Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFβ signaling pathways.
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.
INSERM, UMR991, Université de Rennes 1, Liver Metabolisms and Cancer Rennes, France.
Cédric
C
Coulouarn
Catherine
C
Cavard
Laura
L
Rubbia-Brandt
Anne
A
Audebourg
Florent
F
Dumont
Sébastien
S
Jacques
Pierre-Alexandre
PA
Just
Bruno
B
Clément
Hélène
H
Gilgenkrantz
Christine
C
Perret
Benoît
B
Terris
D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology; D002454:Cell Differentiation; D018281:Cholangiocarcinoma / Q000209:etiology* / Q000473:pathology; D005109:Extracellular Matrix / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011379:Prognosis; D015398:Signal Transduction / Q000502:physiology; D046888:Tissue Array Analysis; D016212:Transforming Growth Factor beta / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
C495270:CTNNB1 protein, human; D016212:Transforming Growth Factor beta; D051176:beta Catenin