Cancer Stem Cells
231
mutations are necessary for a cell to be-
come cancerous. Since both progenitor
cells and mature cells have a very limited
lifespan
,itisun
like
lythata
l
lofthemuta-
tions could occur during the life of these
relatively short-lived cells. This evidence
suggests that, in many cases, mutations
accumulate in a stem cell. Second, the
regulation of stem cell expansion and self-
renewal is under strict genetic regulation
by multiple genes. Unregulated expan-
sion of the stem cell pool would therefore
be analogous cancer. Third, most cancers
arise in tissues that contain stem cells
that have the intrinsic ability to self-renew.
Cancer cells must overcome the tight
genetic regulation restricting both self-
renewal and proliferation. Since cancer
cells must possess the ability to self-renew,
it follows that stem cells (which could be
trans
formedbya
l
ter
ingon
lypro
l
i
fera
t
ive
pathways) may more easily undergo malig-
nant transformation than progenitor cells
that lack this fundamental property and
must therefore activate both proliferative
and self-renewal pathways to become ma-
lignant. In the hematopoietic system, the
only cells with self-renewal capability are
HSCs and mature lymphocytes. The com-
mon blood cancers, acute leukemias, and
lymphomas, may arise from the HSCs
or lymphocytes, respectively. This may
t
ak
ep
l
a
c
eth
roughth
econ
s
t
i
tu
t
i
v
ea
c
t
i
-
vation of mitogenic pathways associated
with the proliferation of normal cells. Fi-
nally, while many cancers contain cells
displaying aberrant expression of differen-
tiation markers from their tissue of origin,
germ cell cancers are the only cancers to
produce differentiated cells from multiple
tissues. For this reason, marker expression
is routinely used to determine the tissue
of origin in metastatic disease. If a dif-
ferentiated cell were to be the origin of a
cancer, it would be necessary for the cell to
dedifferentiate exclusively along its parent
lineage to produce expression of markers
from multiple cell types within the tissue.
However, if a somatic stem cell or early
multipotent progenitor were transformed,
the cell would already be genetically pro-
grammed to give rise to cells expressing
markers of multiple lineages, but from
only one tissue type, as is usually observed
clinically. Since most identiĀ±ed oncogenic
mutations are involved in the regulation
of proliferation and self-renewal and not
lineage commitment, the latter hypothesis
seems more likely.
5.2
Progenitor Cells as Targets for Malignant
Transformation
Although evidence supports the hypothe-
sis that stem cells are frequently the target
of mutations that lead to malignant trans-
formation, it is likely that progenitor cells,
possibly arising from mutated stem cells,
may be transformed by subsequent ge-
netic events that confer immortality and/or
self-renewal potential to these normally
non-self-renewing cells. In CML patients,
the BCR-ABL mutation is present in both
normal HSCs and leukemic stem cells.
In otherwise normal hematopoietic cells,
the BCR-ABL mRNA is expressed solely
by the progenitor cells. BCR-ABL expres-
sion targeted to myeloid progenitor cells
by the hMRP-8 promoter in a transgenic
mouse model of CML resulted in CML-
like disease in a subset of the mice.
Furthermore, when hMRP8p210
BCR
/
ABL
mice were crossed with hMRP8bcl-2 mice
(which possessed myeloid progenitors re-
sistant to apoptosis), a portion of the
mutant mice developed a disease re-
sembling AML. Although expression of
transforming genes was targeted to early
progenitor cells and not the HSCs, the
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