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Pediatric Research 59:59R-64R (2006)
=A9 2006 International = Pediatric=20 Research Foundation, Inc.
DOI: 10.1203/01.pdr.0000203592.04530.06 =

Cancer Stem Cells

WEI GUO, = JOSEPH L.=20 LASKY, III and HONG WU

Department of Molecular and Medical Pharmacology = [W.G.,=20 J.L.L., H.W.], Department of Pediatrics [J.L.L.], University of = California, Los=20 Angeles, CA 90095


3D"   =20 ABSTRACT
= TOP
3D"ABSTRACT
= INTRODUCTION
THE IDENTITY AND ORIGIN...
MOLECULAR MECHANISMS UNDERLYING...
CLINICAL IMPLICATIONS
PROSPECTIVE
REFERENCES
 
C= ancer=20 stem cells (CSC) are recently proposed to be the cancer = initiating=20 cells responsible for tumorigenesis and contribute to cancer=20 resistance. Advances have been made in identifying and = enriching CSC=20 in leukemia and several solid tumors, including breast, brain = and=20 lung cancers. These studies suggest that, like normal stem = cells,=20 CSCs should be rare, quiescent, and capable of self-renewing = and=20 maintaining tumor growth and heterogeneity. Although the = concept of=20 CSC originates from that of normal stem cells, CSCs are not=20 necessarily aberrant counterparts of normal stem cells. In = fact, they=20 may arise from stem cells or committed progenitors of = corresponding=20 tissues, and even cells from other tissues. At the molecular = level,=20 the alteration of stem cell self-renewal pathway(s) has been=20 recognized as an essential step for CSC transformation. = Better=20 understanding of CSC will no doubt lead to a new era of both = basic=20 and clinical cancer research, re-classification of human = tumors and=20 development of novel therapeutic strategies specifically = targeting=20 CSC.

Abbreviations:
ALL, acute lymphoblastic=20 leukemia
AML, acute myelogenous leukemia
APML, acute = promyelocytic leukemia
CML, chronic myelogenous=20 leukemia
CSC, cancer stem cells
HSC, hematopoietic = stem=20 cells
MPD, myeloproliferative disorder
NSC, neural = stem=20 cells


3D"   =20 INTRODUCTION
= TOP
= ABSTRACT
3D"INTRODUCTION
THE IDENTITY AND ORIGIN...
MOLECULAR MECHANISMS UNDERLYING...
CLINICAL IMPLICATIONS
PROSPECTIVE
REFERENCES
 
S= tem cells=20 are defined as undifferentiated cells that are capable of=20 self-renewing and differentiating into a large number of = diverse=20 mature progeny. Amongst the various categories of stem cells, = the=20 embryonic stem (ES) cells are totipotent and able to = differentiate=20 into many cell types under appropriate conditions in = vitro and=20 contribute to all different tissues in vivo (1=963),=20 making them a very promising foundation for stem cell-based=20 therapeutics. Somatic stem cells from different organs, on = the=20 other hand, are pluripotent and responsible for tissue = regeneration=20 and repair. Adult stem cells have been identified in several=20 organs, such as the hematopoietic system, brain, skin, = mammary=20 gland and lung, but it is not yet clear whether they are = present=20 in all other adult organs (4,5).=20 The best-studied somatic stem cells are hematopoietic stem = cells=20 (HSC). With the aid of cell surface markers for positive=20 identification, fluorescence-activated cell sorting (FACS) = for=20 prospective isolation, and in vitro and in vivo = assays=20 for functional testing; HSCs in mice and humans have been = positively=20 identified and successfully isolated by Weissman and = colleagues (5,6).=20 HSCs are known to be responsible for the generation of all = cell types=20 in the blood (Fig.=20 1, middle panel), although their potential for giving = rise to=20 other tissues (or plasticity) is still controversial (4,5).=20



