Mechanisms of biliary carcinogenesis: A pathogenetic multi-stage cascade towards cholangiocarcinoma

Abstract

SummaryCarcinomas of the biliary tract are rare cancers developing from the epithelial or blast-like cells lining the bile ducts. A variety of known predisposing factors and recent experimental models of biliary carcinogenesis (e.g., infection with the liver fluke Opisthorchis viverrini, models of chemically induced carcinogenesis and experimental models of pancreaticobiliary maljunction) have elucidated different stages of this complex system of biliary tumorigenesis. Chronic inflammatory processes, generation of active oxygen radicals, altered cellular detoxification mechanisms, activation of oncogenes, functional loss of tumor-suppressor genes and dysregulation of cell proliferation and cell apoptotic mechanisms have been identified as important contributors in the development of cholangiocarcinomas. In this review, the known mechanisms involved in the carcinogenesis of biliary epithelium are addressed. We will divide the topic into four stages: 1) Predisposition and risk factors of biliary cancer. 2) Genotoxic events and alterations leading to specific DNA damage and mutation patterns. 3) Dysregulation of DNA repair mechanisms and apoptosis, permitting survival of mutated cells and 4) Morphological evolution from premalignant biliary lesions to cholangiocarcinoma. Finally, established and hypothetical future therapeutic strategies directed towards specific pathogenetic events during biliary carcinogenesis will be addressed.

Cholangiocarcinoma: Molecular targeting strategies for chemoprevention and therapy

“…Figure 1 depicts salient cellular events associated with chronic inflammation and bile acids that have been postulated to contribute to the cholangiocarcinogenic pro-cess. 7,17 As depicted, excess generation of endogenous nitric oxide resulting from induction by proinflammatory cytokines of inducible nitric oxide synthase (iNOS) in the inflamed biliary tract has been linked to bile duct cell damage and potentially to cholangiocarcinogenesis 18,19 by virtue of its demonstrated effects on potentiating oxidative DNA damage and on mediating inhibition of DNA repair, 20,21 thereby favoring the possibility of oncogenic mutations. In addition, nitric oxide has been demonstrated to inhibit apoptosis downstream of cytochrome c by a mechanism involving nitrosylation of caspase-9.…”

The expression of antiapoptotic proteins Bcl-2, Bcl-XL, and Mcl-1 in benign, dysplastic, and malignant biliary epithelium

“…There are some researchers who have hypothesised that high concentrations of antiapoptotic proteins, such as the Bcl-2 protein, within the biliary tree play a key role in the development of cholangiocarcinoma by allowing cells that harbour growth promoting mutations, such as mutations of K-ras, c-erb-B-2, or c-myc, to survive by evading apoptosis, which would otherwise be triggered by an unstable genome. 1 The role that antiapoptotic proteins play in the pathogenesis and the response of cholangiocarcinoma to cytotoxic treatment are unclear. It may be that studies looking into the eVects on apoptosis sensitivities after antagonising Bcl-X L and/or Mcl-1 target function, directly or indirectly, may provide some evidence for their possible role in the resistance to anticancer treatment.…”

“…Oxidative damage, oncogene activation, and impaired apoptosis have been suggested to play a part in the pathogenesis. 1 Despite advances in diagnosis, surgery oVers the only possible chance for long term survival. [2][3][4] Resection rates are at best between 25-50%.…”

Chemopreventative Effect of Hochu-ekki-to (TJ-41) on Chemically Induced Biliary Carcinogenesis in Hamsters

“…Chronic infection and inflammation involving the biliary tree, such as mechanical irritation by means of cholelithiasis (28), chronic intrahepatic cholangitis with hepatolithiasis (29), bile stasis and bacterial infection (30), and primary sclerosing cholangitis (PSC) (31)(32)(33), are the risk factors for the development of biliary carcinoma. We have obtained evidence that persistent cholangitis after bilioenterostomy in hamsters accelerates the development of biliary carcinoma through an increase in the proliferative activity of the biliary epithelium in accordance with the severity of cholangitis (9,10) and that etodolac, a selective COX-2 inhibitor, reduces both the occurrence of severe cholangitis and the acceleration of biliary epithelial cell kinetics after bilioenterostomy in hamsters, resulting in the prevention of BOP-induced biliary carcinogenesis (34).…”