228
Cancer Stem Cells
4
Genetic Regulation of Self-renewal in
Normal Stem Cells and Cancer Cells
4.1
Tissue and Tumor Growth: A Balancing
Act
The maintenance and composition of a tis-
sue or tumor is determined by the balance
of proliferation and cell death. It is there-
fore logical that many of the mutations
that are known to drive tumor expansion
and progression regulate either cell pro-
liferation or survival. For example, the
prevention of apoptosis by enforced ex-
pression of the oncogene
BCL-2
promotes
the development of lymphoma as well as
results in an increased number of HSCs
in vivo
, suggesting that cell death plays a
role in the regulation of HSC homeostasis.
Inhibition of intrinsic cell death pathways
has been further implicated in tumorigen-
esis by the observation that the progression
to experimental AML in a mouse model
requires at least three, and likely four
independent events. Proto-oncogenes that
drive proliferation of tumor cells, such as
c-myb
and
c-myc
, are also essential for HSC
development and proliferation.
4.2
Multiple Oncogenes Implicated in
Self-renewal
Self-renewal is critical for the maintenance
of both normal and cancer stem cell popu-
lations. In a normal tissue, stem cell num-
bers are under strict genetic regulation,
resulting in the maintenance of a stable
stem cell pool. Cancer stem cells, however,
have escaped this homeostatic regulation.
Not only is the number of stem cells
constantly expanding but they are also pro-
liferating without the normal constraints
on their expansion. This results in the re-
lentless growth of the tumor. Since cancer
cells and normal stem cells share the abil-
ity to self-renew, it is not surprising that
a number of genes classically associated
with cancer have recently been implicated
in normal stem cell development.
In combination with other growth fac-
tors, Sonic Hedgehog (Shh) signaling was
implicated in the regulation of self-renewal
when it was found that cell populations
highly enriched for human HSCs exhib-
ited increased self-renewal in response to
Shh stimulation
in vitro
.M
icethatarede
-
±cient in
tal-1
/
SCL
, which is involved in
some cases of human acute leukemia, lack
embryonic hematopoiesis. This suggests
that
tal-1/SCL
is required either to initi-
ate hematopoiesis for the maintenance of
the earliest de±nitive blood cells, or for
the decision to form blood cells down-
stream of embryonic HSCs. Members of
the Hox family have likewise been im-
plicated in human leukemia. Enforced
expression of
HoxB4
can affect stem cell
functions. One of the major targets of
the p53 tumor suppressor gene, p21
cip
1
,is
necessary for HSCs to repopulate lethally
irradiated recipients. Failure at serial trans-
fer could result from exhaustion of the
stem cell pool, loss of telomeres, or loss of
transplantability. The
bmi-1
gene, which
cooperates with
c-myc
in mice to induce
lymphoma, is required for the mainte-
nance of both adult HSCs and leukemia
cells. Taken together, this body of evidence
suggests that the same pathways involved
in stem cell fate decisions and the ability of
stem cells to self-renew are also involved
in malignant transformation.
The Wnt/
β
-catenin and Notch pathways,
which have been implicated in cancer in
both mice and humans, may have critical
functions in the self-renewal of both
normal and cancer stem cells. The Notch
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