Molecular Pathogenesis and Current Therapy in Intrahepatic Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (iCCA) comprises one of the most rapidly evolving cancer types. An underlying chronic inflammatory liver disease that precedes liver cancer development for several decades and creates a pro-oncogenic microenvironment frequently impairs progress in therapeutic approaches. Depending on the cellular target of malignant transformation, a large spectrum of molecular and morphological patterns is observed. As such, it is crucial to advance our existing understanding of the molecular pathogenesis of iCCA, particularly its genomic heterogeneity, to improve current clinical strategies and patient outcome. This was achieved for other cancers, such as breast carcinoma, facilitated by the delineation of patient subsets and of precision therapies. In iCCA, many questions persevere as to the evolutionary process and cellular origin of the initial transforming event, the context of tumor plasticity and the causative features driving the disease. Molecular profiling and pathological techniques have begun to underline persistent alterations that may trigger inherited drug resistance (a hallmark of hepatobiliary and pancreatic cancers), metastasis and disease recurrence. In this review, we will focus on the key molecular achievements that are currently advancing the characterization and stratification of iCCA. We will discuss current clinical practice and how genomic achievements may advance diagnosis and therapy as well as ultimately improve patient outcome.

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

“…Nevertheless, several pathological conditions associated with chronic liver inflammation carry an increased risk to develop CCA, including infection with hepatobiliary flukes, hepatolithiasis, primary sclerosing cholangitis, and congenital malformations of the bile ducts (e.g., Caroli’s disease, choledochal cysts). It has now become clear that also patients with hepatitis B virus (HBV)- and HCV-related cirrhosis, as well as patients with metabolic syndrome, are at higher risk of developing iCCA 3,4,9 . Although CCA is commonly thought to originate from biliary epithelial cells (cholangiocytes), hepatic progenitor cells (HPCs) and mature hepatocytes have also been proposed as candidate cells of origin, particularly for the intrahepatic variant 4,8 .…”

“…In particular, point mutations, copy number variations and chromosome fusions have been reported to alter the expression of genes regulating key cellular processes, such as DNA repair (e.g., TP53 ), receptor tyrosine kinases signaling (e.g., KRAS , FGFR2 , EGFR ), and epigenetic regulation of gene expression (e.g., IDH1 , IDH2 , ARID1A ). In addition, a number of inflammatory [e.g., interleukin (IL)-6, transforming growth factor (TGF)-β], proliferative [e.g., hepatocyte growth factor (HGF)], and developmental (e.g., Notch, Wnt/β-catenin) pathways have been found to be aberrantly activated since the early stages, supporting the progression from precancerous lesions to full-blown neoplasia 4,8,9 .…”

High mobility group A1 enhances tumorigenicity of human cholangiocarcinoma and confers resistance to therapy

“…Currently, first‐line chemotherapy consists of gemcitabine in combination with cisplatin or oxiplatin. Furthermore, several ongoing trials use gemcitabine in combination with targeted therapy . HMGA1 has been described to confer resistance to gemcitabine in lung and pancreatic cancer .…”

“…24,31 Therefore, we wondered if HMGA1 in CCA could exert resistance to gemcitabine, the drug usually used as first-line in CCA. 1,32 After reduction of HMGA1 expression in HUCCT1 cells, we treated them with 10 μM gemcitabine for 48 h and analyzed cell viability by the MTS assay. Silencing HMGA1 with shRNA in HUCCT1 cells enhanced the effect of gemcitabine.…”

Suppression of miR-16 promotes tumor growth and metastasis through reversely regulating YAP1 in human cholangiocarcinoma

“…Although radical surgery is the only curative treatment for CCA, patients benefit little because they are usually diagnosed at an advanced stage [ 4 ]. Therefore, an improved understanding of the pathogenesis of CCA to find novel diagnostic and therapeutic approaches are urgently needed [ 5 , 6 ].…”