230
Cancer Stem Cells
enforced expression of an activated
β
-
catenin increased the ability of epidermal
stem cells to self-renew and decreased their
ability to differentiate. In the intestinal
epithelium, it has been observed that
β
-
catenin levels are highest in the bottom of
the crypts (where the epithelial stem cells
are thought to reside), and decrease in a
gradient as cells differentiate and move
up and out of the crypt. Knockout mice
for TCF-4, one of the transcription factors
that is activated when bound to
β
-catenin,
soon exhaust their undifferentiated crypt
epithelial progenitor cells; this further
suggests that Wnt signaling is involved
in the self-renewal of epithelial stem cells
in the intestine.
Activation of the Wnt/
β
-catenin can take
place by one of several mechanisms. In
colon cancer, inactivation of the
β
-catenin
protein degradation pathway, most fre-
quently by mutation of APC, is common.
Alternatively, elevated expression of
Wnt
genes in some epithelial cancers suggests
that activation of
β
-catenin might some-
times be secondary to ligand activation.
There is now evidence that constitutive
activation of the Wnt/
β
-catenin pathway
may confer upon cancer cells some of the
key properties of cancer stem cells. Inhi-
bition of
β
-catenin/TCF-4 signaling in a
colon cancer cell line induced the expres-
sion of the cell cycle inhibitor p21
cip–1
and induced the cells to stop proliferat-
ing and to acquire a more differentiated
phenotype. Additionally, enforced expres-
sion of the proto-oncogene
c-myc
,wh
ich
is activated by
β
-catenin through TCF-4,
inhibited the expression of p21
cip–1
and
allowed the colon cancer cells to prolifer-
ate when
β
-catenin/TCF-4 signaling was
blocked. This further enforced the notion
that
c-myc
is a key
Wnt
signaling target
gene in the regulation of cell proliferation
and differentiation.
4.3
Possibility of a Common Self-renewal
Pathway among Multiple Cell Types
The implication that genes such as
Notch,
Wnt
,
c
-
myc
,and
Shh
all play roles in the
regulation of not only HSC self-renewal,
but also in the self-renewal of stem cells
from multiple tissues, suggests that there
may be a common set of self-renewal
pathways utilized both in normal stem
cells and possibly in cancer stem cells.
It is clear that identifying the molecular
mechanisms by which these pathways
produce their biological effects, as well
as determining whether these pathways
interact to regulate the self-renewal of
normal stem cells and cancer stem cells,
could have profound importance in our
understanding of cancer biology and our
ability to effectively treat the disease.
5
Target Cells for Malignant Transformation
5.1
Stem Cells as Targets for Malignant
Transformation
It has been established that oncogenic mu-
tations often target signaling pathways that
regulate proliferation and self-renewal.
This fact raises an interesting question: are
stem cells, highly proliferative progenitor
cells, or both, the target cells of neoplastic
transformation? Theoretically, stem cells
could be transformed by acquiring muta-
tions that deregulate proliferation, while
highly proliferative progenitors could be
transformed by mutations conveying the
ability to self-renew.
Several lines of evidence suggest that
stem cells may play several key roles in
the evolution of a cancer. First, multiple
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