View = larger=20 version (25K):
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  		Figure 1. A schematic = relationship=20 between normal HSC differentiation and CSC and = leukemia/lymphoma=20 development. During normal hematopoietic development, = long-term HSC=20 maintain normal homeostasis by self-renewing and = differentiating=20 into functional mature cells of multiple lineages. = Hematopoietic=20 differentiation normally proceeds through the pathway of = stem cells,=20 committed multipotent progenitors, lineage-specific = progenitors to=20 mature cells (middle panel). Under rare conditions, an = oncogenic=20 event alters the tight regulation of stem cells or = progenitors and=20 transforms either of the two populations into CSC. The = leukemic=20 transformation also results in an aberrant hierarchial=20 differentiation pathway. Stem cell-derived CSC may retain=20 uncontrolled self-renewal capacity and be able to give rise = to=20 aberrant differentiating but immature leukemic cells due to=20 maturation arrest (left panel). Conversely, = progenitor-derived CSC=20 may acquire self-renewal capacity but be subject to = maturation=20 arrest after transformation event(s) take place (right = panel). In=20 certain types of cancer, multiple oncogenic mutations may be = required for full transformation. =

 = ;

Dick et al. have recently revealed that, like the normal = hematopoietic=20 system, leukemia is organized as a hierarchy in which only a=20 rare population retains a clonogenic capacity upon = transplantation=20 (7).=20 Similarly, a solid tumor can be likened to an organ developed = in an=20 aberrant way, as it contains a heterogeneous mixture of cell = types=20 and abnormal tissue structures. More importantly, such an = aberrant=20 organ can be maintained and even formed at remote sites if no = therapeutic intervention is performed. It is well established = that=20 tumor engraftment, although requiring a large number of = cells,=20 results in the formation of secondary tumors that = recapitulate=20 primary ones. The clonogenic and heterogenic nature of tumors = suggests that a rare cell population in cancer, which acts = like stem=20 cells, is responsible for tumor growth and metastasis. These = rare=20 cells are named cancer stem cells (CSC) after normal stem = cells, as=20 both have similar abilities to self-renew and to give rise to = heterogeneous differentiated cell types (8).=20 Recent advances have begun to disclose the biologic identity = and=20 origin of CSC in several types of cancers and to elucidate = the=20 mechanisms underlying the transformation of normal cells into = CSC.=20 This review will highlight recent progress in the field, and = discuss=20 key issues of CSC research and their clinical = implications.=20


3D"    THE=20 IDENTITY AND ORIGIN OF CSC
= TOP
= ABSTRACT
= INTRODUCTION
3D"THE IDENTITY AND ORIGIN...
MOLECULAR MECHANISMS UNDERLYING...
CLINICAL IMPLICATIONS
PROSPECTIVE
REFERENCES
 
T= o draw a=20 true cellular and molecular picture of CSC, it is critical to = identify CSC or purify the population to homogeneity. = Recently,=20 efforts have been made in isolating CSCs from human cancer = samples as=20 well as animal models as summarized in Table=20 1 (7,9=9617).=20 Although most of these studies are able to show cancers = initiated by=20 certain enriched populations for CSCs, homogeneity has not = been=20 reached. In fact, data revealing that CSCs can originate from = either=20 stem cells or progenitors (Table=20 1) raise the possibility that multiple CSC populations = may be=20 formed during cancer progression and even co-exist in = advanced=20 cancers.


View = this=20 table:
[in=20 this window]
[in a new window]
  		Table 1. A summary of = putative=20 cancer stem cells from cancer =

 = ;

The stem cell population is a logical candidate as a target = for=20 oncogenic transformation because of the inherent abilities of = self-renewal and multilineage differentiation (Fig.=20 1, left panel). Using the hematopoietic system as an = example, it=20 has been known for some time that an oncogenic event can=20 initiate at HSC level. It is well accepted that the t(9;22)=20 chromosomal translocation (or the Philadelphia chromosome), = which=20 leads to the formation of the p210 BCR-ABL1 oncoprotein, is=20 present in the HSCs of patients with chronic myelogenous = leukemia=20 (CML) (18,19).=20 In a subset of acute lymphoblastic leukemia (ALL), this = t(9;22)=20 breakpoint was detected in the=20 CD34+CD38=96CD19=96 HSCs (13).=20 The transcripts of another leukemic fusion oncogene, = AML1-ETO,=20 were also detected in the=20 CD34+Thy+CD38=96Lin=96 = HSCs=20 of patients with acute myelogenous leukemia (AML) in long-term=20 remission (10).=20 Consistent with the observations in human leukemia, only the = murine=20 JunB=96/=96 HSC population was capable of = transplanting=20 myeloproliferative disorder (MPD) to recipients (20).=20 These lines of evidence underscore the stem cell origin of = CSC.=20 However, in most of the cases described above, additional = mutations=20 appear to be required for their malignant transformation.

