Bile Acid Load on the DNA Distribution Pattern of Bile Ductules and Cholangiocarcinoma Induced by Diisopropanolnitrosamine in Hamsters

Abstract

This study evaluated the influence of bile acid load on the DNA distribution pattern of proliferated bile ductules and cholangiocarcinoma induced by diisopropanolnitrosamine. Ninety hamsters were separated into control, tauro- and deoxycholic acid (DCA) groups. The DNA distribution pattern of intrahepatic lesions at 15–25 weeks was measured by cytofluorometry and classified into three types: I (-A, -B), II and III, according to the degree of dispersion on the DNA histogram. Regarding proliferated bile ductule lesions, all groups showed an increase in cell populations, indicating the dispersion of nuclear DNA content from the 4C to 6C ranges over the course of 25 weeks, and two groups with bile acids, especially the DCA group, revealed significant high incidences of lesions with type I-B plus II compared with those in the control group (p < 0.05, 0.01). Changes in carcinoma types were similar to those of bile ductule lesions, and the tumors in the DCA group had a significant high frequency of type II plus III (p < 0.05). In addition, heterogeneity of the DNA distribution pattern was observed within individual lesions of not only carcinoma but also bile ductules. These results suggest that bile acid load, especially DCA, promotes an increase in nuclear DNA content or DNA polyploidization and enhances the distribution of the DNA pattern of proliferating bile ductules and carcinoma. Furthermore, a bile ductule-carcinoma sequence may be present in the development of cholangiocarcinoma.

EGFR Signaling in Liver Diseases

“…Conjugated bile acids have been described to be increased in CC patient serum [ 245 ], which might correlate with biliary tract tumorigenesis [ 246 , 247 ]. In human cholangiocyte cell lines, bile acids were shown to transactivate EGFR in a ligand-dependent manner via a TGF-α, which could be blocked by an MMP inhibitor [ 23 ].…”

Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma

“…Secondary bile acids, such as deoxycholic acid and its conjugated forms, which have been reported to be increased in the serum of cholangiocarcinoma patients [83] , may be acting to promote cholangiocarcinogenesis in the biliary tract [20,84,85] through a mechanism involving bile acid-mediated activation of EGFR, leading to upregulation of COX-2 and protein turnover inhibition of the potent antiapoptotic protein, myeloid cell leukemia 1 (Mcl-1). Werneburg et al [26] have demonstrated that bile acids like deoxycholic acid can act to activate EGFR in cultured human H-69 cholangiocyte and KMBC cholangiocarcinoma cell lines by a TGF-α-dependent mechanism mediated by bile acid stimulation of matrix metalloproteinase activity catalyzing TGF-α membrane release.…”

Carcinogenesis in the biliary system associated with APDJ

“…Bile acids, especially deoxycholic acid, promote an increase in nuclear DNA content or DNA polyploidization in cholangiocarcinoma and bile ductule lesions induced by diisopropanolnitrosamine in hamsters 15. With analysis of bile acid content in a choledochal cyst, Reveille et al14 proposed that unconjugated secondary bile acids (deoxycholate and chenodeoxycholate) may participate in the development of carcinoma.…”

“…This mixture contains not only activated pancreatic enzymes but also certain mutagens 12,13. Changes in bile may induce chronic inflammation and increased cellular proliferation in the biliary tract mucosa, leading to epithelial hyperplasia, metaplasia, and carcinoma of the biliary system . Matsubara et al18 reported that inflammatory changes were found in all histologic specimens of noncancerous biliary epithelium in patients with APDJ, and 50% of these patients also showed hyperplasia and/or metaplasia.…”