Cancer stem cells in solid tumors Laurie E Ailles1 and Irving L Weissman2
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Cancer stem cells in solid tumors
Laurie E Ailles1 and Irving L Weissman2
Cancer stem cells (CSCs) are cells that drive tumorigenesis, as several important biological properties of CSCs: first,
well as giving rise to a large population of differentiated progeny what is the cell of origin for a given tumor? Second, what
that make up the bulk of the tumor, but that lack tumorigenic are the signaling pathways that drive self renewal and/or
potential. CSCs have been identified in a variety of human differentiation of CSCs? Third, are there molecules
tumors, as assayed by their ability to initiate tumor growth in uniquely expressed on CSCs, regardless of whether they
immunocompromised mice. Further characterization studies are functional, that will allow targeted therapies to be
have demonstrated that gene expression profiles in breast developed? Fourth, what are the mechanisms by which
cancer correlate with patient prognosis, and brain CSCs are CSCs escape conventional therapies and can we defeat
specifically resistant to radiation through DNA damage repair. these mechanisms? Answers to these questions should
In addition, specific signaling pathways play a functional role in lead to the development of therapies that target the CSC
CSC self renewal and/or differentiation, and early studies population and eliminate the ‘engine’ that drives tumors
indicate that CSCs are associated with a microenvironmental to grow, invade, and seed metastatic lesions. The chal-
niche. Thus the biological properties of CSCs are just beginning lenges involved in identifying a CSC population from a
to be revealed, and the continuation of these studies should solid tumor, and recent successes in this area are
lead to the development of CSC-targeted therapies for cancer described in this review, as well as early studies that
treatment. represent the first steps toward understanding the bio-
Addresses logical properties of these cells.
1
Institute for Stem Cell Biology and Regenerative Medicine, Stanford
University School of Medicine, 1050 Arastradero Road, Palo Alto, CA Identification of markers for the prospective
94304, United States
2
Department of Pathology and Institute for Stem Cell Biology and
isolation of cancer stem cells
Regenerative Medicine, Stanford University School of Medicine, B257 A recent AACR workshop stated that ‘cancer stem cells can
Beckman Center, Stanford, CA 94305, United States . . . only be defined experimentally by their ability to
recapitulate the generation of a continuously growing
Corresponding author: Ailles, Laurie E (lailles@stanford.edu) and
tumor’ [1]. The most widely accepted assay to validate a
Weissman, Irving L (irv@stanford.edu)
candidate CSC population is therefore tumor initiation and
serial transplantation in immunocompromised mice, where
Current Opinion in Biotechnology 2007, 18:460–466 the tumor that grows in the mice recapitulates the hetero-
This review comes from a themed issue on
geneity of the primary patient tumor. This was first
Tissue and cell engineering achieved for human acute myeloid leukemia (AML).
Edited by Alan Trounson and Andrew Elefanty The availability of cell surface markers allowing the iso-
lation of cells at distinct stages of hematopoietic devel-
opment, including hematopoietic stem cells (HSCs) [2,3],
0958-1669/$ – see front matter combined with specific and quantitative assays, greatly
Published by Elsevier Ltd. facilitated the identification of AML stem cells. In this
case, it was found that a population of cells with the
DOI 10.1016/j.copbio.2007.10.007
phenotype CD34+CD38 [4] and CD90 [5], that
represented 0.1–1% of the total cells, were the only cells
able to initiate AML that resembled the human disease in
Introduction NOD/SCID mice. Adding in vitro assays led to the finding
The cancer stem cell (CSC) model of tumor development that the CSCs were in the blood lineage panel marker
and progression states that tumors, like normal adult negative fraction [Lin ], while true CD34+38-90+lin
tissues, contain a subset of cells that both self renew HSCs contains the AML1/ETO translocation in nonleu-
and give rise to differentiated progeny. As in other tissues, kemic, or preleukemic, HSC [6]. The CD34+38-90-
the stem cells are a minority of the whole organ, and are CD45RA Lin population has recently been identified
the only cells that can maintain tumor growth indefinitely. in normal human hematopoietic tissues as a multipotent
The remaining cells, though actively proliferating and progenitor, but not a HSC [7]. Thus, the phenotype of the
making up the majority of the cells in the tumor, are also AML stem cell indicates that they probably originate in the
differentiating and destined to die. The self renewal hematopoietic stem/progenitor cell compartment, possibly
properties of the CSCs are thus the real driving force from the multipotent progenitor. It has been demonstrated
