Cancer stem cell biology: from leukemia to solid tumors
Craig T Jordan
The biology of stem cells and their intrinsic properties are
now recognized as integral to tumor pathogenesis in several
types of cancer. This observation has broad ramifications
in the cancer research field and is likely to impact our
understanding of the basic mechanisms of tumor formation
and the strategies we use to treat cancers. A role for stem cells
has been demonstrated for cancers of the hematopoietic
system, breast and brain. Going forward it is likely that stem
cells will also be implicated in other malignancies. Hence, a
detailed understanding of stem cells and how they mediate
tumor pathogenesis will be critical in developing more
effective cancer therapies.
Division of Hematology/Oncology, University of Rochester School of
Medicine, 601 Elmwood Avenue, Box 703, Rochester, New York 14642,
Current Opinion in Cell Biology 2004, 16:708–712
This review comes from a themed issue on
Edited by Larry Goldstein and Sean Morrison
Available online 17th September 2004
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# 2004 Elsevier Ltd. All rights reserved.
acute lymphoblastic leukemia
acute myeloid leukemia
chronic myeloid leukemia
cancer stem cell
hematopoietic stem cell
leukemic stem cell
Despite the clonal origin of many cancers, a notable
characteristic of primary tumors is a marked degree of
cellular heterogeneity. While this feature of tumors has
been widely described, the process by which a single
tumor-initiating cell can give rise to multiple distinct cell
types has not yet been clearly defined. One contribution
to our understanding of tumor initiation and growth
comes from considering the developmental biology of
stem cell systems. Normal stem cells intrinsically possess
three hallmark features: first, the potential to undergo
self-renewal; second, the potential to undergo extensive
proliferation; and third, the potential to differentiate into
multiple distinct cell types. Given these three natural
properties, it is easy to imagine that even a minor sub-
version of normal stem cell processes might be sufficient
to create a malignant condition. Intriguingly, substantial
evidence now indicates that stem cells do indeed play an
important role in the pathogenesis of some cancers [1,2].
So-called ‘cancer stem cells’ (CSCs) have been identified
for several malignancies, and a variety of experimental
approaches have begun to analyze the unique properties
of such cells. In particular, myeloid leukemias have been
extensively characterized with regard to stem and pro-
genitor cell involvement . Leukemic stem cells (LSCs)
appear to retain many characteristics of normal hemato-
poietic stem cells (HSCs) . This observation indicates
that the malignant stem cell population can arise in two
direct target ofmutationsthatcause conversiontoanLSC
phenotype. Alternatively, more differentiated cell types
might acquire mutations that confer stem-cell-like prop-
erties on cells that typically would not display stem cell
characteristics. Regardless of the cell of origin, the result-
of the properties described above. Thus, defining the
unique properties of cancer stem cells is a high priority for
research aimed at elucidating the molecular mechanisms
driving tumor initiation, and for developing therapeutic
strategies that specifically target CSC populations.
This article will review recent developments in the
leukemia and solid tumor fields, and discuss therapeutic
ramifications of cancer stem cells.
The original paradigm of cancer stem cells
established by leukemia
Stem cells from somatic tissues have been best character-
ized in the hematopoietic system, largely owing to the
easy accessibility of blood-forming cells and the wide
range of in vitro and in vivo functional assays . Hence, it
is not surprising that the stem cell malignancies that have
been analyzed in most detail are from the hematologic
cancer leukemia. Specifically, in both acute and chronic
forms of myeloid leukemia (AML and CML, respec-
tively), as well as in some forms of acute lymphoid
leukemia (ALL), a malignant stem cell population has
been identified [3,6,7]. Using the same methodologies
employed to characterize normal hematopoietic stem
cells are readily apparent. Importantly, such cells main-
tain the key stem cells properties of self-renewal, exten-
sive proliferative potential and differentiative potential.
Thus, a hierarchical development structure for the leu-
kemic population can be envisaged that originates from
Current Opinion in Cell Biology 2004, 16:708–712www.sciencedirect.com
the malignant stem cell and is similar to normal hema-
topoietic processes (Figure 1).
While a large amount of indirect evidence for AML stem
cells has accumulated since the mid 1960s, two seminal
papers from the laboratory of John Dick have most
directly identified and characterized the human leuke-
mia-initiating cell population [8,9]. In particular, studies
by Bonnet et al. identified a common immunophenotype
(CD34+/CD38?)forLSCsin multipleAML subtypesand
demonstrated their self-renewal potential. Subsequent
studies have further refined the immunophenotype of
AML stem cells and substantially added to our under-
standing of their biology [10–13]. In addition, a study by
Guan et al. showed that AML stem cells reside mostly in a
quiescent cell cycle state, analogous to their normal
hematopoietic stem cell counterparts [14?]. This observa-
tion is important because most therapeutic approaches to
leukemia are directed towards actively cycling popula-
tions. The quiescent nature of LSCs indicates that stand-
ard chemotherapy drugs will not generally be effective
against AML stem cells. Similar studies on human CMLs
strates a quiescent phenotype . Notably, while treat-
ment of CML patients with the drug imatinib mesylate
(also known as STI571 or GleevecTM) has been highly
effective for inducing remission, increasing evidence
indicates the disease is suppressed but not eradicated
[15,16]. Direct analysis of CML stem cells treated with
imatinib mesylate shows the drug is cytostatic but not
cytotoxic [17?], thus supporting the concept that ablation
of the LSC is necessary to destroy the tumor population
permanently. Collectively, these studies have set the
stage for detailed molecular and mechanistic analysis of
conversion from normal HSC to LSC and what mechan-
isms of growth and survival are unique to the LSC
of how leukemias arise and what pathways represent the
best targets for therapeutic intervention.