In addition to stem cell origin, recent findings point out that=20 CSC can also arise from committed progenitors that acquire=20 self-renewal capacity (Fig.=20 1, right panel). Such progenitors are normally derived = from=20 self-renewable HSC but have no or very limited self-renewal = capacity.=20 With progressive proliferation and differentiation, these = progenitor=20 cells are capable of producing terminally differentiated = functional=20 cells. The oncogenic fusion genes, such as ETV6-RUNX1 = or p190=20 BCR-ABL, could only be detected in=20 CD34+CD38=96CD19+ B = progenitor=20 population of some ALL patients (13).=20 From these patients, the purified CD19+ B cells, = but not=20 the CD34+CD38=96 CD19=96 = HSC,=20 exclusively reconstituted CD19+ leukemia in=20 immunodeficient nonobese diabetic-severe combined = immunodeficiency=20 (NOD-SCID) mice (13),=20 providing conclusive evidence of a B progenitor origin for = CSC. In=20 the case of acute promyelocytic leukemia (APML), the fusion = gene=20 PML-RAR3D{alpha},=20 resulting from the t(15;17) translocation, was detected only = in=20 CD34=96CD38+ progenitors, but not in=20 CD34+CD38=96 HSC (9).=20 The progenitor origin of CSC in APML is supported by the = transgenic=20 mouse model of PML-RAR3D{alpha}=20 = under the=20 control of a human myeloid-specific promoter of MRP8, which = is=20 expressed in common myeloid progenitors (CMP) and = granulocyte/monocyte=20 progenitors (GMP). These PML-RAR3D{alpha}=20 transgenic = mice=20 recapitulated human APML (21).=20 In contrast, the transgenic mice expressing PML-RAR3D{alpha}=20 in more = differentiated=20 CD11b+ myelomonocytic cells failed to develop = leukemia (22).=20 Results from these studies of hematopoietic malignancies = suggest that=20 CSC can also originate from lineage-committed and = stage-specific=20 progenitors (Fig.=20 1, right panel).

In addition to differentiation stage-dependent origin, a study = of=20 ependymoma, a CNS (CNS) tumor, adds regional difference to = the origin=20 of CSC. Taylor et al. reported that histologically = identical=20 ependymomas from the supratentorial, the posterior fossa and = the=20 spinal cord region might be initiated from altered radial = glia cells=20 (RGC, CD133+Nestin+RC2+BLBP+ = progenitors). However, these tumors maintained different = chromosomal=20 abnormalities and only recapitulated the gene expression = profiles of=20 the progenitors from their respective anatomic sites (16).=20

Although CSCs are generally considered to be derived from = mutated=20 stem cells or progenitors of corresponding tissues or organs, = some surprisingly originate from cells recruited from other=20 tissues. This was shown in a mouse model of gastric cancer = induced=20 by chronic infection with Helicobacter felis, analogous to=20 human H. pylori infection. In lethally irradiated mice = transplanted with LacZ-positive bone marrow (BM) = cells, these=20 LacZ+ BM-derived cells could home to and = repopulate=20 the gastric mucosa and contribute to metaplasia, dysplasia = and=20 intraepithelial cancer after H. felis infection (23).=20 In vitro culture further suggested that BM-derived = mesenchymal=20 stem cells (MSC) may be a candidate origin for CSC, as they, = but not=20 HSC, can acquire a gastric mucosa gene expression pattern = when=20 exposed to primary gastric cell cultures (23).=20 However, it remains to be elucidated how the BM-derived cells = are=20 transformed to CSC.