behind tumor growth. The identification of markers that in CML that has progressed to blast crisis, the progression
allow the prospective isolation of CSCs from whole tumor step is linked to the activation of a self renewal program in
tissues will allow us to develop an understanding of the granulocyte-macrophage progenitor population, thus
Current Opinion in Biotechnology 2007, 18:460–466 www.sciencedirect.comCancer stem cells in solid tumors Ailles and Weissman 461
conferring cells that normally cannot self renew with CSC Table 1
properties [8]. Thus while CSCs may derive from normal Cell surface phenotype of CSCs identified in human cancers
stem cells, this may not be the case in all tumors. More
Tumor type CSC phenotype Reference
differentiated cells could acquire self renewal capacity
through multiple mutagenic events, leading them to Breast CD44+ CD24 /low [9]
CNS CD133+ [10]
become the CSC that is driving tumor growth. Multiple myeloma CD138 [11]
Melanoma CD20+ [22]
In order to identify CSCs, patient-derived tumor cells are Prostate CD44+ a2b1+ CD133+ [23,24]
stained with labeled antibodies to various cell surface HNSCC CD44+ [12]
Colon CD133+ [15,16]
markers, either singly or in combination, and techniques
Colon CD44+ EpCam+ CD166+ [14]
such as magnetic columns or fluorescence-activated cell Pancreatic CD44+ EpCam+ CD24+ [13]
sorting (FACS) are used to separate labeled versus
unlabeled populations of cells. These populations are
then assayed for their ability to initiate tumor growth
in immunocompromised mice. Immunostaining and flow was demonstrated that as few as 100 CD133+ cells from
cytometric analysis of the engrafted tumor must then human brain tumors could initiate new tumors in the
show recapitulation of all of the original populations that brains of immunocompromised mice, while 100 000
were in the primary tumor, and upon resorting of the CSC CD133 cells did not contain any tumor-initiating
phenotype and retransplantation, a fully heterogeneous activity [11]. In 2004 it was also shown that multiple
tumor must again be initiated. Ultimately, clonal mark- myeloma contains a rare subset of cells, defined by their
ing, for example by retroviral insertion sites, and the lack of expression of the plasma cell marker CD138, that
demonstration of multiple secondary tumors containing are clonogenic in vitro and tumorigenic in vivo [12]. More
the same clone will be necessary to truly demonstrate self recently, similar findings have been made for HNSCC
renewal. To date this has only been demonstrated in [13], pancreatic cancer [14], and colon cancer [15–17].
AML [9]. The cell surface phenotypes of CSC populations from
these human solid tumors are described in Table 1.
In the case of solid tumors, the challenge of identifying
and characterizing CSCs is significant. In most cases, There have also been compelling studies in which
unlike the hematopoietic system, the normal tissue putative CSCs have been identified based on their ability
developmental hierarchy has not been identified or to form colonies in vitro. Sphere-forming ability as a
characterized. This makes the selection of candidate measure of stem cells was first developed for central
markers more difficult, and provides no basis for com- nervous system (CNS) cells, where it has been shown
parison between normal and malignant cells, or means to that a subset of cells isolated from human fetal brain, and
identify the cell of origin. In vivo models of human solid subsequently from human CNS tumors, can form spheres
tumors can also be challenging to achieve, as in some when cultured under the appropriate conditions [11,18–
cases orthotopic injection is not feasible or is technically 22]. These spheres can self renew in vitro, and differen-
challenging (e.g. lung, colon, and bladder cancers). In tiate into all of the neuronal lineages, both in vitro and in
these cases, subcutaneous injection or implantation under vivo. Importantly, it was subsequently demonstrated for
the kidney capsule can be successful, but it is essential to brain tumors that the neurosphere-forming cells could be
confirm that these xenografts recapitulate the histology of prospectively isolated from fresh tissue using the cell
the patient tumors. surface marker CD133, and that the CD133+ cells did
indeed initiate brain tumors in vivo, without any in vitro
Al-Hajj et al. [10] were the first to identify and prospec- manipulation, indicating that they do in fact represent
tively isolate a minority subpopulation of cells from a CSCs [11]. Fang et al. [23] have shown that upon culturing
human solid tumor (breast cancer) that contained all of of metastatic melanoma cell suspensions under appropri-
the in vivo tumor-forming ability, while the remaining ate conditions, a subset of cells could be propagated as
bulk of cells from these tumors had none, even when nonadherent spheres, which could then be induced to
injected at many-fold higher cell doses. The tumorigenic differentiate in vitro and to generate tumors in vivo.
