Perspectives in CancerResearch Is There a Liver Stem Cell

The role of a putative liver stem cell in liver regeneration and carcinogenesis is reviewed. There is increasing evidence that there is a liver stem cell that has the capacity to differentiate into parenchyma! hepatocytes or into bile ductular cells. These stem cells may be activated to proliferate after severe liver injury or exposure to hepatocarcinogens. They are not activated by moderate liver injury, which is repaired by proliferation of mature hepatocytes. Exposure to most chemical hepato carcinogens results in proliferation of a small morphologically indistinct cell population termed "oval cells. " These cells have been shown to have the capacity to differentiate into hepatocytes or into ductular cells. The origin of these cells appears to be from transition duct cells, but there is also evidence of an even less mature periportal liver stem cell. Study of the development of these cells during carcinogenesis indicates that liver cancer arises from oval cells by aberrant differentiation of stem cells. From a biological standpoint two major postulates of the origin of cancer are: Cancer arises from differentiated expres sive cells by "dedifferentiation" or from pluripotential stem cells by aberrant differentiation (1). One of the fundamental postulates of the stem cell theory of cancer is that the incidence of cancers arising in a given tissue is directly related to the rate of cell division in that tissue. Thus tumors appear in relative high incidence in organs with rapid cellular turnover, such as skin, gastrointestinal mucosa, or bone marrow, but in low incidence in tissues with low turn over, such as neurological tissue. Tumors of neurons, which essentially do not proliferate in the adult, are extremely rare. One exception to this, which may prove the rule, is the liver. Although primary malignant tumors of the liver are rare in the western world, the extremely high incidence of primary hepatocellular carcinomas in other parts of the world (Africa, Southeast Asia) actually makes primary hepatocellular carcinoma one of the world's most common malignant tumors. This brief review will address the question, "Do hepatocellular carcinomas arise from dediffer entiation of adult hepatocytes or do these cancers arise by activation and aberrant differentiation of liver stem cells? " Stem cells are defined as multipotent cells that divide to produce one daughter cell that stays as a stem cell while the other daughter cell expresses a differentiated phenotype. Tissue stem cells are determined; i.e., they lack the biochemical and structural markers of differentiation but are determined for differentiation to a specific cell type (1). Stem cells respond by proliferation and differentiation to replace senescent cells under normal circumstances or to restore destroyed tissues in patho logical conditions. The epithelium of the skin is the classic example of the former. The basal cells send daughter cells through the maturational pathways to replace senescent cells. The basal cells may not be the true stem cells in this case but are already partially differentiated. Another example is the cell type responsible for limb regeneration in the amphibian that can replicate and differentiate into the composite of mature cells of the regenerated limb. The limb blastema or stem cell actually is not multipotential but is limited to expression of