The challenge of cholangiocarcinoma: dissecting the molecular mechanisms of an insidious cancer

Abstract

Cholangiocarcinoma is a fatal cancer of the biliary epithelium and has an incidence that is increasing worldwide. Survival beyond a year of diagnosis is less than 5%, and therapeutic options are few. Known risk factors include biliary diseases such as primary sclerosing cholangitis and parasitic infestation of the biliary tree, but most cases are not associated with any of these underlying diseases. Numerous in vitro and in vivo models, as well as novel analytical techniques for human samples, are helping to delineate the many pathways implicated in this disease, albeit at a frustratingly slow pace. As yet, however, none of these studies has been translated into improved patient outcome and, overall, the pathophysiology of cholangiocarcinoma is still poorly understood. There remains an urgent need for new approaches and models to improve management of this insidious and devastating disease. In this review, we take a bedside-to-bench approach to discussing cholangiocarcinoma and outline research opportunities for the future in this field.

Fig. 1.

Anatomy of the biliary tree showing the position of the different categories of CCA. The bile ducts carry bile from its site of production in the liver parenchyma to the duodenum. Primary malignancy of the endothelium of these ducts forms CCA. CCA is classified as intrahepatic, perihilar or extrahepatic, according to its position relative to the bifurcation of the hepatic ducts (see inset). Cellular proliferation of the duct lining causes it to become narrowed and strictured, obstructing bile flow, and causing jaundice. By this point the disease is usually advanced.

Fig. 2.

IL-6 contributes to CCA through multiple pathways, linking chronic inflammation with the development of malignancy. IL-6-mediated activation of STAT-3 confers resistance to apoptosis via upregulating Mcl-1. SOCS3, a negative regulator of IL-6 signalling, seems to be downregulated in CCA. IL-6-mediated upregulation of p38 MAPK leads to dysregulation of the cell cycle, whereas increased PGRN increases cellular proliferation. IL-6 also alters the expression and activity of various miRNAs (only some are shown here), at least in part by upregulating DNMT1 and increasing miRNA methylation. These changes lead to downregulation of Rassf1a and p16INK4a, and derepression of MAP3K8, causing the dysregulation of cell-cycle control.