Biomedical Engineering Reference
In-Depth Information
investigators believed that teratocarcinomas were different from other can-
cers, and so still supported the de-differentiation theory of cancer. The para-
digm for de-differentiation was the result of experimental models of chemical
hepatocarcinogenesis. In these models, the cellular changes that were seen
during induction of hepatocellular carcinoma (HCC) were held up as exam-
ples of de-differentiation. However, as we will see next, more recent examina-
tion of the cellular events during experimental chemical hepatocarcinogenesis
actually supports the idea that the liver stem cell is the cellular origin of HCC.
Given this change in paradigm during the last 30 years, we have seen a swing
back to the stem cell theory of cancer reflected in a spate of reviews on cancer
stem cells (for example, see Sell, 2004a, 2006a; Reya et al., 2001; Wicha et al.,
2006), as well as topics such as this one.
1.4 Chemical Hepatocarcinogenesis and the Stem Cell Origin
of Cancer
Prior to the 1980 s, analysis of the experimental models of chemical hepatocar-
cinogenesis in the rat centered on the development of enzyme-altered foci and
the so-called preneoplastic nodules and persistent nodules. These nodules
appeared to depict a sequence of morphologic and histologic changes extending
from the histologic structure of normal liver to that of hepatocellular carcinoma
(HCC). Thus, it is not surprising that the nodules were considered to arise from
altered mature hepatocytes and to represent precursor lesions to HCC (Farber,
1956; Bannasch, 1984; Aterman, 1992). The conclusion that these nodules were
precursors to cancer implied that HCC arises by de-differentiation frommature
hepatocytes.
1.4.1 Oval Cells
De-emphasized in the interpretation of the nodular changes preceding HCC
was the fact that many of the hepatocarcinogenic regimens produced a notable
proliferation of small oval cells (Farber, 1963). Later oval cells were shown to
produce AFP, which suggested that these cells could represent fetal liver cells
(Sell, 1989, 2001). Different kinetics of production of AFP associated with
different preneoplastic changes suggested that multiple cell types in the liver
lineage might be involved in the early carcinogenic process (Sell and Becker,
1978). In particular, during the cyclic feeding of acetylaminofluorene (AAF), a
model designed to produce maximal preneoplastic nodule formation (Teebor
and Becker, 1971), AFP elevations appeared early, before preneoplastic nodule
formation; further AFP was not found in nodules (the presumed precursors to
HCC), but rather in small oval cells located in-between the nodules (Sell, 1978).
The fact that the HCC produced by this regimen also produced AFP was the
first clue that HCC did not arise from nodular cells per se, but from putative
