Proliferative drive and liver carcinogenesis: too much of a good thing?

There have been innumerable studies published in the attempt to identify gene expression signatures in hepatocellular carcinoma (HCC). When all the regulators and targets of the differentially expressed genes are analyzed from larger studies, the most striking theme is upregulation of mitosis-promoting and cell proliferation genes in HCC compared with 'liver-specific gene clusters' in non-tumorous tissue. A major limitation of expression profiling is that it only provides a 'snapshot' of what is an evolving process and thus cannot distinguish the differences in gene expression that are primary effectors of dysregulated growth from those that represent downstream consequences. The development of HCC in a chronically diseased liver, often referred to as hepatocarcinogenesis, is a multistep process characterized by the progressive accumulation and interplay of genetic alterations causing aberrant growth, malignant transformation of liver parenchymal cells, followed by vascular invasion and metastasis. This review will discuss HCC precursor lesions, draw on the 'proliferation cluster' genes highlighted from HCC expression profiling studies, relate them to a selection of regulatory networks important in liver regeneration, cell cycle control and their potential significance in the pathogenesis of HCC or primary liver cancer.