The Effect of Incomplete Bile Duct Obstruction on Diisopropanolnitrosamine—Induced Cholangiocarcinoma

Abstract

This study was carried out to clarify the influence of incomplete bile duct obstruction (IBDO) on the occurrence and proliferation of cholangiocarcinoma and to evaluate the effect of release of IBDO at an early stage, using 175 Syrian golden hamsters. These hamsters received 500mg/kg body weight of diisopropanolnitrosamine (DIPN) once weekly for 10 weeks, and then were divided into 3 groups, consisting of the simple laparotomy group (SL group), the IBDO group and 2 week IBDO group, in which IBDO was released after 2 weeks. The occurrence rates of cholangiocarcinoma at 20 weeks were 42% in the SL group, 76% in the IBDO group and 30% in the 2 week IBDO group. The mean numbers of tumors per hamster in the IBDO group were significantly greater than those in other groups (p < 0.05). Both occurrence rates and numbers of tumors in the 2 week IBDO group were similar to those in the SL group. The proliferation of bile ductules and isolation of bacteria from bile in the IBDO group had higher rates at 15, 20 weeks than those found in the other groups. These results suggest that IBDO has an influence, as promoter, on the occurrence of cholangiocarcinoma induced by DIPN, and the disappearance of its promoting effect is caused by release of the obstruction.

A novel “patient‐like” model of cholangiocarcinoma progression based on bile duct inoculation of tumorigenic rat cholangiocyte cell lines†‡

“…Chronic cholestasis associated with progressive incomplete bile duct obstruction is common in patients with known risk factors for intrahepatic cholangiocarcinoma, and in the Western world, bile duct obstruction is often seen as a serious complication following cholangiocarcinoma development. Earlier reports demonstrating promotion of cholangiocarcinogenesis by bile duct obstruction in hamsters after initiation with dimethylnitrosamine7 or diisopropanolnitrosamine8, 9 further support the link between chronic cholestasis and the promotion of cholangiocarcinoma growth and progression. However, although bile duct obstruction has long been known to induce nonneoplastic bile duct proliferation and accompanying fibrogenesis as a prominent feature of both malignant neoplastic and nonmalignant cholestatic liver disease, the potential impact of tumor‐induced bile duct obstruction on intrahepatic cholangiocarcinoma cell growth and aggressiveness has not been investigated.…”