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Liver fibrosis and liver cancer are two very major causes of human morbidity and mortality, and both appear to have their foundations in stem cells. In the mouse liver, transplanted bone marrow cells can acquire the phenotype of quiescent stellate cells and after liver injury can become activated into aSMA-expressing cells.103 In human cirrhosis, by examining sex-mismatched allografts, Forbes etal. have shown that up to 40% of myofibroblasts are of bone

marrow origin.104

Stem cell biology and cancer are inextricably linked. In continually renewing tissues such as the intestinal 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 identity of the founder cells for the two major primary tumors, hepatocellular carcinoma (HCC) and cholangiocarcinoma, is more problematic. The reason for this is that no such unidirectional flux occurs in the liver; moreover, the existence of bipotential hepatic progenitor cells (HPCs), often called oval cells, 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, what is clear is that cell proliferation at the time of carcinogen exposure is pivotal for "fixation" of the genotoxic injury into a heritable form. Taking this view, Sell has opined that in models of experimental hepatocarcinog-nesis as a whole, there may be at least four distinct cell lineages susceptible to neoplastic transformation.105 This supposition is based on the fact that there is considerable heterogeneity in the proliferative responses that ensue after injury in the many different models of hepatocarcino-genesis. Thus, hepatocytes are implicated in some models of HCC; direct injury to the biliary epithelium implicates unipotent cholangiocytes in some models of cholangiocarcinoma; while HPC/oval cell activation accompanies very many instances of liver damage irrespective of etiology, making such cells very likely carcinogen targets. A fourth cell type that might be susceptible to neoplastic transformation is the so-called non-descript periductular cell that responds to periportal injury; the suggestion that such a cell may be of bone marrow origin would be experimentally verifiable in the context of a sex-mismatch bone marrow transplantation (see above) and the appropriate carcinogenic regimen. In the mouse, an origin of HCC from bone marrow has been discounted in a model of chemical hepatocarcinogenesis.81

The direct involvement of hepatocytes in hepatocarcinogenesis has been clearly established in rats. Gournay et al.W6 found that some preneoplastic foci (expressing gamma glutamyl transpeptidase and the placental form of glutathione-S-transferase) were directly descended from hepatocytes. This was achieved by stably labeling hepatocytes at one day after a 2/3 PH with ^-galactosidase, using a recombinant retroviral vector containing the ^-galactosidase gene; subsequent feeding with

2-acetylaminofluorene lead to foci, some of which were composed of galactosidase-expressing cells. Using the same labeling protocol, Bralet etal.107 observed that 18% of hepatocytes expressed |-galactosidase at the completion of regeneration after a 2/3 PH; subsequent chronic treatment with diethylnitrosamine (DEN) resulted in many HCCs, of which 17.7% of the tumors expressed |-galactosidase, leading to the conclusion that a random clonal origin of HCC from mature hepatocytes was operative in the model.

As discussed above, there is now compelling evidence that oval cells/HPCs are at the very least bipotent, capable of giving rise to both hepatocytes and cholangiocytes. The fact that oval cell activation (ductular cell reaction) precedes the development of HCC in almost all models of hepatocarcino-genesis and invariably accompanies chronic liver damage in humans, makes it almost certain that the mature hepatocyte is not the cell of origin of all HCCs; indeed, perhaps only a small minority of HCCs are derived from the mature hepatocyte. The fact that oval cells/HPCs can be infected with HBV is also consistent with a possible histogenesis of HCC from such cells.108 An origin of HCC from HPCs is often inferred from the fact that many tumors contain an admixture of mature cells and cells phenotypically similar to HPCs. This would include small oval-shaped cells expressing OV-6, CK7 and 19, and chromogranin-A, along with cells with a phenotype intermediate between HPCs and the more mature malignant hepatocytes.109 Cells with an HPC phenotype have also been noted in a relatively rare subset of hepatic malignancies, where there are clearly two major components, an HCC component and a cholangiocarcinoma component, again suggestive of an origin from a bipotential progenitor.110 Direct evidence of a role for oval cells in the histogenesis of HCC can be obtained experimentally; Dum-ble et al.111 isolated oval cells from p53 null mice and when the cells were transplanted into athymic nude mice they produced HCCs.

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