Novel approaches in search for biomarkers of cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) arises from the ductular epithelium of the biliary tree, either within the liver (intrahepatic CCA) or more commonly from the extrahepatic bile ducts (extrahepatic CCA). This disease has a poor prognosis and a growing worldwide prevalence. The poor outcomes of CCA are partially explained by the fact that a final diagnosis is challenging, especially the differential diagnosis between hepatocellular carcinoma and intrahepatic CCA, or distal CCA and pancreatic head adenocarcinoma. Most patients present with an advanced disease, unresectable disease, and there is a lack in non-surgical therapeutic modalities. Not least, there is an acute lack of prognostic biomarkers which further complicates disease management. Therefore, there is a dire need to find alternative diagnostic and follow-up pathways that can lead to an accurate result, either singlehandedly or combined with other methods. In the "-omics" era, this goal can be attained by various means, as it has been successfully demonstrated in other primary tumors. Numerous variants can reach a biomarker status ranging from circulating nucleic acids to proteins, metabolites, extracellular vesicles, and ultimately circulating tumor cells. However, given the relatively heterogeneous data, extracting clinical meaning from the inconsequential noise might become a tall task. The current review aims to navigate the nascent waters of the non-invasive approach to CCA and provide an evidence-based input to aid clinical decisions and provide grounds for future research.

Keywords: Biomarker; Cholangiocarcinoma; Circulating nucleic acids; Extracellular vesicles; Metabolomics; Proteomics.

Figure 1

An overview on the biomarkers for cholangiocarcinoma. Created with biorender.com. A1AG1: Alpha-1 acid glycoprotein; AFP: Alpha fetoprotein; Ang-2: Angiopoietin-2; ASGPR1: Asialoglycoprotein receptor 1; CA19-9: Charbohydrate antigen 19-9; CDH17: Cadherin-17; CEA: Carcinoembryonic antigen; CIAPIN1: Cytokine-induced apoptosis inhibitor 1; CRP: C-reactive protein; CTLA-4: Cytotoxic T-lymphocyte antigen 4; CYFRA 21-1: Cytokeratin 19 fragment; DKK1: Dickkopf-1; EGFR: Epidermal growth factor receptor; EpCAM: Epithelial cell adhesion molecule; FGFR2: Fibroblast growth factor receptor 2; FIBG: Fibrinogen gamma chain; FOXP3: Forkhead box P3; FSCN: Fascin; HHLA2: Human endogenous retrovirus-H long terminal repeat-associating protein 2; IDH1: Isocitrate dehydrogenase 1; IDH2: Isocitrate dehydrogenase 2; IGHA1: Immunoglobulin heavy constant alpha 1; IL-6: Interleukin 6; Ki67: Proliferation marker protein Ki67; KL-6: Krebs von den Lungen 6; KLK11: Kallikrein related peptidase 11; LC3: Microtubule-associated protein 1A/1B-light chain 3; MMP-7: Metalloproteinase 7; MUC1: Mucin 1; MUC4: Mucin 4; MUC5AC: Mucin 5AC; OPN: Osteopontin; PD-L1: Programmed death-ligand 1; S100A6: S100 calcium-binding protein A6; S100A9: S100 calcium-binding protein A9; S100P: Tissue protein S100P; SSP411: Spermatogenesis-associated protein 20; TGF-β1: Transforming growth factor-β1; TSP-2: Thrombospondin-2; uPA: Urokinase-type plasminogen activator; uPAR: Urokinase-type plasminogen activator receptor; VNN1: Pantetheinase.