Abstract 4252: Mechanistic and clinical implications of epigenetic modulation in liver cancer stem cells

Abstract

Abstract Epigenetic mechanisms play critical roles in both stem cell and cancer biology. Epigenetic modulation directs stem cells towards pluripotency and promotes differentiation of more mature derivatives. We hypothesized, that if similar mechanisms are relevant to the cancer stem cell (CSC) model, then epigenetic modulation might enrich the CSC population, thereby facilitating CSCs isolation and rigorous evaluation. Five hepatoma cell lines were treated with Zebularine (ZEB), an effective DNMT1-inhibitor. Putative CSC were isolated using the “side population” (SP) approach. FACS-sorted SP and non-SP fractions were examined for tumorigenic capacity and differences in gene expression. SP-derived signatures were integrated with HCC microarray database and tested for a prognostic value. ZEB-treatment significantly reduced the SP size while remarkably increasing the proportion of cells with CSC properties as judged by a superior tumor-initiation capacity relative to the untreated SP cells. This was further confirmed in serial transplantation as well as direct cell tracking experiments using genetically labeled SP and non-SP cells. Furthermore, integrative transcriptome analysis of the ZEB-enriched CSC populations identified common stemness traits although various oncogenic pathways (e.g. EGFR, SRC and MYC) were activated in individual hepatoma cell lines. Moreover, each individual as well as the common CSC signatures were associated with poorly differentiated tumors, high recurrence rate and poor survival in liver as well as lung cancers. In conclusion, we demonstrate that modulation of the liver cancer epigenome is a useful tool to increase the representation of highly tumorigenic cells with CSC properties within the SP fraction. The integrative analysis of the CSC transcriptome revealed a pernicious interaction of common CSC stemness genes with variety of known oncogenic pathways in liver cancer. The significance of CSC- enriched gene signature for the prognosis of liver and other cancers provides a rationale for therapeutic targeting of CSCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4252.