cell population was identified based on its cell surface However, a marker has not definitively been identified
phenotype, which was Lineage-CD44+CD24 /low. This to allow the prospective isolation of melanoma sphere-
population could initiate tumors in immunocompromised forming cells from fresh tumors, though the authors
mice with as few as 200 cells, while as many as 500 000 or provided some evidence to suggest that CD20 can enrich
more of the remaining cells in the tumor did not initiate for the multipotent fraction from established sphere
new tumors in mice. A similar finding was subsequently cultures and melanoma cell lines. However, the ability
made in human brain tumors (GBMs and medulloblas- to acutely isolate and assay subpopulations of cells from
tomas). In this case, it was already known that normal tumors that behave as CSCs is essential before perform-
neuronal stem cells express the marker CD133 [19], and it ing characterizations such as gene expression profiling, to
www.sciencedirect.com Current Opinion in Biotechnology 2007, 18:460–466462 Tissue and cell engineering
avoid artifacts introduced by culturing cells for extended cells that are unique and that may otherwise not have
periods of time. Another tumor for which CSCs have been been revealed. They also found that CD24+ cells in one
potentially identified based on in vitro assays is prostate patient sample had an additional genetic change not
cancer. Cells that are CD44+ a2b1+ CD133+ possess a present in the CD44+CD24 cells. The authors state
significant capacity for self renewal, differentiation, and that it has not been proven that the CD24+ cells are the
invasiveness in vitro [24]. In this case, it also remains to be progeny of the CD44+CD24 cells; however this is not
seen whether these cells can reproduce the original tumor the case. In the study by Al-Hajj et al. [10], it was shown
in vivo. that tumors grown from the CD44+CD24 tumorigenic
population gave rise again to the original tumor hetero-
Understanding the biological properties of geneity, including the CD24+ cells. Thus the finding of
CSC genetic changes present in the CD24+ cells but not in the
Once CSCs have been identified, the real work begins, CD44+CD24 population, but not vice versa, does not
which is the characterization of their molecular and question the validity of the CSC hypothesis as Shipitsin
biological properties, in hopes of identifying ways to et al. suggest. It is conceivable that additional genetic
specifically target and eradicate these cells in cancer changes could take place in differentiating progenitors
patients. This is a new field in which we have barely that are the progeny of the CSC, or that clonal evolution
begun to scratch the surface because of the only very could occur within the CSC population itself as the tumor
recent ability to prospectively isolate CSCs from various grows and the CSC population expands. Thus although
tumors. Some of the approaches towards gaining a deeper the authors state that their data calls the CSC hypothesis
understanding of CSC biology that have been reported into question, in our opinion their data very nicely sup-
are described below. ports it.
