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Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFbeta signaling pathways

ABSTRACT: Primary liver tumours include hepatocellular carcinomas (HCC), cholangiocarcinomas (CC) and a group of rare tumours exhibiting biliary and hepatocytic differentiation called combined hepatocholangiocarcinomas (cHCC-CC). To better define this latter group, we take advantage of a series of these tumours based on their morphological characteristics and we performed transcriptional analysis allowing thereafter global comparison with published data. We show that most cHCC-CCs express progenitor cell traits, are committed to biliary lineage and are mainly associated to the activation of Wnt/beta-catenin and TGFbeta signalling pathways. Wnt/beta-catenin pathway activation in cHCC-CC is evidenced by the expression of both its direct targets such as LEF1 and EPCAM. In addition, extracellular matrix (ECM) genes and ECM-remodelling genes which are upon the control of TGF profibrotic program were found up-regulated in cHCC-CC. Interestingly, we show that CC and most cHCC-CC share characteristics associated to a subtype of poorly differentiated HCC suggesting that these tumours could originate from a stem/progenitor cell. The plasticity of these cells may explain the phenotypical heterogeneity of these tumors with the maintenance of some hepatocellular differentiation features such as albumin expression. Interestingly, this is shared by at least one third of CC, raising the hypothesis of a potential continuum between CC, cHCC-CC and poorly differentiated HCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE35306 | GEO | 2012/04/01

SECONDARY ACCESSION(S): PRJNA150737

REPOSITORIES: GEO

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Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFbeta signaling pathways

Project description:Primary liver tumours include hepatocellular carcinomas (HCC), cholangiocarcinomas (CC) and a group of rare tumours exhibiting biliary and hepatocytic differentiation called combined hepatocholangiocarcinomas (cHCC-CC). To better define this latter group, we take advantage of a series of these tumours based on their morphological characteristics and we performed transcriptional analysis allowing thereafter global comparison with published data. We show that most cHCC-CCs express progenitor cell traits, are committed to biliary lineage and are mainly associated to the activation of Wnt/beta-catenin and TGFbeta signalling pathways. Wnt/beta-catenin pathway activation in cHCC-CC is evidenced by the expression of both its direct targets such as LEF1 and EPCAM. In addition, extracellular matrix (ECM) genes and ECM-remodelling genes which are upon the control of TGF profibrotic program were found up-regulated in cHCC-CC. Interestingly, we show that CC and most cHCC-CC share characteristics associated to a subtype of poorly differentiated HCC suggesting that these tumours could originate from a stem/progenitor cell. The plasticity of these cells may explain the phenotypical heterogeneity of these tumors with the maintenance of some hepatocellular differentiation features such as albumin expression. Interestingly, this is shared by at least one third of CC, raising the hypothesis of a potential continuum between CC, cHCC-CC and poorly differentiated HCC. Patients serie include 3 intra-hepatic CC, 7 typical HCC and 20 cHCC-CC that was used for microarray hybridisation. All these tumours did not show any mutation of the beta-catenin gene. The degree of hepatic fibrosis of the non-cancerous liver was graded according to the METAVIR classification. Paraffin sections were processed as described previously. Immunohistochemistry was done on standard slides for the series.

2012-03-31 | E-GEOD-35306 | biostudies-arrayexpress

Proteomic landscape of cholangiocarcinomas reveals 3 different subgroups according to their localization and the underlying non-tumor liver

Project description:Cholangiocarcinomas (CC) define a heterogeneous entity based upon their anatomic localization along the biliary tree and, for those developing in the liver (iCC), depending on the aspect of non tumoral liver (cirrhosis or not). Gene expression analysis of iCC revealed 2 main subgroups (inflammatory and proliferative). The aim of the study was to address the heterogeneity of CC by comparing their protein expression using a global quantitative proteomic approach.

2018-12-11 | PXD010294 | Pride

Human hepatocytes can give rise to intrahepatic cholangiocarcinomas

Project description:To determine the transcriptomic similarity of undifferentiated carcinomas (UDCs) and intrahepatic cholangiocarcinomas (iCCAs) generated from primary human hepatocytes (phHeps) by oncogene expression and transplantation into immue-deficient mice with liver injury to iCCAs and hepatocellular carcinomas (HCCs) resected from patients.

2024-01-12 | GSE221589 | GEO

Identification of cholangiocarcinoma-like gene expression traits in hepatocellular carcinoma

Project description:We performed gene expression profiling of hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and mixed type of combined HCC and CC (CHC). In comparison of the profiles, a novel class of HCC expressing CC-like traits was identified. Gene expression profiling of 70 hepatocellular carcinoma (HCC), 13 cholangiocarcinoma (CC), and 7 mixed type of combined HCC and CC (CHC) were performed.