The foundation for a better understanding of both ques-
tions above has been established by reports published in
the past three to four years. Although a detailed mechan-
ism for HSC transformation has not been clearly defined,
a prevalent theme observed in a variety of studies is
alteration of self-renewal potential. By increasing and/
or deregulating the frequency at which primitive cells
self-renew, malignancy would be expected to give popu-
lations an overall competitive advantage. In addition, a
skewing towards less differentiated cell types might be
found. For example, recent studies have demonstrated
that the polycomb group gene Bmi-1 is necessary for self-
renewal of both normal and leukemia stem cells [18,19?].
Interestingly, a mechanism functioning via Bmi-1 impli-
cates the Ink4a locus (p16 and p19Arf genes) in the self-
renewal process. Similarly, deregulated activation of the
Wnt/Catenin pathway has also been shown to affect
normal stem cell self-renewal and is implicated in several
hematologic and non-hematologic cancers . Further,
intriguing new data indicates that JunB is a regulator of
stem cell number and overexpression of JunB leads to a
stem-cell-based myeloproliferative disorder akin to early
stages of leukemia (E Passague and I Weissman, personal
communication). With regard to LSC survival, evidence
Cancer stem cell biology Jordan709
Normal blood cells
Leukemia blast cells
Current Opinion in Cell Biology
Normal HSCs undergo mutations which give rise to LSCs. These LSCs then begin the differentiation process but arrest and accumulate at an
intermediate stage of development. Such cells are generally termed leukemic blast cells and are biologically distinct from LSCs.
Current Opinion in Cell Biology 2004, 16:708–712
suggests the NF-kB and PI3 kinase pathways may be
important. Recent studies have demonstrated constitu-
tive activation of NF-kB in primitive AML cells, and
drugs that inhibit NF-kB also function to induce apop-
tosis in LSCs but not normal HSCs . Similarly,
activation of Akt is commonly observed in primary
AML cells, and inhibition of the PI3 kinase pathway
appears to inhibit growth of LSCs . Furthermore,
pro-apoptotic activation of p53 and downstream targets
GADD45, Bax and p21 has been correlated with LSC-
specific apoptosis [22?].
In addition to studies of primary human cells, several
animal model systems have emerged that are likely to
provide powerful means of LSC analysis. Using ex vivo
retroviral gene transfer into primary hematopoietic cells
followed by transplantation into appropriate host animals,
ithasbeen demonstrated that several differentoncogenes
(and oncogene combinations) are sufficient to induce
acute leukemias in mice. Importantly, the characteristics
of disease in such models appear to recapitulate human
leukemia. For example, infection of bone marrow cells
with a retroviral vector expressing the BCR/ABL onco-
widely used model of human CML . Similarly, co-
infectionofbonemarrowcellswithvectors expressing the
BCR/ABL and Nup98/HoxA9 translocation products is
sufficient to induce an acute leukemia that mimics blast
crisis CML [24,25]. Importantly, in these models disease
initiates from a relatively rare subset of cells, which
undergo varying degrees of differentiation and/or inap-
propriate growth. To date, these models have been
excellent tools to analyze the molecular and cellular
characteristics of leukemia disease. Going forward, they
should also provide a unique means to study in vivo
properties of leukemic stem cells. Indeed, such studies
have already begun with a recent report by Cozzio et al.
[26?]. This study used a mouse model to investigate the
target cell that gives rise to leukemia in vivo. Intriguingly,
the authors demonstrate that certain types of myeloid
progenitors are, like the most primitive HSCs, able to
mediate leukemogenesis upon retroviral transduction
with the MLL-ENL oncogene. Thus, it may not always
be necessary for myeloid leukemia to initiate in the most
primitive stem cells.
The new paradigm of cancer stem cells in
While studies of hematopoiesis have provided a powerful
means of investigating normal versus malignant stem cell
biology, the relative role of stem cells in the broader
context of most cancers has been unclear. However,
several recent studies have provided striking direct evi-
dence that a stem or progenitor cell basis for at least some
solid tumors is apparent. Notably, these efforts have
relied upon methodologies first developed in the study
of hematopoietic stem cells. In 2003, Al-Hajj et al.
reported that a phenotypically distinct and relatively rare
population of tumor-initiating cells (TICs) was respon-
sible for the propagation of tumors from eight of nine
human metastatic breast cancer specimens [27?]. Primary
tumor cells expressing a CD44+/CD24low/lineage-nega-
tive cell surface phenotype were shown to initiate tumors
upon transplantation into immune-deficient NOD/SCID
mice, whereas all other tumor cells failed to propagate
tumors. Importantly, as few as 100 purified cells could
transmit the tumor and were able to recapitulate a more
differentiated population in secondary recipient mice.
