1. Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFβ signaling pathways
- Author
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Hélène Gilgenkrantz, Cédric Coulouarn, Sébastien Jacques, Anne Audebourg, Catherine Cavard, Florent Dumont, Christine Perret, Pierre-Alexandre Just, Bruno Clément, Benoit Terris, Laura Rubbia-Brandt, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microenvironnement et remodelage, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
- Subjects
MESH: Signal Transduction ,Cancer Research ,Pathology ,MESH : Liver Neoplasms ,Cellular differentiation ,MESH: beta Catenin ,ddc:616.07 ,Cholangiocarcinoma/etiology/pathology ,Cholangiocarcinoma ,0302 clinical medicine ,Transforming Growth Factor beta ,MESH: Liver Neoplasms ,MESH: Carcinoma, Hepatocellular ,Wnt Signaling Pathway ,beta Catenin ,Hepatocyte differentiation ,MESH : Prognosis ,Tissue microarray ,Neoplastic Stem Cells/pathology ,Liver Neoplasms ,MESH : Extracellular Matrix ,MESH: Wnt Signaling Pathway ,Wnt signaling pathway ,Cell Differentiation ,General Medicine ,Prognosis ,Extracellular Matrix ,3. Good health ,Transforming Growth Factor beta/physiology ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,[ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,030211 gastroenterology & hepatology ,Wnt Signaling Pathway/physiology ,Stem cell ,MESH: Tissue Array Analysis ,MESH : Cell Differentiation ,Signal Transduction ,MESH : Carcinoma, Hepatocellular ,MESH: Cell Differentiation ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,MESH : Wnt Signaling Pathway ,Beta Catenin/physiology ,MESH: Extracellular Matrix ,Biology ,MESH: Prognosis ,MESH: Gene Expression Profiling ,03 medical and health sciences ,MESH : Neoplastic Stem Cells ,medicine ,Extracellular Matrix/physiology ,Humans ,Progenitor cell ,MESH: Transforming Growth Factor beta ,Progenitor ,MESH : Signal Transduction ,MESH: Humans ,Carcinoma, Hepatocellular/etiology/pathology ,Signal Transduction/physiology ,Gene Expression Profiling ,MESH : Gene Expression Profiling ,MESH : Humans ,Liver Neoplasms/etiology/pathology ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,MESH : Cholangiocarcinoma ,MESH : beta Catenin ,MESH: Cholangiocarcinoma ,MESH: Neoplastic Stem Cells ,Gene expression profiling ,Bile Ducts, Intrahepatic ,MESH : Transforming Growth Factor beta ,Bile Duct Neoplasms ,Tissue Array Analysis ,MESH : Tissue Array Analysis - Abstract
International audience; 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.
- Published
- 2012