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.

The Emerging Role of Immunotherapy in Intrahepatic Cholangiocarcinoma

“…Chemokines are a class of cytokines with approximately 8–12 kilodaltons mass and the ability to induce chemotaxis of nearby leukocytes (monocytes, macrophages, T lymphocytes, etc.) [ 133 ]. Together with their receptors, they represent emerging key factors of a well-orchestrated network of tumor-promoting events, including cancer cell migration, invasion, and immune evasion [ 133 ].…”

“…[ 133 ]. Together with their receptors, they represent emerging key factors of a well-orchestrated network of tumor-promoting events, including cancer cell migration, invasion, and immune evasion [ 133 ].…”

“…CXCL1–3, CXCL5–6, CXCL8, CXCL12, CCL2, CCL11, and CCL16 are among the various chemokines which contribute to angiogenesis, either in a direct or indirect way [ 134 ]. In cholangiocarcinoma, CXCL12 is positively modulated by angiotensin II and negatively by TGF-β, while CXCR4 expression is promoted by TNF-a-secreting TAMs [ 133 ]. Interactions between CXCR4 and CXCL12 have been demonstrated to activate the PI3K/AKT and ERK1/2 pathway, and Wnt/β-caterin signaling pathway [ 133 ].…”

“…In cholangiocarcinoma, CXCL12 is positively modulated by angiotensin II and negatively by TGF-β, while CXCR4 expression is promoted by TNF-a-secreting TAMs [ 133 ]. Interactions between CXCR4 and CXCL12 have been demonstrated to activate the PI3K/AKT and ERK1/2 pathway, and Wnt/β-caterin signaling pathway [ 133 ]. Via the activation of the PI3K/AKT and ERK1/2 pathway, CXCL5 acts as chemoattractant for neutrophils, while FAP-induced CCL2 secretion mediates the migration of both macrophages and MDSCs [ 133 ].…”

Research Progress of Biliary Tract Cancers

“…Meanwhile, Malenica et al discuss recent research progress in the immunological characterization of BTCs and its implications for the development of novel immune-based therapies. Caligiuri et al review the role of chemokines in the regulation of CCA development and progression, and the modulation of angiogenesis, metastasis and immune control [ 21 , 22 ]. They summarize the most recent findings on the role played by chemokine-induced signals in driving CCA malignancy and discuss the potential role of chemokines and their receptors as possible biomarkers and/or therapeutic targets for hepatobiliary cancers.…”