The role of cancer stem cells in liver cancer heterogeneity and subtypes

Division Of Basic Sciences - Nci

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Abstract

In a gene expression array study comparing signatures of chronic liver diseases with hepatocellular carcinoma, we revealed a molecular signature that separates these patients for their risk of developing advanced disease. Epithelial cell adhesion molecule was identified as the lead gene in this signature and silencing of this gene resulted in growth suppression of hepatocellular carcinoma cells. Our results support the notion that large numbers of procarcinogenic genes can be acquired before a solitary tumor is formed, and suggest that an alternative mechanism exists for hepatocellular carcinoma, whereby multiple tumor-initiating events can simultaneously occur at the beginning of tumor initiation. The identification of these procarcinogenic genes in premalignant tissues and the mechanisms for their activation or inactivation may improve the future diagnosis of high-risk populations and may guide new strategies for chemoprevention. We have also used global molecular profiling to analyze the gene expression differences among epithelial cell adhesion molecule positive or negative hepatocellular carcinoma. We found that epithelial cell adhesion molecule could significantly differentiate hepatocellular carcinoma into two subtypes that resembled liver lineages. In particular, epithelial cell adhesion molecule-positive hepatocellular carcinoma displayed distinct features of hepatic stem/progenitor cells including an activation of the wnt-beta actenin pathway. Meanwhile, epithelial cell adhesion molecule-negative hepatocellular carcinoma displayed features of mature hepatocytes. We also found that hepatocellular carcinomas could be further stratified into four distinct subtypes with the additional assessment of alpha-fetoprotein status. These four subtypes were associated with prognostic outcome of hepatocellular carcinoma and cells double positive for epithelial cell adhesion molecule and alpha-fetoprotein had the worst prognosis. Furthermore, these subtypes resembled certain stages of liver lineages and epithelial cell adhesion molecule/alpha-fetoprotein-positive cells displayed a distinct molecular signature with features of hepatic stem/progenitor cells. This work suggests that epithelial cell adhesion molecule is a novel diagnostic marker for hepatocellular carcinoma and can be used as a convenient classification system for prognosis. We also explored the mechanism by which epithelial cell adhesion molecule is elevated in hepatocellular carcinoma subtypes with stem/progenitor cell features. We found that the activation of wnt-beta-catenin pathway regulates epithelial cell adhesion molecule expression. We demonstrate that epithelial cell adhesion molecule is a biosensor for wnt-beta-catenin signaling and is transcriptionally up-regulated by this pathway through direct Tcf binding element interactions. Our data suggest that the convergence of epithelial cell adhesion molecule expression and wnt-beta-catenin signaling functions to maintain hepatocellular carcinoma cell growth. Inhibition of hepatocellular carcinoma cell growth could be achieved through blockade of epithelial cell adhesion molecule/wnt-beta-catenin signaling in epithelial cell adhesion molecule-positive hepatocellular carcinoma cells. With these findings, we propose that epithelial cell adhesion molecule/wnt-beta-catenin signaling functions to maintain hepatocellular carcinoma stem cell growth and that epithelial cell adhesion molecule expression-based classification of hepatocellular carcinoma could be useful in clinical settings to stratify hepatocellular carcinoma patients who may benefit from beta-catenin/epithelial cell adhesion molecule adjuvant therapies.In a gene expression array study comparing signatures of chronic liver diseases with hepatocellular carcinoma, we revealed a molecular signature that separates these patients for their risk of developing advanced disease. Epithelial cell adhesion molecule was identified as the lead gene in this signature and silencing of this gene resulted in growth suppression of hepatocellular carcinoma cells. Our results support the notion that large numbers of procarcinogenic genes can be acquired before a solitary tumor is formed, and suggest that an alternative mechanism exists for hepatocellular carcinoma, whereby multiple tumor-initiating events can simultaneously occur at the beginning of tumor initiation. The identification of these procarcinogenic genes in premalignant tissues and the mechanisms for their activation or inactivation may improve the future diagnosis of high-risk populations and may guide new strategies for chemoprevention. We have also used global molecular profiling to analyze the gene expression differences among epithelial cell adhesion molecule positive or negative hepatocellular carcinoma. We found that epithelial cell adhesion molecule could significantly differentiate hepatocellular carcinoma into two subtypes that resembled liver lineages. In particular, epithelial cell adhesion molecule-positive hepatocellular carcinoma displayed distinct features of hepatic stem/progenitor cells including an activation of the wnt-beta actenin pathway. Meanwhile, epithelial cell adhesion molecule-negative hepatocellular carcinoma displayed features of mature hepatocytes. We also found that hepatocellular carcinomas could be further stratified into four distinct subtypes with the additional assessment of alpha-fetoprotein status. These four subtypes were associated with prognostic outcome of hepatocellular carcinoma and cells double positive for epithelial cell adhesion molecule and alpha-fetoprotein had the worst prognosis. Furthermore, these subtypes resembled certain stages of liver lineages and epithelial cell adhesion molecule/alpha-fetoprotein-positive cells displayed a distinct molecular signature with features of hepatic stem/progenitor cells. This work suggests that epithelial cell adhesion molecule is a novel diagnostic marker for hepatocellular carcinoma and can be used as a convenient classification system for prognosis. We also explored the mechanism by which epithelial cell adhesion molecule is elevated in hepatocellular carcinoma subtypes with stem/progenitor cell features. We found that the activation of wnt-beta-catenin pathway regulates epithelial cell adhesion molecule expression. We demonstrate that epithelial cell adhesion molecule is a biosensor for wnt-beta-catenin signaling and is transcriptionally up-regulated by this pathway through direct Tcf binding element interactions. Our data suggest that the convergence of epithelial cell adhesion molecule expression and wnt-beta-catenin signaling functions to maintain hepatocellular carcinoma cell growth. Inhibition of hepatocellular carcinoma cell growth could be achieved through blockade of epithelial cell adhesion molecule/wnt-beta-catenin signaling in epithelial cell adhesion molecule-positive hepatocellular carcinoma cells. With these findings, we propose that epithelial cell adhesion molecule/wnt-beta-catenin signaling functions to maintain hepatocellular carcinoma stem cell growth and that epithelial cell adhesion molecule expression-based classification of hepatocellular carcinoma could be useful in clinical settings to strati [summary truncated at 7800 characters]