3D"   =20 MOLECULAR MECHANISMS UNDERLYING CSC FORMATION =
= TOP
= ABSTRACT
= INTRODUCTION
THE IDENTITY AND ORIGIN...
3D"MOLECULAR MECHANISMS UNDERLYING...
CLINICAL IMPLICATIONS
PROSPECTIVE
REFERENCES
 
R= ecent=20 studies suggest that both cell intrinsic and environmental = factors=20 can control the normal stem cells and thus may contribute to = the=20 formation of CSCs. As for cell intrinsic effects, studies of = human=20 hematopoietic malignancies in murine models indicate the = existence of=20 a hierarchy among oncogenic fusion proteins in their ability = of=20 endowing a self-renewal capacity to committed progenitors and = blocking cell differentiation (24,25).=20 MOZ-TIF2 and MLL-ENL are AML-associated = oncogenes that=20 are capable of conferring a self-renewal capacity to myeloid=20 progenitors and blocking cell differentiation. These = oncoproteins=20 alone are sufficient to transform committed progenitors to = CSC (24,26).=20 On the other hand, the oncoprotein p210 BCR-ABL1 in human = CML,=20 which provides HSC proliferation and survival advantage but = not=20 self-renewal activity, is not sufficient to trigger leukemic=20 transformation on committed myeloid progenitors (24,27).=20 This class of oncoproteins usually requires additional=20 alteration(s), or a 2nd hit in the self-renewal pathways, = e.g.=20 Bmi-1 or Wnt/=DF-catenin, for complete transformation. The = differences=20 in cellular transformation potency between these oncogenic = fusion=20 proteins remain to be further confirmed in human diseases. = Since=20 disease-specific chromosomal translocations are generally = rare in=20 epithelial tumors (28,29),=20 multi-step mutational mechanisms are likely to be required = for CSC=20 formation in most of them.

Based upon the above observations, alteration of self-renewal=20 pathways seems to be an important mechanism underlying CSC = formation.=20 It is known that the signaling pathways required for normal=20 stem cell self-renewal are also involved in cancer = development,=20 such as Hox genes, Wnt, Sonic Hedgehog, and Notch signaling=20 pathways (30,31).=20 Recently, we have demonstrated that the PTEN tumor suppressor = appears=20 to negatively regulate the self-renewal of neural stem cells = (NSC)=20 (32)=20 by modulating their G0-G1 cell cycle entry (33).=20 The roles for these genes/pathways in normal and cancer stem = cells=20 have drawn an increased attention from both developmental and = cancer=20 biologists.

It is hypothesized that the self-renewal and differentiation = of=20 stem cells are maintained by asymmetric division, through = which a=20 stem cell gives rise to two unequal daughter cells: one = resembling=20 the parental stem cell in the niche and the other proceeding = toward=20 differentiation. Any change in the control of asymmetric = division may=20 result in aberrant self-renewal activity of stem cells. = Support for=20 this hypothesis came from Drosophila studies. = Aberrations in=20 the stem cell asymmetric division, caused by mutations in=20 polarity-controlling genes, e.g. raps, mira,=20 numb, or pros, resulted in enhanced self-renewal = activity=20 and altered neuroblasts to form neuroblastoma-like tumors in=20 adult hosts (34).=20 It is suggested that the human tumor suppressor gene = LKB1,=20 which is reported to regulate polarity and is lost in the=20 Peutz-Jeghers cancer syndrome, may contribute to tumorigenesis = in=20 mammalian systems via a similar mechanism (35).=20

Of those self-renewal regulators, the polycomb family = transcriptional=20 repressor Bmi-1 and Wnt/=DF-catenin signaling pathway = have=20 recently been studied in the regulation of CSC self-renewal = (25,36).=20 Bmi-1 has been shown to be required for the self-renewal of = adult HSC=20 and NSC (37=9639).=20 Park et al. demonstrated that the number of HSC was = normal in=20 the fetal liver of Bmi-1=96/=96 mice but = markedly=20 reduced in postnatal BM. Moreover, Bmi-1=96/=96 = fetal=20 liver and bone marrow cells were only able to transiently=20 reconstitute hematopoiesis (37).=20 The studies of Bmi-1 in NSC further confirmed that NSC = self-renewal=20 is also dependent on Bmi-1, distinct from the = Bmi-1-independent=20 proliferation of restricted progenitors (39).=20 Intriguingly, Bmi-1 plays an essential role in the = self-renewal of=20 CSC. Although introduction of Hoxa9 and Meis1 = into=20 Bmi-1=96/=96 fetal liver cells resulted in = AML in host=20 mice, leukemic cells from = Bmi-1=96/=96Hoxa9=96Meis1=20 recipients failed to reconstitute AML in any of secondary = recipient=20 mice (36).=20 Besides Bmi-1, Wnt/=DF-catenin signaling is reported to = regulate=20 HoxB4 and Notch1, two critical regulators of = HSC=20 self-renewal activity (40).=20 The ectopic expression of Axin or a frizzled = ligand-binding=20 domain, inhibitors of Wnt/=DF-catenin signaling, led to = inhibition of=20 HSC growth in vitro and reduced reconstitution in = vivo.=20 This self-renewal role for Wnt/=DF-catenin signaling appears = to be=20 conserved in self-renewing CSC. For example, committed = myeloid=20 progenitors or GMP, putative CSC from CML patients in = accelerated=20 phase or blast crisis, showed increased nuclear =DF-catenin = activity=20 and self-renewal in a replating assay. Correspondingly, their = replating capacity was reduced by the lentiviral introduction = of=20 Axin (25).=20 PI3 K/AKT signaling is reported to positively regulate=20 Wnt/=DF-catenin signaling through AKT-mediated = phosphorylation of=20 GSK-3=DF (41).=20 In a murine MPD model carrying a conditional deletion of = Pten,=20 a potent negative regulator of PI3 K/AKT signaling, we also = observed=20 elevated cytosolic and nuclear =DF-catenin in leukemic blasts = (W.G.,=20 J.L.L., and H.W., unpublished data).

