid production of this cancer can occur in Syrian hamster and what its features are. METHODS: Sixteen Syrian hamsters aged 6-7 weeks and weighing 100 gm were used. All hamsters received 70 mg/kg body weight of BOP followed by three cycles of dl-ethionine, choline-deficient diet, l-methionine and 20mg/kg BOP. Hamsters were killed 9, 10 and 11 weeks after the beginning of the experiment and their gross and histologic features were observed. RESULTS: Nine cases, killed withan 10weeks after the begining of experiment, showed no development of cancer. Of seven Syrian hamsters, killed more than 10weeks after the begining of experiment, the incidences of BOP-induced cancer included one case(14.3%) of pancreas cancer and five cholangiocarcinomas( 71.4%). The morphological change of pancreas carcinogenesis was shown at first in cell mitosis and atypia(6 weeks) and then in atypical ductal hyperplasia(9 weeks) and carcinoma in situ(10 weeks). The change in cholangiocarcinoma, first progressed with ductular proliferation and surrounding fibrosis(6 weeks) followed by focal cholangiocarcinoma(10 weeks) and multiple invasive cholangiocarcinomas( 11 weeks). CONCLUSION: Pancreas cancer and intrahepatic cholangiocarcinomas can be induced rapidly within 10 weeks by cyclic injections of carcinogens in Syrian hamsters initiated with Nnitrosobis( 2-oxopropyl)amine and the morphologic changes can be observed.
Animals ; Bile Ducts ; Body Weight ; Carcinogenesis ; Carcinogens* ; Cholangiocarcinoma* ; Cricetinae* ; Diet ; Ethionine ; Humans ; Incidence ; Mesocricetus ; Methionine ; Mitosis ; Pancreas* ; Pancreatic Neoplasms*

Tumor necrosis factor-inducible gene 6 protein (TSG-6) has recently been shown to protect the liver from acute damage. However, the mechanism underlying the effect of TSG-6 on the liver remains unclear. Autophagy is a catabolic process that targets cell components to lysosomes for degradation, and its functions are reported to be dysregulated in liver diseases. Here we investigate whether TSG-6 promotes liver regeneration by inducing autophagic clearance in damaged livers. Mice fed a methionine choline-deficient diet supplemented with 0.1% ethionine (MCDE) for 2 weeks were injected with TSG-6 (the M+TSG-6 group) or saline (the M+V group) and fed with MCDE for 2 additional weeks. Histomorphological evidence of injury and increased levels of liver enzymes were evident in MCDE-treated mice, whereas these symptoms were ameliorated in the M+TSG-6 group. Livers from this group contained less active caspase-3 and more Ki67-positive hepatocytic cells than the M+V group. The autophagy markers ATG3, ATG7, LC3-II, LAMP2A and RAB7 were elevated in the M+TSG-6 group compared with those in the M+V group. Immunostaining for LC3 and RAB7 and electron microscopy analysis showed the accumulation of autophagy structures in the M+TSG-6 group. TSG-6 also blocked both tunicamycin- and palmitate-induced apoptosis of hepatocytes and increased their viability by inducing autophagy formation in these cells. An autophagy inhibitor suppressed TSG-6-mediated autophagy in the injured hepatocytes and livers of MCDE-treated mice. These results therefore demonstrate that TSG-6 protects hepatocytes from damage by enhancing autophagy influx and contributes to liver regeneration, suggesting that TSG-6 has therapeutic potential for the treatment of liver diseases.
Animals ; Apoptosis ; Autophagy* ; Caspase 3 ; Cellular Structures ; Diet ; Ethionine ; Hepatocytes ; Liver Diseases ; Liver Regeneration ; Liver* ; Lysosomes ; Methionine ; Mice* ; Microscopy, Electron ; Necrosis*