Biomedical Engineering Reference
In-Depth Information
proposed that cancers can be treated by induction of differentiation of the
cancer cells (Pierce and Spears, 1988). In fact, teratocarcinoma cells may be
forced to differentiate when treated with retinoic acids, a principle that has
been applied to other types of cancer (Sell, 2004a; Camacho, 2003). However,
when treatment is discontinued, the cancer will regrow from those cancer stem
cells that are resistant to differentiation therapy. Resistance to therapy is
another classical property of cancer stem cells that will be illustrated below
for leukemia.
1.3.2 Teratocarcinomas Arise from Stem Cells
Leroy Stevens (1964) demonstrated that teratocarcinomas arise from normal
stem cells. Using a mouse strain in which teratocarcinomas arose spontaneously,
Stevens transplanted normal testicular germ cells (Stevens, 1967), tubal mouse
eggs (Stevens, 1968), or early mouse embryo cells (Stevens, 1970), from their
natural sites to abnormal tissue sites. He found that, in these sites, teratocarci-
nomas appeared. Thus, apparently normal stem cells could be transformed into
cancer cells if removed from their normal tissue environment and placed into an
unnatural niche. A proposed lineage of germinal cell tumors according to the
stage of maturation arrest of the transit-amplifying teratocarcinoma cells and
based on the model of Pierce et al. (1978) is illustrated in Fig. 2B. Mintz and
Ilmmensee (1975; Ilmmenesee, 1978) then demonstrated that transplantable
teratocarcinoma stem cells can give rise to normal tissues in mosaic mice formed
from injection of teratocarcinoma cells into the blastocyst of a normally devel-
oping embryo. Clearly, the malignant teratocarcinoma cells differentiated into
normal benign cells of various tissues when placed in a controlling and nurturing
environment. Richman Prehn (2005) proposed that stem cells in adult tissue are
restricted through silencing of embryonic genes by the adult tissue microenviron-
ment. He further postulated that when embryonic genes are silenced in tissue
stem cells, mutations take place in those embryonic genes that go un-repaired.
Then, an altered tissue environment allows activation of mutated embryonic
genes in tissue stem cells that can lead to expression of a cancer phenotype.
1.3.3 What Have We Learned from Teratocarcinomas?
From the study of teratocarcinomas, we have learned that (1) cancers arise
frommaturation arrest of stem cells; (2) cancers contain the same cell popula-
tions as do normal tissues (stem cells, transit-amplifying cells, and terminally
differentiated cells); (3) proteins released by the embryonic components of a
teratocarcinoma can be used to detect the tumor; (4) malignant cells can
become benign; (5) differentiation of cancer cells can be forced (differentiation
therapy); (6) therapeutic regimens can be directed against the cancer transit-
amplifying cells, but the cancer may regrow from the treatment-resistant
cancer stem cells when treatment is discontinued. Clearly, these findings
support a stem cell theory of cancer. However, until the 1980 s, many
