Cholangiocarcinoma: novel therapeutic targets

Abstract

Introduction: Cholangiocarcinoma (CCA) is a liver cancer derived from the biliary tree with a less than 30% five-year survival rate. Early diagnosis of CCA is challenging and treatment options are limited. Some CCA patients have genetic mutations and several therapeutic drugs or antibodies have been introduced to target abnormally expressed proteins. However, CCA is heterogeneous and patients often present with drug resistance which is attributed to multiple mutations or other factors. Novel approaches and methodologies for CCA treatments are in demand.Area covered: This review summarizes current approaches for CCA treatments leading to the development of novel therapeutic drugs or tools for human CCA patients. A literature search was conducted in PubMed utilizing the combination of the searched term 'cholangiocarcinoma' with other keywords such as 'miRNA', 'FGFR', 'immunotherapy' or 'microenvironment'. Papers published within 2015-2019 were obtained for reading.Expert opinion: Preclinical studies have demonstrated promising therapeutic approaches that target various cells or pathways. Recent studies have revealed that hepatic cells coordinate to promote CCA tumor progression in the tumor microenvironment, which may be a new therapeutic target. Although further studies are required, novel therapeutic tools such as extracellular vesicles could be utilized to manage CCA and its microenvironment.

Keywords: Cholangiocarcinoma; extracellular vesicles; immunotherapy; long non-coding RNA; microRNA; tumor microenvironment.

Figure 1.. Classes of cholangiocarcinoma.

Cholangiocarcinoma (CCA) can be classified as intrahepatic, hilar or perihilar, or distal CCA according to the location where the tumors emerge. *The incidence is from the previous study analyzing 564 CCA patients at a single institution (2).

Figure 2.. Current strategies for the treatments of cholangiocarcinoma.

Cholangiocarcinoma (CCA) patients often have genetic mutations or aberrations causing abnormal protein expression or function. Antibodies or inhibitors for these proteins can be utilized to inhibit CCA progression. CCA cells express receptors for various mediators such as melatonin or serotonin, and administration of these mediators could regulate CCA cell proliferation. CCA cells express elevated levels of proteins such as PD-L1 which bind to PD-1 of T cells to escape T cell-induced cell deaths. Antibodies targeting these immune checkpoint proteins inhibit PD-1-PD-L1 interaction promoting T cell function and killing CCA cells. T cells can be activated by dendritic cells, and stimulation of dendritic cells by pulsing with CCA cell lysates could lead to effective T cell activation leading to inhibition of CCA growth. Recent studies have demonstrated that extracellular vesicles (EVs) can be utilized as therapeutic tools to deliver cargo microRNAs (miRNAs) and regulate cell proliferation or function of CCA cells or cells associated with the tumor microenvironment such as hepatic stellate cells, myofibroblasts, or cancer-associated fibroblasts.

Figure 3.. Origins of cholangiocarcinoma cells.

Cholangiocarcinoma (CCA) is heterogeneous and can emerge from various origins. Hilar/perihilar and distal CCA are mainly derived from the bile duct epithelia (i.e., cholangiocytes). Intrahepatic CCA can be derived from cholangiocytes, hepatic progenitor cells, or hepatocytes. Classical intrahepatic CCA classified as adenocarcinoma is derived from cholangiocytes that line intrahepatic bile ducts. Hepatic progenitor cells are located in the Canal of Hering and can contribute to CCA development as cancer stem cells. Some previous studies classified this CCA phenotype as cholangiolocellular carcinoma. Other studies have demonstrated that hepatocytes can transdifferentiate into cholangiocyte-like cancerous cells expressing biliary markers CK8 and CK19 in rodents. It is not fully defined whether this hepatocyte-derived CCA is identical to cholangiocyte-derived classical intrahepatic CCA or cholangiolocellular carcinoma or a different phenotype which has different characteristics and responses against therapies. This heterogeneity of the CCA origin may contribute to the poor efficacy of current CCA treatments.