Basic Science of Liver Cancer Stem Cells and Hepatocarcinogenesis

The cellular origin of hepatocellular carcinoma (HCC) is unknown. The most likely precursors are the hepatocyte or one of the putative liver stem cells (LSCs), such as the oval cell (OC) or the liver cancer stem cell (LCSC), residing within the HCC. By definition, LCSCs have the capacity to generate a population of daughter HCC cells. By definition, hepatocytes and LSCs do not have this capability, and the chronology of progression to malignancy and the putative intermediates involved are unknown. If there is a transition from one of these cells to another during such a progression, it has not been definitively shown. This article reviews some historical studies which defined the stem cell, and discusses some current experimental attempts to determine these defining characteristics, such as asymmetric division or limiting‐dilution analysis, multipotency and carcinogenicity. There is a constant search for unique markers for any of these potential precursors, which would have great clinical and experimental value, and in the absence of specific identifying markers to date, growing sets of signature markers are used for putative identifications; in one case, the ‘null’ cell is defined by its lack of markers, but it is a reliable product of certain types of liver injury, and DNA‐labelling retention appears to localize this cell to a unique site in the liver lobule. Increasingly, cells are being localized to particular niches, and they are also being isolated and cultured in the lab. One characteristic of cancer stem cells seems to be the ability to form floating spheroids in culture, and the variation in this capability has been used for isolation of LCSCs of different carcinogenicities. New marker‐inducible animal models are providing ways of tracing cells that have led to surprises and to new experiments. All of these approaches together will bring clarity to the science of liver stem cells and liver cancer stem cells.