Interestingly, these two self-renewal pathways appear to play=20 important roles in the regulation of metastasis. Brabletz = et=20 al. observed that a high level of =DF-catenin was = detected in=20 mesenchyme-like colorectal tumor cells at the invasive fronts,=20 implicating Wnt/=DF-Catenin signaling in the = epithelial-to-mesenchymal=20 transition (EMT) or dissemination process of primary tumors = (42).=20 They proposed that low-level activation of =DF-catenin in the = nucleus=20 may be enough to confer self-renewal capacity, but its higher = activation is required to trigger EMT, an essential step for=20 metastasis (43).=20 This phenomenon appears to hold true for the Bmi-1 pathway.=20 Expression profiling on metastatic versus primary prostate = tumors=20 from human patients and the murine TRAMP transgenic model = revealed=20 substantial elevation of Bmi-1 and its associated molecular = signature=20 of 11 genes in metastatic cancer (44).=20 Furthermore, this metastasis/stem cell signature was used to = predict=20 the risk of metastatic recurrence and poor clinical outcomes = using=20 samples from 1,153 cancer patients with 11 different types of = cancer=20 (44).=20 Future studies are required to investigate the link between = stem-ness=20 and metastatic potential and the dual roles that = Wnt/=DF-catenin or=20 Bmi-1 pathway may play.

As stem cell niches control normal stem cells, it is currently=20 unknown how extrinsic or environmental factors control CSC = formation.=20 Studies on the development of Drosophila germ cells = suggest=20 that stem cell faith is determined by the instructive signals = from their microenvironment=97the "stem-cell niche" (45).=20 In Drosophila germ cell niches, instructive signals are=20 reported to be comprised of dpp and Yb/Piwi/hh = in ovary=20 or Unpaired (Jak-Stat signaling) in testis (45).=20 In mammalian systems, signaling pathways conserved in = niche-mediated=20 stem cell control are reported to include TGF=DF/BMP, NOTCH, = JAK-STAT,=20 and context-dependent WNT (46,47).=20 Furthermore, the size of a stem cell niche determines the = number of=20 stem cells in this niche. In Drosophila, the number of = germline stem cells is positively correlated with the number = of cap=20 cells, a component of germline niches (48).=20 Consistently, an increased number of murine osteoblasts, a = component=20 of HSC niches, leads to an increase in the number of HSCs (49,50).=20 Although the role of the stem cell or CSC-specific niches in=20 CSC formation remains unclear, some indirect evidence = underscores=20 their importance. For example, dpp overexpression induced = by=20 heat shock in Drosophila germaria resulted in stem = cell-like=20 germline tumors (51).=20


3D"   =20 CLINICAL IMPLICATIONS
= TOP
= ABSTRACT
= INTRODUCTION
THE IDENTITY AND ORIGIN...
MOLECULAR MECHANISMS UNDERLYING...
3D"CLINICAL = IMPLICATIONS
PROSPECTIVE
REFERENCES
 
T= he=20 introduction of the CSC concept has provided exciting insights = into=20 the roots of carcinogenesis and sheds light on the future = cure of=20 cancer. The impact from current and future studies of CSC = will=20 revolutionize clinical practice with regards to both cancer = diagnosis=20 and therapy. Two of the implicated changes will be the=20 re-classification of human tumors and development of novel=20 therapeutic strategies targeting CSC.

