Proteomic Landscape of Cholangiocarcinomas Reveals Three Different Subgroups According to Their Localization and the Aspect of Non‐Tumor Liver

Abstract

Purpose Cholangiocarcinomas (CCs) define a heterogeneous entity based upon their anatomic localization (intra versus extrahepatic) and, for the intrahepatic CCs, the aspect of background liver (normal versus cirrhosis). The aim of the study was to characterize the molecular heterogeneity of CCs by a global proteomic approach. Experimental design Thirty‐three tumor samples from 17 intrahepatic CCs (iCC) (9 developed on normal (iCCN) and 8 developed in cirrhotic liver (iCCC)); 5 hilar CCs (CCH); 5 pancreatic CCs (CCP) and 6 hepatocellular carcinomas (HCC), were submitted to label‐free quantitative proteomic analysis. Differential proteins were analyzed by immunohistochemistry in a validation set of 30 CCs. Results Unsupervised analysis revealed two main clusters: cluster 1 contained most of the iCCC while cluster 2 was divided in 2 subgroups, one containing most of the iCCN and the other regrouping CCH and CCP. Compared to iCCN, iCCC displayed upregulation of molecules involved in cell adhesion, motility and angiogenesis. Epithelial markers associated with secretory pathway and fibroblast markers were overexpressed in CCH compared to iCCN Conclusion and clinical relevance This study demonstrated that iCCC is a specific entity, suggesting a major impact of the background liver on tumor biology, and confirmed that extrahepatic CCs define a homogeneous subgroup.

Quantitative proteomic analysis of bile in extrahepatic cholangiocarcinoma patients

“…Bile analysis for diagnosis of CCA is a promising method, especially in differentiation of biliary stricture, because CCA which originates from the biliary epithelium might release proteins from cancer cells into bile [9]. Thus, proteomic analyses of bile for discovering CCA biomarkers have been done in many studies [9][10][11][12][13][14][15]. However, the bile-protein profiles of CCA were different from the studies.…”

“…Previous studies enrolled both of intrahepatic and extrahepatic CCA in the same study. CCA is a heterogeneous entity and is defined by anatomic location as intra or extrahepatic CCA [15]. For intrahepatic CCA, the different characterization depended on whether the liver is cirrhotic or not [15].…”

“…CCA is a heterogeneous entity and is defined by anatomic location as intra or extrahepatic CCA [15]. For intrahepatic CCA, the different characterization depended on whether the liver is cirrhotic or not [15]. Thus, the tumor character differences by anatomical location might affect the bile-protein profile.…”

“…Thus, the tumor character differences by anatomical location might affect the bile-protein profile. One study demonstrated that intrahepatic CCA is a heterogeneous group affected by background liver conditions on tumor biology, while extrahepatic CCA is a more homogeneous subgroup [15]. For elimination of heterogeneity of cancer tissue, we enrolled only extrahepatic CCA in our study.…”

Proteomics in Pathology: The Special Issue

“…[7] Le Faouder et al depicted the proteomic landscape of cholangiocarcinoma using LC-MS/MS-based proteomics in data-dependent acquisition mode. [23] Zhu et al presented an application of pressure cycling technology-sequential window acquisition of all theoretical fragment ion spectra (PCT-SWATH)-MS for the analysis of hepatocellular carcinoma biopsies. From 19 hepatocellular carcinoma patients, they could identify and quantify about 12 000 peptides that corresponded to 2579 proteins.…”