2010-06-09 | E-GEOD-15765 | biostudies-arrayexpress

Role of bcatenin in hepatocellular carcinoma

Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. β-catenin is widely thought to be a major oncogene in HCC based on the frequency of mutations associated with aberrant Wnt signaling in HCC patients. Challenging this model, our data reveal that β-catenin nuclear accumulation is restricted to the late stage of the disease. Until then, β-catenin is primarily located at the plasma membrane in complex with multiple cadherin family members where it drives tumor cell survival by enhancing the signaling of growth factor receptors such as EGFR. Therefore, our study reveals the evolving nature of β-catenin in HCC to establish it as a compound tumor promoter during the progression of the disease.

2019-03-29 | PXD013095 | Pride

Cavard Agilent

Project description:Through the combined use of glutamine synthase / GLUL immunostaining, and CTNNB1 genotyping, we previously analyzed nearly 200 hepatocellular carcinomas (HCC). Little was reported on HCC with mutant B-catenin excepted their low genomic instability, their lack of association with hepatitis B virus and their well-differentiated pattern. We have demonstrated that HCC with mutant B-catenin exhibit specific features such as an homogeneous well differentiated pattern with a mixture of microtrabecular and acinar architecture, the absence of steatosis and the presence of frequent extra-cellular cholestasis. The aim of our study was to characterize the bile components in HCC with mutant B-catenin. To this end, we carried out transcriptome profiling of five typical B-catenin activated HCCs and we analysed the composition of the bile accumulated in these tumors. The transcriptional analysis of these tumors showed overexpression of genes belonging both to the synthesis (CYP7A1, CYP27A1 and CYP7B1) and transport (ABCG2/BCRP, ABCC2/MRP2, ABCB11/BSEP, OATP8/SLC01B3) of bile acids. However, the composition of bile in these tumors is not significantly modified. The large amount of bilirubin in these tumors follows the increase in biliverdin pigment reflecting the characteristic green color of these tumors and biliary acids content is not profoundly altered. Surprisingly, the main change affects the non-tumoral counterparts of HCC with mutant B-catenin which display an unexpected high content in biliary acids. These observations suggest that increased bile acids level due to an underlying pathology may play a role in the emergence of HCC with mutant B-catenin.

2011-06-01 | E-MEXP-2821 | biostudies-arrayexpress

Quantitative proteome analysis of hepatocellular carcinoma tissue

Project description:Hepatocellular carcinoma (HCC) is one of the most aggressive tumors and the treatment outcome of this disease is improved when the cancer is diagnosed at early stages. This requires biomarkers allowing for an accurate and early tumor diagnosis. To identify potential markers for such applications we performed a label-free proteome analysis using samples collected from 19 patients. We analyzed the data considering events known to take place in early events of HCC development such as abnormal regulation of Wnt/b-catenin and activation of receptor tyrosine kinases (RTKs). We expected that such analysis can lead to the identification of potential biomarkers for early-stage HCC diagnosis. 31 proteins functionally linked to downstream interactors of Wnt/b-catenin and parts of RTKs´-activated pathways Ras and JAK/STAT were selected for verification in a larger and independent cohort (n= 31) using selected (multiple) reaction monitoring (SRM/MRM).

2016-04-13 | PXD002171 | Pride

Identification of cholangiocarcinoma-like gene expression traits in hepatocellular carcinoma

2010-05-21 | GSE15765 | GEO

Bulk transcriptomic analysis of two models of zebrafish beta-catenin-driven HCC

Project description:Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. β-catenin has dual cellular functions as a component of the Wnt signaling pathway and adherens junctions. HCC-associated CTNNB1 mutations stabilize the β-catenin protein, leading to nuclear and/or cytoplasmic localization of β-catenin and downstream activation of Wnt target genes. In patient HCC samples, β-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in β-catenin activation are not well understood. To define mechanisms of β-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated β-catenin in 1) a small number of hepatocytes in early development; or 2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated β-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/β-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish β-catenin-driven HCC. Ingenuity Pathway Analysis of differentially expressed genes in the Cre-lox HCC model revealed that “Cancer” and “Liver Tumor” categories were significantly altered, indicating transcriptional similarities with human HCC and other vertebrate HCC models. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish β-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca, and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous β-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.

2019-09-27 | GSE137787 | GEO

Single-cell transcriptomic analysis of two models of zebrafish beta-catenin-driven HCC

2019-09-27 | GSE137784 | GEO

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