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.

Expression of COX-2 and VEGF-C in cholangiocarcinomas at different clinical and pathological stages

“…This finding is similar to those in previous reports of COX-2 expression and function at different stages of cholangiocarcinoma (Wu et al, 2010;Yoon et al, 2010;Rodriguez-Enriquez et al, 2011;Schoppmann et al, 2011). On the other hand, COX-2 inhibitors have been confirmed as effective auxiliary drugs for cholangiocarcinoma (Murmu, 2014;Zabron et al, 2013). Thus, we focused on cell invasion and found that inhibition of COX-2 activity reduced the invasion ability of cultured cholangiocarcinoma cells.…”

“…None of the patients had received preoperative chemoradiotherapy or immune therapy. The clinical stage of the specimen was based on the TNM staging criteria for cholangiocarcinoma issued by the American Cancer Society (Zabron et al, 2013). Twenty-six cases were stage I, 30 were stage II, 19 were stage III, and 5 were stage IV.…”

“…Owing to in-depth research on tumorigenesis and progression, the angiogenic characteristics of cholangiocarcinoma have gained attention. Indicators of tumor angiogenesis such as cyclooxygenase-2 (COX-2) and vascular endothelial growth factor C (VEGF-C) are overexpressed in many types of malignant tumors (Zabron et al, 2013). However, the role of COX-2 and VEGF-C in cholangiocarcinoma is still unclear, especially in respect to clinical stage.…”

Cholangiocarcinoma, gone without the Wnt?

“…CCA frequently arises on a background of chronic liver inflammation and cholestasis, as reflected by risk factors of cholangiocarcinogenesis (e.g., liver cirrhosis, viral hepatitis, hepatolithiasis, liver fluke infestation, primary sclerosing cholangitis). Chronic inflammation is accompanied by enhanced cell turnover with generation of additional inflammatory stimuli, and a microenvironment rich in pro-inflammatory mediators and proliferative factors that enable accumulation of mutations, transformation and expansion of mutated cells [3,4] . Cholestasis may contribute to cholangiocarcinogenesis through effects of (conjugated) bile salts on proliferation and invasion of cholangiocytes [5,6] .…”

Biomolecular prognostic factors in Klatskin tumor

“…Среди первичных опухолей печени ХЦР зани-мает второе место в мире по распространенности [9,30]. Заболеваемость этим типом рака на протяжении послед-них трех десятилетий растет, и в связи с плохим прогнозом и низкой выживаемостью пациентов ХЦР опередил гепа-тоцеллюлярный рак в структуре основных причин смерти от первичных гепатобилиарных опухолей [26,30].…”