224
Cancer Stem Cells
drives tumor growth. These tumorigenic
cells would have acquired oncogenic mu-
tations that result in deregulated self-
renewal, but their phenotypically diverse
progeny would still be differentiated and
lack the ability to self-renew. Several lines
of evidence suggest that this model ac-
counts for some of the cellular hetero-
geneity seen in tumors, although genetic
instability and environmental factors un-
doubtedly contribute to the variability in
phenotypes of cancer cells in a partic-
ular tumor. It is well documented that
many types of cancer contain heteroge-
neous populations of cells, which variably
express differentiation markers that reflect
the tissue or origin, as well as cancer cells
that have an immature morphology. Ex-
amples of this observation include the vari-
able expression of milk proteins by some
breast cancers and the variable expression
of myeloid and/or lymphoid markers in
chronic myelogeous leukemia (CML) and
acute myelogenous leukemia (AML). By
contrast, in some tumors, speciFcally in
mature germ cell teratomas, only a minor-
ity of the cancer cells express immature cell
markers such as
α
-fetoprotein. Because the
terminally differentiated cells that form the
teeth and hair in germ cell teratomas are
unlikely to be able to proliferate and form
new tumors, these data are consistent with
the notion that the minority population
of
α
-fetoprotein expressing cancer cells
might have the exclusive ability to form
new tumors consisting of more tumori-
genic cells as well as the phenotypically
diverse populations of abnormally differ-
entiated cells lacking the ability to self-
renew. If this proved to be true, these cells
couldbeconsideredtobecancerstemcells.
The evidence suggesting that cancer
is a disease of aberrant differentiation,
proliferation, and self-renewal makes it
plausible to view tumors as abnormal
organs; in this context, the principles of
stem cell biology can be applied to better
understand the biology of these diseases.
It has been shown in both hematopoietic
malignancies and solid cancers that only
a subset of cancer cells are clonogenic
when placed in tissue culture or injected
into immunodeFcient mice. ±or example,
only 0.01 to 1% of the mouse myeloma
cells formed colonies in
in vitro
colony-
forming assays. Similarly, only 1 to 4%
of leukemic cells formed spleen colonies
when transplanted into mice. This trend
was demonstrated in solid cancers as well,
with only 0.02 to 0.1% of ovarian cancer
or lung cancer cells forming colonies in
soft agar. Since only a minority of normal
bone marrow cells were clonogenic, the
clonogenic
cancer
cells
were
initially
described as cancer stem cells; this implied
that only a distinct population of cancer
cells were able to proliferate extensively
in these assays. However, an alternative
explanation was
that
all
cancer cells
have the intrinsic ability to proliferate
extensively, but only a small minority of
cells do so in a particular assay.
2.2
Recent Evidence for AML and Breast Cancer
Stem Cells
Proving that a phenotypically distinct pop-
ulation of cancer cells is responsible for
perpetuating the disease would require
isolating different populations of cancer
cells and demonstrating that one or more
groups were enriched for the ability to
initiate the disease while other popula-
t
i
on
sl
a
c
k
e
dt
h
i
sa
b
i
l
i
t
y
.Th
i
sw
a
sF
r
s
t
shown in AML when it was shown that a
leukemia tumor-initiating subpopulation
of cells could be prospectively identi-
Fed and puriFed from multiple patients’
bone marrows. In most cases of AML,
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