Cancer Stem Cells
229
family of receptors was Frst identiFed
in
Drosophila
and has been implicated
in both development and differentiation.
In
Caenorhabditis
elegans
,N
o
t
c
hp
l
a
y
s
a role self-renewal of germ cells. In
higher animals, Notch plays a critical
role in the fate determination of neural
crest stem cells. SpeciFcally, transient
Notch activation induces an irreversible
switch from neurogenesis to gliogenesis.
In cultured HSCs, Notch activation using
either of the Notch ligands (Jaged-1 or
Delta) transiently increased the number of
primitive progenitors; this result proved
true in
in
vivo
s
t
u
d
i
e
sa
sw
e
l
l
.T
h
i
s
suggests that Notch activation promotes
either the maintenance of progenitor cell
multipotentiality or the maintenance of
self-renewal in HSCs. The Notch pathway
was implicated in cancer when it was
determined that the mouse oncogene
int-
3
was a truncated Notch-4. However, the
role for Notch in
de novo
human cancer is
complex and incompletely understood. It
is known that some members of the Notch
signaling family are expressed in cancers
of epithelial origin, and activation of Notch
by chromosomal translocation is involved
in some cases of leukemia. Microarray
analysis has demonstrated overexpression
by tumor cells. SpeciFcally, overexpression
of Notch-1 leads to growth arrest of a
small cell lung cancer cell line, while
inhibition of Notch-1 signals can induce
leukemia cell lines to undergo apoptosis.
Elegant work by Miele and colleagues
showed that activation of Notch-1 signaling
maintains the neoplastic phenotype in ras-
transformed human cells. They also found
that in
de novo
cancers, cells with an
activating ras-mutation also demonstrated
increased
expression
of
Notch-1
and
Notch-4. Additionally, a truncated Notch-4
mRNA is expressed by some breast cancer
cell lines.
In addition to the Notch pathway,
Wnt/
β
-catenin signaling has also been
implicated
as
a
major
player
in
the malignant transformation and self-
r
en
ew
a
lo
fno
rm
a
ls
t
emc
e
l
l
s
.Th
eWn
t
pathway was Frst implicated in cancer
when it was discovered that some murine
mammary tumors were the result of
mouse mammary tumor virus proviral
insertion into the
Wnt-1
gene, causing
deregulated
expression
of
the
locus.
Subsequently, it has been shown that Wnt
proteins play a central role in pattern
formation during embryogenesis as well
as in some adult tissues. The Wnts are
a large family of highly hydrophobic
secreted proteins that signal through their
cognate receptors, members of the frizzled
and
low-density
lipoprotein
receptor-
related protein families. Activation of
these receptors results in the cytoplasmic
and nuclear stabilization of
β
-catenin by
blocking its degradation. In the absence of
receptor activation,
β
-catenin is marked
for degradation by ubiquitination by a
complex consisting of the adenomatous
polyposis coli
(APC), axin, and glycogen
synthase-3
β
proteins. Activation of Wnt/
β
-
catenin signaling by Wnt proteins in
HSCs
in
vitro
or by expression of a
constitutively active
β
-catenin in HSCs
expands the pool of early progenitor
cells and enriches normal transplantable
HSCs in tissue culture and
in
vivo
.
Inhibition of Wnt/
β
-catenin by ectopic
expression
of
axin
(which
promotes
β
-catenin
degradation)
leads
to
the
inhibition of stem cell proliferation both
in vitro
and
in vivo
. Additional studies
implicate the Wnt/
β
-catenin pathway in
the maintenance of stem cell or progenitor
cell self-renewal in other tissues as well.
SpeciFcally, the level of
β
-catenin within
a particular keratinocyte directly correlates
with its proliferative capacity. Additionally,
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