Molecular Mechanisms Linking Risk Factors to Cholangiocarcinoma Development

Abstract

The poor prognosis of cholangiocarcinoma in humans is related to several factors, such as (i) the heterogeneity of the disease, (ii) the late onset of symptoms and (iii) the limited comprehension of the carcinogenic pathways determining neoplastic changes, which all limit the pursuit of appropriate treatment. Several risk factors have been recognized, including different infective, immune-mediated, and dysmorphogenic disorders of the biliary tree. In this review, we report the details of possible mechanisms that lead a specific premalignant pathological condition to become cholangiocarcinoma. For instance, during liver fluke infection, factors secreted from the worms may play a major role in pathogenesis. In primary sclerosing cholangitis, deregulation of histamine and bile-acid signaling may determine important changes in cellular pathways. The study of these molecular events may also shed some light on the pathogenesis of sporadic (unrelated to risk factors) forms of cholangiocarcinoma, which represent the majority (nearly 75%) of cases.

Keywords: bile duct cysts; cholangiocarcinoma; cirrhosis; liver fluke; primary sclerosing cholangitis; risk factor.

Figure 1

CCA risk in less associated factors. (For reference, in consolidated risk conditions, such as PSC, the hazard is considered more than 10 times higher).

Figure 2

Possible factors leading from primary sclerosing cholangitis (PSC) to cholangiocarcinoma (CCA). The characteristic enhanced: (1) levels of IL-6 and miR-483-5p; (2) stimulation of histamine or histamine receptors; (3) concentration of bile acids (stimulating the specific TGR-5 and S1PR2 receptors) observed in PSC. They are all possible actors in promoting carcinogenesis.