Role of Chemokines in the Biology of Cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA), a heterogeneous tumor with poor prognosis, can arise at any level in the biliary tree. It may derive from epithelial cells in the biliary tracts and peribiliary glands and possibly from progenitor cells or even hepatocytes. Several risk factors are responsible for CCA onset, however an inflammatory milieu nearby the biliary tree represents the most common condition favoring CCA development. Chemokines play a key role in driving the immunological response upon liver injury and may sustain tumor initiation and development. Chemokine receptor-dependent pathways influence the interplay among various cellular components, resulting in remodeling of the hepatic microenvironment towards a pro-inflammatory, pro-fibrogenic, pro-angiogenic and pre-neoplastic setting. Moreover, once tumor develops, chemokine signaling may influence its progression. Here we review the role of chemokines in the regulation of CCA development and progression, and the modulation of angiogenesis, metastasis and immune control. The potential role of chemokines and their receptors as possible biomarkers and/or therapeutic targets for hepatobiliary cancer is also discussed.

Keywords: cancer associated fibroblasts; chemokines; cholangiocarcinoma.

Figure 1

Schematic representation of paracrine effects between stromal cells and CCA cells. Tumor associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), cholangiocarcinoma (CCA).

Figure 2

Major effects of chemokines on cancer. Epithelial-mesenchymal transition (EMT).

Figure 3

Modulation of CCA development by chemokine networks. Chemokines produced by CCA cells and by intratumor stromal cells, such as CAFs, activate signaling transduction pathways and attract different immune cell types into the CCA TME. CXCL12 released by fibroblast acts on the biological activities of CCA cells. CXCL12 released in CCA microenvironment is negatively modulated by TGF-β and positively by Ang II. TNF-α released by tumor-infiltrating macrophages, promotes the increase of CXCR4 expression in CCA cells. CXCL12/CXCR4 interaction induces activation of PI3K, ERK, Akt and the canonical Wnt signaling in CCA cells. CCL2 secretion, which is induced by FAP in CAFs, mediates migration of MDSCs and macrophages in CCA. CXCL5, secreted by CCA cells and induced by IL-1β released by HSCs, promotes cell migration and invasion through an autocrine loop. In addition, CXCL5 acts as potent chemotactic stimulus for neutrophils inducing neutrophil infiltration through PI3K/Akt and ERK1/2 activation. CXCL9 released by CCA cells correlates with an increase of tumor-infiltrating NK cells. The figure represents a selection among various chemokines involved in CCA progression. Cholangiocarcinoma (CCA), Tumor microenvironment (TME), transforming growth factor-β (TGF-β), angiotensin II (Ang II), tumour necrosis factor-α (TNF-α), phosphoinositide 3-kinase (PI3K), metalloproteinase (MMP), hepatic stellate cell (HSC), cancer-associated fibroblast (CAF), fibroblast activation protein (FAP), myeloid-derived suppressor cell (MDSC), Interleukin-1 β (IL-1β), natural killer cell (NK).