Global gene expression profiling Identification of self renewal signaling pathways in
One approach is to perform global gene expression profil- CSCs
ing, and compare the CSC profile to that of the non-CSCs In addition to gene expression profiling, CSCs have been
within the tumor, or to known profiles from the corre- demonstrated to express known stem-cell-associated
sponding normal tissue. Such a study was performed for genes by other methods, including qRT-PCR and immu-
breast cancer, in which the gene expression profile of the nostaining. HNSCC CSCs differentially express BMI-1
CSC was compared to that of normal breast epithelium, in the CD44+ population compared to the CD44 popu-
leading to the identification of 186 genes that were lation, and pancreatic CSCs differentially express SONIC
differentially expressed in the CSC population. Upon HEDGEHOG. Studies have yet to be done to determine
comparison with previously reported gene signatures in whether these genes are functionally important in these
breast cancer, there was a significant association between human tumor types, but their known roles in the self-
the CSC signature and both overall and metastasis-free renewal of normal tissue stem cells and other CSC popu-
survival [25]. The finding that detectable expression of a lations suggest that they may also be important in these
specific set of CSC-related genes upon analysis of whole tumors. For example, in mice, BMI-1 is essential for the
tumor tissue correlates with prognosis suggests that more self renewal of hematopoietic and neural stem cells
aggressive tumors may contain a relatively higher per- [27,28] and has been shown to be required for the self-
centage of CSC, possibly caused by mutations that arrest renewal of leukemic stem cells [29], and BMI-1 is over-
cells in an immature state of differentiation. Indeed, expressed in human AML compared to normal bone
differentiation status correlates with prognosis in many marrow. The Hedgehog pathway has long been impli-
cancers. cated in many different kinds of cancer [30] and more
recently has been related specifically to human CSCs
A similar approach was taken by Shipitsin et al. [26], in from multiple myeloma [31], breast cancer [32], and
which breast tumor cells with the CSC phenotype were gliomas [33,34]. The Wnt signaling pathway has also
analyzed for their global gene expression profile com- been implicated in both stem cell self renewal and cancer
pared to the nontumorigenic cells from the same tumors. [35–37], and has been shown specifically to be active in
The profiles found indicated that cells of the CSC phe- the CSC population of human CML blast crisis patients
notype expressed stem/progenitor-associated genes while [8]. BMPs and their antagonists are known to play import-
the non-CSC expressed differentiation-associated genes. ant roles in regulating homeostasis of various organs and
They also found a correlation of their gene expression tissues via the control of differentiation, proliferation, and
signature with patient clinical outcome. Furthermore, apoptosis [38,39]. They have also been implicated in
they identified a signaling pathway (TGF-b) specifically several cancers [39,40]. Piccirillo et al. [41] recently
active in the CSC population, and found that inhibition of demonstrated that BMPs, in particular BMP4, depleted
this pathway in vitro led to differentiation. These obser- the brain tumor stem-cell population in vitro via a pro-
vations once again demonstrate that purification of CSC differentiation effect, and inhibited tumorigenicity in
allows the identification of biological properties of those vivo [41]. There are several other signaling pathways that
Current Opinion in Biotechnology 2007, 18:460–466 www.sciencedirect.comCancer stem cells in solid tumors Ailles and Weissman 463
have known roles in maintenance and/or control of normal state. Finally, increasing the number of endothelial cells
and CSC compartments in mice, as well as being impli- or blood vessels in xenografts expanded the CSC popu-
cated in cancer, including the Notch, PTEN, and Hox lation and accelerated their growth, while antiangiogenic
pathways [42,43], but to date no studies have been therapies depleted the CSCs from the xenografts and
performed to demonstrate a possible functional role arrested tumor growth. Thus the concept of the role of a
specifically in human CSC populations. CSC niche and the potential of inhibiting its interactions
with CSC populations appears to be an approach with a
The discovery of signaling pathways that play a functional great deal of therapeutic potential, both for disease treat-
role in CSC selfrenewal is extremely important from a ment and for chemoprevention [50]. Furthermore, the
therapeutic perspective, as some of these pathways have identification of the CSC niche should allow the devel-
known chemical inhibitors (e.g. the Hh pathway can be opment of in vitro assay systems that mimic the in vivo
inhibited by cyclopamine treatment), or function as indu- environment, providing more rapid results than the cur-
cers of differentiation (e.g. BMPs). rently cumbersome and time-consuming in vivo assays, as
well as allowing manipulations that are currently not
Identification of a CSC niche feasible with in vivo systems. Ultimately, an understand-
A well-known property of normal stem cells is their ing of the CSC niche in addition to the CSCs themselves
dependence upon their microenvironment, or ‘niche’ to for each different type of cancer should lead to a better
maintain their quiescent and undifferentiated state, while understanding of the signals that are important for CSC
maintaining their proliferation and differentiation poten- self renewal and/or differentiation in those cancers.
tials [44]. It is well known that a large component of solid
tumors is made up of nonepithelial stromal cells, which Are CSCs selectively resistant to conventional
include inflammatory cells, vascular endothelial cells, and therapies?
