Liver cancer: a disease of stem cells?

Studies of aggregation chimaeras and X-linked polymorphisms strongly suggest that most liver tumours are derived from single cells (monoclonal): this review looks at the various cells in the liver that could be the founder cells for the two major primary tumours, namely hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). In continually renewing tissues such as the gut mucosa and epidermis, where a steady flux of cells occurs from the stem cell zone to the terminally differentiated cells that are imminently to be lost, it is widely accepted that cancer is a disease of stem cells, since these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic development. In the liver the existence of bipotential hepatic progenitor cells (HPCs), along with hepatocytes endowed with longevity and long-term repopulating potential suggests there may be more than one type of carcinogen target cell. Cell proliferation at the time of carcinogen exposure is essential for fixation' of any genotoxic injury into a heritable form, thus any proliferative cell in the liver can be susceptible to neoplastic transformation. Hepatocytes are implicated in many instances of HCC (e.g. in mouse models of HCC, oncogenic transgenes are driven by albumin promoters): chronic inflammatory injury to the biliary epithelium suggests cholangiocytes can give rise to CC, while HPC/oval cell activation accompanies many instances of liver damage irrespective of aetiology, making such cells likely carcinogen targets. Of course, we must qualify this assertion by stating that many carcinogens are both cytotoxic and cytostatic, and that HPC proliferation may be merely a bystander effect of this toxicity.