Cancer Stem Cells
233
blood is well understood. When this knowl-
edge is combined with analysis of onco-
genic mutations, it can be inferred from
which cell type along the differentiation
lineage the cancer arose. One of the most
frequent mutations in AML is the t(8 : 21)
mutation, which results in the expression
of a chimeric AML-ETO transcript in the
leukemic cells. HSCs isolated from pa-
tients in clinical remission were found
to express chimeric AML-1-ETO transcript
up to 90% of the time. When analyzed us-
ing
in vitro
assays, these HSCs gave rise to
normal progeny, thus demonstrating that
the mutation was present in phenotypi-
cally normal stem cells. In these patients,
the Thy1
subset of CD34
+
CD38
Lin
cells gave rise to leukemic colonies
in vitro
.
These cells could represent HSCs that lost
Thy1 expression, or downstream multi-
potent progenitors that have gained the
ability to self-renewal. Collectively, these
observations support the idea that muta-
tions accumulate in stem cells, and either
subsequent mutations in stem cell progeny
or selective activation in downstream pro-
genitors results in overt leukemia.
6
Implications of Cancer Stem Cells for the
Diagnosis and Treatment of Cancer
6.1
Cancer Stem Cells Would Explain Several
Conundrums of Cancer Biology
Although the NOD/SCID mouse model
provides compelling evidence in support
of the cancer stem cell model, the ulti-
mate conFrmation of this hypothesis will
require proof in humans. If this model
c
anb
econF
rm
edinhum
an
s
,how
e
v
e
r
,
it will have profound implications for the
diagnosis and treatment of cancer. Several
conundrums of cancer biology would be
explained if it were conclusively demon-
strated that, in most tumors, only a small
population of cancer cells has the abil-
ity to self-renew while other populations
of cancer cells have only a limited abil-
ity to proliferate. ±or example, for many
years it has been recognized that dissem-
inated cytokeratin-positive breast cancer
cells can be detected in the bone mar-
row of patients that never relapse. One
possible explanation of this observation
is that the cancer cells lie dormant un-
til some unknown event triggers them
to renew proliferation. An alternative ex-
planation is that the disseminated cancer
cells in this group of patients arose from
the spread of nontumorigenic cells, and
only when cancer stem cells dissemi-
nate and subsequently self-renew, will
metastatic tumors form. Thus, the devel-
opment of diagnostic reagents that allow
cancer stem cells to be identiFed may have
prognostic signiFcance for patients with
breast cancer.
6.2
Tumor Relapse Might Result from a Failure
to Target Cancer Stem Cells
A frustrating clinical observation is that
in most solid cancers such as breast
cancers,
chemotherapy
can
frequently
shrink tumors, but in most patients the
tumors rapidly recur and there is only a
small increase in patient survival. Most
of the present cancer therapeutic agents
have been developed for their ability to
shrink a tumor; essentially, all of the
phenotypically diverse cancer cells are
treated as if they possess the ability to
signiFcantly contribute to the growth and
maintenance of the tumor, as shown in
±ig.2a. However, the failure of oncogenic
mutations to confer unto all breast cancer
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