Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells Journal Article


Authors: Oikawa, T.; Wauthier, E.; Dinh, T. A.; Selitsky, S. R.; Reyna-Neyra, A.; Carpino, G.; Levine, R.; Cardinale, V.; Klimstra, D.; Gaudio, E.; Alvaro, D.; Carrasco, N.; Sethupathy, P.; Reid, L. M.
Article Title: Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells
Abstract: The aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs), cancers occurring increasingly in children to young adults, is poorly understood. We present a transplantable tumour line, maintained in immune-compromised mice, and validate it as a bona fide model of hFL-HCCs by multiple methods. RNA-seq analysis confirms the presence of a fusion transcript (DNAJB1-PRKACA) characteristic of hFL-HCC tumours. The hFL-HCC tumour line is highly enriched for cancer stem cells as indicated by limited dilution tumourigenicity assays, spheroid formation and flow cytometry. Immunohistochemistry on the hFL-HCC model, with parallel studies on 27 primary hFL-HCC tumours, provides robust evidence for expression of endodermal stem cell traits. Transcriptomic analyses of the tumour line and of multiple, normal hepatic lineage stages reveal a gene signature for hFL-HCCs closely resembling that of biliary tree stem cells-newly discovered precursors for liver and pancreas. This model offers unprecedented opportunities to investigate mechanisms underlying hFL-HCCs pathogenesis and potential therapies. © 2015 Macmillan Publishers Limited.
Keywords: immunohistochemistry; vasculotropin; adult; controlled study; pathogenesis; liver cell carcinoma; nonhuman; animal cell; mouse; mus; vascular cell adhesion molecule 1; animal experiment; animal model; cell differentiation; uvomorulin; scatter factor; cancer stem cell; carcinogenicity; cell count; epithelial cell adhesion molecule; liver cell; hermes antigen; cell suspension; bmi1 protein; octamer transcription factor 4; transcription factor sox2; transcription factor nanog; rna sequence; kruppel like factor 4; syndecan 1; transcription factor sox17; transcription factor sox9; cancer graft; human; male; female; article; ascites tumor cell; human fibrolamellar hepatocellular carcinoma
Journal Title: Nature Communications
Volume: 6
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2015-10-06
Start Page: 8070
Language: English
DOI: 10.1038/ncomms9070
PROVIDER: scopus
PMCID: PMC4600730
PUBMED: 26437858
DOI/URL:
Notes: Export Date: 2 November 2015 -- Source: Scopus
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  1. David S Klimstra
    925 Klimstra