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

Coulouarn, Cédric
Cavard, Catherine
Audebourg, Anne
Dumont, Florent
Jacques, Sébastien
Just, Pierre-Alexandre
Clément, Bruno
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Published in Carcinogenesis. 2012, vol. 33, no. 9, p. 1791-6
Abstract Intrahepatic malignant tumours include hepatocellular carcinomas (HCC), cholangiocarcinomas (CC) and combined hepatocholangiocarcinomas (cHCC-CC), a group of rare and poorly characterized tumours that exhibit both biliary and hepatocytic differentiation. The aim of the study was to characterize the molecular pathways specifically associated with cHCC-CC pathogenesis. We performed a genome-wide transcriptional analysis of 20 histologically defined cHCC-CC and compared them with a series of typical HCC and of CC. Data were analysed by gene set enrichment and integrative genomics and results were further validated in situ by tissue microarray using an independent series of 152 tumours. We report that cHCC-CC exhibit stem/progenitor features, a down-regulation of the hepatocyte differentiation program and a commitment to the biliary lineage. TGFβ and Wnt/β-catenin were identified as the two major signalling pathways activated in cHCC-CC. A β-catenin signature distinct from that observed in well-differentiated HCC with mutant β-catenin was found in cHCC-CC. This signature was associated with microenvironment remodelling and TGFβ activation. Furthermore, integrative genomics revealed that cHCC-CC share characteristics of poorly differentiated HCC with stem cell traits and poor prognosis. The common traits displayed by CC, cHCC-CC and some HCC suggest that these tumours could originate from stem/progenitor cell(s) and raised the hypothesis of a potential continuum between intrahepatic CC, cHCC-CC and poorly differentiated HCC.
Keywords Carcinoma, Hepatocellular/etiology/pathologyCell DifferentiationCholangiocarcinoma/etiology/pathologyExtracellular Matrix/physiologyGene Expression ProfilingHumansLiver Neoplasms/etiology/pathologyNeoplastic Stem Cells/pathologyPrognosisSignal Transduction/physiologyTissue Array AnalysisTransforming Growth Factor beta/physiologyWnt Signaling Pathway/physiologyBeta Catenin/physiology
PMID: 22696594
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Research group Métastases du foie (657)
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COULOUARN, Cédric et al. Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFβ signaling pathways. In: Carcinogenesis, 2012, vol. 33, n° 9, p. 1791-6. https://archive-ouverte.unige.ch/unige:27546

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Deposited on : 2013-04-24

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