No abstract

High hepatocyte-selective enhancement is induced by expression patterns of transporters, which may result in accumulation of gadoxetic acid in cytoplasm of tumor cells or in lumina of pseudoglands. An HCC with gadoxetic acid enhancement is characterized by bile accumulation in tumors.

BACKGROUND & AIMS Human primary liver cancer (PLC) is classified into biologically distinct subgroups, based on cellular origin. Liver cancer stem cells (CSCs) have been recently described. We investigated the ability of distinct lineages of hepatic cells to become liver CSCs and the phenotypic and genetic heterogeneity of PLC. METHODS We transduced mouse primary hepatic progenitor cells (HPC), lineage-committed hepatoblasts, and differentiated adult hepatocytes with transgenes encoding oncogenic H-Ras and simian virus 40 large-T antigen. The CSC properties of transduced cells and their ability to form tumors were tested by standard in vitro and in vivo assays and transcriptome profiling. RESULTS Irrespective of origin, all transduced cells acquired markers of CSC/progenitor cells, side populations, and self-renewal capacity in vitro. They also formed a broad spectrum of liver tumors, ranging from cholangiocarcinoma to hepatocellular carcinoma, which resembled human liver tumors, based on genomic and histologic analyses. The tumor cells co-expressed hepatocyte (HNF4A), biliary progenitor cell (keratin 19, EpCAM, A6), and mesenchyme (vimentin) markers and showed disregulation of genes that control the epithelial–mesenchymal transition. Gene expression analyses could distinguish tumors of different cellular origin, indicating the contribution of lineage-stage dependent genetic changes to malignant transformation. Activation of c-Myc and its target genes was required to reprogram adult hepatocytes into CSC and for tumors to develop. Stable knockdown of c-Myc in transformed adult hepatocytes reduced their CSC properties in vitro and suppressed growth of tumors in immunodeficient mice. CONCLUSIONS Any cell type in the mouse hepatic lineage can undergo oncogenic reprogramming into a CSC, by activating different cell type-specific pathways. Identification of common and cell-of-origin specific phenotypic and genetic changes could provide new therapeutic targets for liver cancer.