fibroblasts, and that in fact these stromal components are Normal stem cells are known to be relatively quiescent,
essential for tumor growth, most probably through direct resistant to drugs and toxins through the expression of
cell contacts and/or secreted factors [45,46]. In an effort to drug efflux pumps, and have an active DNA-repair
better understand the role of the microenvironment in capacity and resistance to apoptosis [51]. If CSCs share
tumor growth, Sneddon et al. [39] described a study in many of the properties of normal stem cells, as is hypoth-
which they compared gene expression profiles of squa- esized, this means that conventional chemo and radiation
mous cell carcinoma (SCC)-derived stromal cells versus therapies, which target rapidly cycling cells, will lead to
stromal cells from nontumor skin and identified two BMP reduction of the tumor through killing of the progeny of
antagonists (GREMLIN1 and FOLLISTATIN), that the CSCs, but the CSCs themselves will remain unaf-
were differentially expressed in the tumor-derived fected. Furthermore, the expression of drug efflux pumps
stroma. Furthermore, BMP2 and BMP4 were expressed and DNA-repair mechanisms will make them addition-
in SCC tumor cell nests, and GREMLIN1 was able to ally resistant to these forms of therapy. Several studies
prevent inhibition of SCC growth by BMP4 in vitro. have been done which support this hypothesis. In the
GREMLIN1 is expressed by stromal cells in diverse hematopoietic system, both normal and leukemic stem
human carcinomas, but not in corresponding normal cells are largely quiescent and express drug efflux mol-
tissues. This study suggests that the expression of factors ecules such as ABCG2 [52,53], and AML stem cells are
by the tumor microenvironment that regulate self renewal selectively resistant to both daunorubicin and Ara-C
may be a general feature of human cancer, and identifi- [54,55]. More recently, it was shown that CD133+ brain
cation of such factors may lead to the identification of tumor stem cells are selectively resistant to radiation, both
potential therapeutic targets. Prince et al. [13] demon- in vitro and in vivo, and the mechanism for this resistance
strated that the CSC-containing population in well and was shown to be through preferential activation of the
moderately differentiated HNSCC is physically located DNA damage checkpoint response and an increase in
adjacent to stroma, further indicating that there may be DNA-repair capacity [56]. By understanding the mech-
important interactions between the CSC and the stroma anisms that allow CSCs to resist conventional therapies, it
in carcinomas. may be possible to find ways to manipulate them to
become sensitive to these therapies.
Brain tumor stem cells also appear to interact with a niche.
Mouse neural stem cells have been shown to lie within a Conclusions
vascular niche in which endothelial cells regulate stem The CSC field, particularly in the area of solid tumors, is a
cell self renewal [47,48]. Therefore Calabrese et al. [49] very young one. A model of solid tumor stem-cell biology
investigated whether the CD133+Nestin+ cells that con- is shown in Figure 1, highlighting the properties that are
tain the CSC fraction are associated with vasculature and currently viewed as important for tumor growth, and that
found that indeed they are. Furthermore, endothelial may represent therapeutic targets. We are still in the very
cells supply secreted factors that maintain the brain tumor technically challenging stage of identifying the methods
stem cells in vitro in a self renewing and undifferentiated that will allow us to prospectively isolate CSCs from
www.sciencedirect.com Current Opinion in Biotechnology 2007, 18:460–466464 Tissue and cell engineering
Figure 1
Model of cancer stem cells (CSCs) in solid tumors. CSCs are associated with the stromal components of the tumor, including fibroblasts and/or
blood vessels, which make up the CSC ‘niche’. The niche cells secrete factors that support CSC self renewal. CSCs retain differentiation
potential, giving rise to non-self renewing tumor cells that make up the bulk of the tumor. CSCs may be drug and/or radiation resistant, and may
express CSC-specific antigens. Current research focuses on identification of the molecular mechanisms regulating these properties of CSCs
(highlighted in green), as they represent potential targets for therapy.
various solid tumors, and most importantly, to demon- Conflict of interest
strate in vivo that the populations we are looking at are ILW has stock in Amgen, Inc., was a member of the Amgen scientific
advisory board, and is a cofounder and member of the Board of Directors of
truly CSCs. In the cases where CSCs have been ident- Cellerant, Inc., and Stem Cells, Inc.
ified, early studies have already shown that they possess
important biological properties that directly relate to Acknowledgements
patient outcome. The breast CSC gene expression profile This work was supported in part by National Institutes of Health Grants
R01CA086017 and R01CA086065 and an anonymous gift fund for Cancer
was shown to correlate with patient prognosis, and the Stem Cell research at Stanford University. In addition LEA is a recipient of
brain CSC has been shown to be specifically resistant to a Stanford Comprehensive Cancer Center Developmental Research Award.
radiation through DNA damage repair. In addition,
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