The current diagnosis and classification of human cancer is = mainly=20 based on pathologic characterization of the entire tumor. = However, we=20 now understand that a rare CSC population(s) initiates and = maintains=20 cancer. As indicated by the above cases (13,16),=20 although tumors are histologically identical, their CSC may = be=20 derived from different stem cell or progenitor populations, = depending=20 on where the transformation occurs. This difference at the = level of=20 CSC will likely be very important for diagnosis and therapy,=20 especially for future therapies targeting CSC. Once CSC = isolation=20 approaches are established and verified, it will be critical = to=20 characterize human cancers based on both CSC and bulk tumor = and=20 establish a new system of cancer classification. However, = since the=20 current identification of CSC is fully dependent on in = vivo=20 reconstitution assays, a more practical and quicker approach = to=20 identify CSC will be essential for diagnosis. Both molecular=20 signatures for altered self-renewal pathways, e.g. = Bmi-1 (39)=20 and =DF-catenin (25)=20 in CSC, and in vitro replating capacity may serve as=20 biomarkers for diagnosis based on CSC.

In most cases, current therapeutic strategies are developed = to=20 target the bulk of cancer and likely do not eradicate CSC = completely,=20 although they may have some effects on CSC, e.g. = inhibition of=20 CSC proliferation, and so reduce CSC number. For example, = imatinib=20 administration for CML can achieve complete remission, but = the=20 BCR-ABL1 fusion gene is often detected in HSC of = patients in=20 remission, suggesting a potential risk of CML relapse. Thus, = the=20 complete eradication of CSC is likely the key to the cure of = cancer.=20 For clinical elimination of CSC, the cellular and molecular=20 properties described below need to be taken into = account.

The rarity of CSC will require therapeutic strategies different=20 from conventional ones. Specific recognition of CSC from the=20 tumor mass will be the first challenge. The identification of = CSC-specific antigens may help develop specific targeting. = Since=20 the origins of CSC vary from cancer to cancer, the = development=20 of therapeutic strategies targeting different CSC = population(s)=20 will also be necessary. For stem cell-derived CSC which = usually=20 require additional mutations to generate malignancy, the use = of=20 inductive differentiation (i.e. trans-retinoic acid therapy=20 for APML) or replacement with normal stem cells may be = required,=20 if it is hard to distinguish between normal stem cells and = CSC.=20 For progenitor-derived malignant CSC, eradication therapies=20 targeting CSC and progenitors can be applied as long as a = normal=20 stem cell pool is still available for reconstitution in = cancer=20 patients (13).=20

Finally, multiple pathways/mechanisms will likely need to be=20 targeted together for effective elimination. CSC may have or=20 acquire stem cell properties that are more resistant to = therapies,=20 such as survival advantage with increased anti-apoptotic = activities=20 and drug resistance due to increased levels of drug efflux = pumps=20 such as BCRP (breast cancer resistance protein) and MDR = (multiple=20 drug resistance) complexes. Future therapeutic strategies = will=20 need to integrate inhibition of these resistant mechanisms = with=20 CSC killing components. Moreover, combination therapies will=20 help to prevent the generation of resistant CSC colonies due = to=20 mutations (52).=20


3D"   =20 PROSPECTIVE
= TOP
= ABSTRACT
= INTRODUCTION
THE IDENTITY AND ORIGIN...
MOLECULAR MECHANISMS UNDERLYING...
CLINICAL IMPLICATIONS
3D"PROSPECTIVE
REFERENCES
 
D= espite=20 recent progress in CSC research, our knowledge of these rare=20 populations is still limited and many questions remain to be=20 answered. Certain types of cancer are known to be multi-stage=20 diseases, which generally progress into more malignant forms=20 with the sequential accumulation of genetic and molecular=20 alterations. For instance, hematological malignancies, such = as CML,=20 are often found to have two distinct phases: chronic phase = and blast=20 crisis (or leukemia). Similarly, some epithelial tumors, = e.g.=20 colon tumors, are thought to progress through at least five=20 stages: pretumor patches/fields, hyperplasia, carcinoma in = situ, invasive carcinoma and metastasis (30).=20 One of the central questions in the CSC research is: how to = link CSC=20 to cancer progression in these tumors? Given sequential = requirements=20 of genetic and molecular alterations and distinct pathologic=20 abnormalities associated with different stages of cancer = progression,=20 one may postulate that there could be multiple CSC = populations,=20 either intrinsically linked or generated independently, = responsible=20 for different stages of cancer progression.

