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 |
