Cancer Stem Cells
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-
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
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.
Implications of Cancer Stem Cells for the
Diagnosis and Treatment of Cancer
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
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.
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
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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