Liver stem cells: implications for hepatocarcinogenesis.

Numerous studies point to the fact that liver tumors are derived from single cells (monoclonal), but the important question is, which cell? Stem cell biology and cancer are inextricably linked. In continually renewing tissues such as the intestinal mucosa and epidermis, in which 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, as 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 identity of the founder cells for the two major primary tumors, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), is more problematic. The reason for this is that no such obvious unidirectional flux occurs in the liver, though it is held that the centrilobular hepatocytes may be more differentiated (polyploid) and closer to cell senescence than those cells closest to the portal areas. Moreover 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. Irrespective of which target cell is involved, cell proliferation at the time of carcinogen exposure is pivotal for "fixation" of the genotoxic injury into a heritable form. Taking this view, any proliferative cell in the liver can be susceptible to neoplastic transformation. Thus, hepatocytes are implicated in many instances of HCC, direct injury to the biliary epithelium implicates cholangiocytes in some cases of CC, whereas HPC/oval cell activation accompanies very many instances of liver damage irrespective of etiology, making such cells very 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. An indepth discussion of causes of cancer in the liver are beyond the scope of this review, but infectious agents (e.g., hepatitis B and C viruses) play a major role, not just in transactivating or otherwise disrupting cellular proto-oncogenes (hepatitis B virus [HBV]), but in also causing chronic inflammation (hepatitis C virus [HCV] and HBV). Sustained epithelial proliferation in a milieu rich in inflammatory cells, growth factors, and DNA-damaging agents (reactive oxygen and nitrogen species produced to fight infection), will lead to permanent genetic changes in proliferating cells. The upregulation of the transcription factor nuclear factor kappaB (NF-kappaB) in transformed hepatocytes, through the paracrine action of tumor necrosis factor-alpha from neighboring endothelia and inflammatory cells, may be critical for tumor progression given the mitogenic and anti-apoptotic properties of proteins encoded by many of NF-kappaB's target genes.