234
Cancer Stem Cells
(a)
(b)
T
NT
NT
NT
Fig. 2
(a) Therapies are currently
evaluated assuming all cancer cells are
equivalently tumorigenic. (b) The cancer
stem cell model says only a distinct
subpopulation drives tumorigenesis.
Symbols: T
=
tumorigenic,
NT
=
nontumorigenic.
and leukemia cells the ability to form
new tumors or proliferate extensively
underscores the fact that the effects of
oncogenic mutations are not equivalent in
all cancer cells, as shown in B in Fig 2.
If only a minority of the cancer cells are
tumorigenic and therefore responsible for
driving tumor growth and metastasis, then
tumor shrinkage must primarily reflect
the elimination of the bulk population
of nontumorigenic cells. If a substantial
number of tumor stem cells were spared
by the therapy, then the tumors would
regenerate from these cells. The clinical
observation that many patients treated
with chemotherapy initially realize tumor
shrinkage but then experience relapse at
sites of prior disease, supports this model.
6.3
Cancer Stem Cells Might Be More Resistant
to Chemotherapy
The similarities between normal stem cells
and AML tumor-initiating cells suggest
that they might share additional clini-
cally signi±cant parallels. For instance,
compared to their differentiated progeny,
normal HSCs express high levels of genes
that make them more resistant to cytotoxic
agents, including both antiapoptotic mem-
bers of the
BCL-2
family and members
of the ABC transporter family that pump
many drugs out of the cell. If the same
is true for cancer stem cells, then these
ce
l
lsmaybes
ign
i±can
t
lymo
reres
is
tan
t
to cytotoxic agents than their nontumori-
genic progeny. In support of this notion,
while the chemotherapeutic agent cytosine
arabinoside very ef±ciently killed leukemic
blast cells isolated from many patients, it
selectively spared the leukemia-initiating
cells. This observation suggests that the ef-
fect of a particular therapeutic agent on the
cancer stem cell population must be taken
into account when evaluating its therapeu-
tic ef±cacy.
6.4
Identifcation o± Cancer Stem Cells Might
Lead to Better Drug Selection
The fact that therapeutic agents are cur-
rently selected on the basis of their ability
to rapidly shrink tumors suggests that
agents that selectively target the cancer
stem cells could be overlooked in screens to
identify potential therapeutic agents. Ini-
tially, such agents would be expected to
produce only a moderate decrease in tu-
mor growth. However, elimination of the
cancer stem cell population would eventu-
ally halt the spread of the tumor, possibly
leaving a residual, benign mass. Perhaps,
the best clinical evidence of this model
occurs in patients with teratocarcinoma.
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