Further, the tumors could be passaged to secondary
recipients by re-isolating CD44+/CD24lowcells from pri-
mary tumors. Thus, these breast tumors displayed a
developmental hierarchy originating from a low-fre-
quency TIC that is phenotypically and functionally dis-
tinct from the bulk tumor. These studies indicate that
breast TICs can undergo self-renewal and differentiate
and are highly proliferative in a xenogeneic transplanta-
tion system. Thus, the breast TIC fulfills the criteria of a
true stem cell. Although the normal cell that gives rise to
the breast TIC remains to be determined (and may or
may not be a normal breast stem cell), upon transforma-
tion, the cell driving breast malignancy can be operation-
ally defined as a cancer stem cell.
tumors has also come recently from the study of brain
tumors . Studies by Singh et al. have shown that the
neural stem cell antigen CD133 is expressed on brain-
derived TICs from pediatric medulloblastomas and pilo-
cytic astrocytomas. The CD133+subpopulations from
these tumors can initiate clonally derived neurospheres
in vitro that show self-renewal, differentiation and pro-
liferative characteristics analogous to normal brain stem
cells [29?,30]. Furthermore, transplantation of CD133+,
but not CD133?, cells into NOD/SCID mice is sufficient
to induce growth of tumors in vivo (P Dirks, personal
communication). Taken together, these findings strongly
implicate TICs in at least some forms of brain cancer. In
addition, given the similarity of normal neural stem cells
transforming events that lead to brain cancer.
Therapeutic ramifications of cancer stem cells
By their nature, CSCs are biologically distinct from other
cancer cell types. Moreover, certain natural properties of
CSCs are likely to increase their resistance to standard
chemotherapy agents. Thus, if cancer therapies do not
effectively target the CSC population during initial treat-
ment, then relapse may occur as a consequence of CSC-
driven tumor expansion. This is almost certainly the case
in many instances of AML, where standard drugs such as
cytarabine and anthracyclines are unlikely to target the
LSC population effectively [20,31]. Therefore, in devel-
oping new cancer therapeutics, analyses that directly
Current Opinion in Cell Biology 2004, 16:708–712www.sciencedirect.com
assess toxicity towards tumor stem cells are an important
While the generation of CSC-specific treatments remains
to be formally established, several recent reports have
described promising methods to target AML stem cells
more effectively. For example, by fusing diphtheria toxin
to interleukin-3 investigators have created a drug that
appears to ablate primitive AML cells . Another study
has suggested that monoclonal antibodies directed to the
CD44 epitope may function to induce differentiation of
LSCs and/or inhibit their localization to the appropriate
microenvironment in vivo . Further, recent data indi-
cates that using a combination of more traditional che-
motherapeutic agents and newly available small molecule
Taken together, these findings indicate that an under-
standing of LSC can potentially be exploited to develop
more effective strategies for leukemia therapy. While
such approaches have not yet been extended into the
solid tumor arena, clearly this will be a very exciting and
active area of research in years to come.
The paradigm of a cancer stem cell and its contribution to
certain types of human cancer is now well established.
Using a variety of sophisticated experimental approaches,
investigators have identified, isolated and begun to char-
acterize malignant stem cells from multiple types of
cancer. Given the newly appreciated role of stem cells
in many normal organ systems, it seems likely that stem
cell contributions in other tumor types will also be
described in the near future. For example, normal stem
cells in the gut , skin , pancreas  and liver
 have been reported and represent potential targets
for transformation that are analogous to those found in
more characterized systems. Moreover, recent evidence
demonstrates how certain mutations might confer em-
bryonic or undifferentiated features to malignant cells,
enabling them to show stem-cell-like behaviors such as
self-renewal and extensive proliferation [38,39]. Thus,
whether a true stem cell is the target of transformation, or
whether more mature cells are converted to a malignant
stem cell phenotype, a detailed consideration of stem cell
biology principles will be useful in better understanding
tumor pathogenesis and in designing strategies for more
A recent paper by Cox et al  has further expanded the
characterization of human lymphoid leukemia stem cells.
Using primary acute lymphoblastic leukemia (ALL) spe-
cimens, these studies demonstrated that only cells with a
CD34+, CD19?or CD34+, CD10?cell surface phenotype
were able to propagate disease in a mouse xenogeneic
model orina long-termsuspensionculturesystem.These
findings indicate that ALL derives from a low frequency
leukemia-initiating cell population and that relatively
primitive cells may be the target for ALL transformation.
I gratefully acknowledge Fay Young and Monica Guzman for critical
evaluation of the manuscript and many helpful discussions. Supported
by grants from the NIH (R01-CA90446) and the American Cancer
Society (RSG-03-096-01-LIB). CT Jordan is a scholar of the Leukemia
and Lymphoma Society.
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review, have been highlighted as:
? of special interest
?? of outstanding interest
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