Biomedical Engineering Reference
In-Depth Information
liver stem cells (oval cells; Sell et al., 1980; Sell and Leffert, 1982; Sell, 2008). As
different models were examined for AFP elevations and early cellular changes,
it became more obvious that different carcinogenic regimens produce different
cellular changes, and that different cells in the liver lineage must give rise to the
cancers, depending on the regimen (Sell, 2001). For a recent review on how the
study of AFP production during normal development, after liver injury, and
during chemical hepatocarcinogenesis led to the conclusion that liver cancer
originates from stem cells, see Sell (2008).
1.4.2 Cellular Changes in the Liver Preceding Development of Liver Cancer
From among the many carcinogenic regimens that have been devised, four that
produce different cellular changes during hepatocarcinogenesis will be adum-
brated: diethylnitrosamine (DEN), furan, the Solt-Farber model, and choline
deficiency combined with ethionine (CD-E) or AAF model. Interpretation of
these models is quite complex and will only be summarized here. For a recent
extensive review by the author citing many earlier references, see Sell (2006b).
Briefly, DEN-induced HCCs appear to arise from hepatocytes; furan tumors
arise from bile duct cells, Solt-Farber model HCCs arise from bipolar ductal
cells, and CD HCCs arise from periductular oval (stem) cells.
Thus, these four different carcinogenic protocols result in distinctly different
patterns of premalignant cell proliferation implicating four types of cells as
possible precursors to cancer: hepatocytes (DEN), duct progenitor cells (furan),
ductular bipolar precursor cells (Solt-Farber), and periductular stem cells (CD
models). The ''blastomas'' of young animals provide the missing link between
fetal hepatocytes and adult liver lineage cells at which stage of maturation arrest
occurs in the formation of HCC (Fig. 2C; Kasai andWatanabe, 1970; Haas et al.,
1989). In summary, reinterpretation of the cellular changes in the liver that are
seen using various chemical hepatocarcinogenic regimens actually supports
maturation arrest of the liver cell lineage and the stem cell theory of cancer.
Most investigators now favor the stemcell origin of cancer over de-differentiation
models, although with some reluctance. The two-step model of initiation and
promotion of skin cancer provides the most convincing argument for the stemcell
origin of at least this cancer (Rous and Kidd, 1942; Friedwald and Rous, 1944;
Berenblum and Shubik, 1947; Berenblum, 1941, 1954; Boutwell, 1964).
1.5 Skin Cancers Arise in Self-Renewing Stem Cells (Initiation
and Promotion)
The time elapsed between the application of a carcinogen to the skin (initiation)
and the elicitation of cancer by promotion demonstrates that the skin cancers
that result from this treatment arise from long-surviving stem cells. In the classic
model, benz(o)pyrene, the initiator, is painted onto the skin. This chemical