To advance CSC research, we need to first understand the normal=20 stem cells and critical pathways controlling stem cell = properties.=20 For this, identification of cell surface molecules for = prospective=20 stem cell isolation and biologically relevant stem cell = assays=20 are essential. In addition, technical improvement will = expedite=20 the studies of these rare and heterogeneous population(s). We = should investigate the molecular mechanisms for the CSC = formation=20 and maintenance, especially their self-renewal regulation, = which=20 holds the key for the development of effective therapeutic = strategies=20 against CSC. Although stem cell niches have been shown to = play=20 an instructive and pivotal role in the regulation of stem = cells,=20 their implication in the CSC formation remains to be = elucidated.=20 Ultimately, with further improvements in our understanding of = CSC, we will be able to develop better diagnostic and = therapeutic=20 methodologies, with which to classify, treat, and cure = cancer.


Acknowledgments. We thank Drs. = Bangyan=20 Stiles and Shunyou Wang for comments and suggestions, and = Bahram=20 Valamehr for proofreading.

Received December 2, 2005; accepted = December 28,=20 2005.

Correspondence: Wei Guo, Ph.D., Department of Molecular and=20 Medical Pharmacology, CHS 23-234, UCLA School of Medicine, = 650=20 CE Young Drive South, Los Angeles, CA90095-1735; e-mail: wguo{at}mednet.ucla.edu .

J.L.L. is a fellow of NCI Scholar for Oncology and Molecular=20 Imaging Training Program.

This work is supported by grants from DOD PC031130 and NCI UO1=20 CA84128-06 and RO1 CA107166 (H.W.).


3D"   =20 REFERENCES
= TOP
= ABSTRACT
= INTRODUCTION
THE IDENTITY AND ORIGIN...
MOLECULAR MECHANISMS UNDERLYING...
CLINICAL IMPLICATIONS
PROSPECTIVE
3D"REFERENCES
&nb= sp;

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Opera = requires=0A= the Sun Java Runtime Environment .=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_01E2_01C70A6E.B53D1CF0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.pedresearch.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else 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quoted-printable Content-Location: http://www.pedresearch.org/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. For now we have to disable=0A= * the callback until we can track down a proper fix=0A= * (or everybody sanely upgrades to version 6 or 7!).=0A= */=0A= if (navigator) {=0A= var appname =3D navigator.appName;=0A= if (appname =3D=3D "Microsoft Internet Explorer") {=0A= var userAgent =3D navigator["userAgent"];=0A= var s =3D "MSIE ";=0A= var n =3D -1; =0A= if ((n =3D userAgent.indexOf(s)) !=3D -1) {=0A= var v =3D parseFloat(userAgent.substring(n+s.length));=0A= if (v < 6) {=0A= return;=0A= }=0A= }=0A= }=0A= }=0A= =0A= /*=0A= * Acquire table row element to update, initiate callback=0A= * to update table with Entrez Links.=0A= */=0A= var tr =3D document.getElementById('entrez_callback_'+pmid);=0A= if (!tr) {=0A= return;=0A= }=0A= var req =3D new XMLHttpRequest();=0A= if (!req) {=0A= return;=0A= }=0A= req.onreadystatechange =3D function() {=0A= if (req.readyState =3D=3D 4 && (req.status =3D=3D 200 || req.status = =3D=3D 304)) {=0A= var src =3D req.responseXML.documentElement;=0A= var dst =3D document.createDocumentFragment();=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], dst);=0A= }=0A= var tbl =3D tr.parentNode;=0A= tbl.replaceChild(dst, tr);=0A= }=0A= }=0A= req.open('GET', callback_url, true);=0A= req.send(null);=0A= }=0A= ------=_NextPart_000_01E2_01C70A6E.B53D1CF0--