A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells

Abstract

The variability in the prognosis of individuals with hepatocellular carcinoma (HCC) suggests that HCC may comprise several distinct biological phenotypes. These phenotypes may result from activation of different oncogenic pathways during tumorigenesis and/or from a different cell of origin. Here we address whether the transcriptional characteristics of HCC can provide insight into the cellular origin of the tumor. We integrated gene expression data from rat fetal hepatoblasts and adult hepatocytes with HCC from human and mouse models. Individuals with HCC who shared a gene expression pattern with fetal hepatoblasts had a poor prognosis. The gene expression program that distinguished this subtype from other types of HCC included markers of hepatic oval cells, suggesting that HCC of this subtype may arise from hepatic progenitor cells. Analyses of gene networks showed that activation of AP-1 transcription factors in this newly identified HCC subtype might have key roles in tumor development.

Ezrin expression is associated with hepatocellular carcinoma possibly derived from progenitor cells and early recurrence after surgical resection

“…Activation of progenitor cell compartments in chronic hepatitis implies that they are vulnerable to genetic alternation, leading to carcinogenesis. Several previous reports 7,10,11,24 have shown that some cases of hepatocellular carcinoma develop Ezrin and hepatocellular carcinoma D Okamura et al through this carcinogenetic mechanism. These tumors usually showed phenotypical features of their cell of origin, such as progenitor cell/ductular markers.…”

“…Lee et al 7 have shown that this heterogeneity was attributable to the cellular origin of the tumor. Patients with hepatocellular carcinoma that probably derived from hepatic progenitor cells, as indicated by a gene expression pattern, had a poor prognosis after surgical treatment.…”

“…Although the mechanisms whereby such types of hepatocellular carcinoma are associated with a poor prognosis and a high rate of recurrence after surgical resection have not been elucidated, it has been reported that several genes involved in tumor invasion and metastasis are upregulated in this type of hepatocellular carcinoma, including VIL2, which encodes ezrin. 7 Ezrin is a member of the ERM (ezrin-radixinmoesin) cytoskeleton-associated protein family. Ezrin and the other ERM proteins act as linkers between the cell membrane and the actin cytoskeleton and are involved in several cellular functions, including cell adhesion to the extracellular matrix, cell-cell communication, signal transduction, and apoptosis.…”

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…Those with the poorest prognosis possessed a sizeable proportion of either EpCAM + AFP + cells (hepatoblastlike) or EpCAM − AFP + cells (HPC-like), whereas those with EpCAM − AFP − cells (mature hepatocytelike) or EpCAM + AFP − cells (cholangiocyte-like) had a more favourable outcome. Moreover, gene expression profiling has identified a subset of HCCs with a poor prognosis that have a profile consistent with an origin from HPCs [151], and simple enumeration of CK19-positive cells in HCC can identify a patient group who have a shorter time to recurrence [152].…”

Drug Therapy: Sorafenib

“…31 Finally, HCC is a heterogeneous disease at the molecular level. 32,33 Rather than approaching all HCCs as ''one disease'' ongoing work is aimed at understanding which patients receive a greater benefit than others. Ultimately, this may identify a predictive marker based on serum or tumor measurements that will allow us to identify which patients will benefit from sorafenib and allow us to individualize treatment decisions.…”