Neuroendocrine Changes in Cholangiocarcinoma Growth

Abstract

Cholangiocarcinoma (CCA) is a highly aggressive malignancy that emerges from the biliary tree. There are three major classes of CCA-intrahepatic, hilar (perihilar), or distal (extrahepatic)-according to the location of tumor development. Although CCA tumors are mainly derived from biliary epithelia (i.e., cholangiocytes), CCA can be originated from other cells, such as hepatic progenitor cells and hepatocytes. This heterogeneity of CCA may be responsible for poor survival rates of patients, limited effects of chemotherapy and radiotherapy, and the lack of treatment options and novel therapies. Previous studies have identified a number of neuroendocrine mediators, such as hormones, neuropeptides, and neurotransmitters, as well as corresponding receptors. The mediator/receptor signaling pathways play a vital role in cholangiocyte proliferation, as well as CCA progression and metastases. Agonists or antagonists for candidate pathways may lead to the development of novel therapies for CCA patients. However, effects of mediators may differ between healthy or cancerous cholangiocytes, or between different subtypes of receptors. This review summarizes current understandings of neuroendocrine mediators and their functional roles in CCA.

Keywords: cholangiocarcinoma; cholangiocytes; ductular reaction; hormones; liver fibrosis; neuropeptides; neurotransmitters.

Figure 1

Strategy for the development of novel CCA therapies. Cholangiocytes express various receptors that interact with neuroendocrine mediators. During cholangiopathies such as primary sclerosing cholangitis (PSC), expression levels of mediators and receptors are upregulated, which induces cholangiocyte proliferation and secretion leading to ductular reaction and liver fibrosis. This alteration of cholangiocyte functions may cause CCA development. Upregulation of these mediators and receptors is also observed in CCA tumors. Inhibition of the mediator/receptor axis using antagonists for receptors decreases cAMP levels as well as activation of PKA/ERK1/2 pathways, which attenuates CCA progression and migration. However, effects of mediators may differ between cancerous and non-cancerous cholangiocytes depending on the mediators. In addition, cholangiocytes may express multiple subtypes of receptors for the specific mediators, and functions of receptors may differ between different subtypes. Further studies are required to develop a novel drug to target the specific mediator or receptor subtype for the regulations of CCA cell functions.