ABSTRACT Cancer stem cells (CSC) are recently proposed to be the cancer initiating cells responsible for tumorigenesis and contribute to cancer resistance. Advances have been made in

identifying and enriching CSC in leukemia and several solid tumors, including breast, brain and lung cancers. These studies suggest that, like normal stem cells, CSCs should be rare,

quiescent, and capable of self-renewing and maintaining tumor growth and heterogeneity. Although the concept of CSC originates from that of normal stem cells, CSCs are not necessarily

aberrant counterparts of normal stem cells. In fact, they may arise from stem cells or committed progenitors of corresponding tissues, and even cells from other tissues. At the molecular

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MALIGNANCIES Article Open access 10 October 2024 MAIN Stem cells are defined as undifferentiated cells that are capable of self-renewing and differentiating into a large number of diverse

mature progeny. Amongst the various categories of stem cells, the embryonic stem (ES) cells are totipotent and able to differentiate into many cell types under appropriate conditions _in

vitro_ and contribute to all different tissues _in vivo_ (1–3), making them a very promising foundation for stem cell-based therapeutics. Somatic stem cells from different organs, on the

other hand, are pluripotent and responsible for tissue regeneration and repair. Adult stem cells have been identified in several organs, such as the hematopoietic system, brain, skin,

mammary gland and lung, but it is not yet clear whether they are present in all other adult organs (4,5). The best-studied somatic stem cells are hematopoietic stem cells (HSC). With the aid

of cell surface markers for positive identification, fluorescence-activated cell sorting (FACS) for prospective isolation, and _in vitro_ and _in vivo_ assays for functional testing; HSCs

in mice and humans have been positively identified and successfully isolated by Weissman and colleagues (5,6). HSCs are known to be responsible for the generation of all cell types in the

blood (Fig. 1, middle panel), although their potential for giving rise to other tissues (or plasticity) is still controversial (4,5). Dick et al. have recently revealed that, like the normal

hematopoietic system, leukemia is organized as a hierarchy in which only a rare population retains a clonogenic capacity upon transplantation (7). Similarly, a solid tumor can be likened to

an organ developed in an aberrant way, as it contains a heterogeneous mixture of cell types and abnormal tissue structures. More importantly, such an aberrant organ can be maintained and

even formed at remote sites if no therapeutic intervention is performed. It is well established that tumor engraftment, although requiring a large number of cells, results in the formation

of secondary tumors that recapitulate primary ones. The clonogenic and heterogenic nature of tumors suggests that a rare cell population in cancer, which acts like stem cells, is responsible

for tumor growth and metastasis. These rare cells are named cancer stem cells (CSC) after normal stem cells, as both have similar abilities to self-renew and to give rise to heterogeneous

differentiated cell types (8). Recent advances have begun to disclose the biologic identity and origin of CSC in several types of cancers and to elucidate the mechanisms underlying the

transformation of normal cells into CSC. This review will highlight recent progress in the field, and discuss key issues of CSC research and their clinical implications. THE IDENTITY AND

ORIGIN OF CSC To draw a true cellular and molecular picture of CSC, it is critical to identify CSC or purify the population to homogeneity. Recently, efforts have been made in isolating CSCs

from human cancer samples as well as animal models as summarized in Table 1 (7,9–17). Although most of these studies are able to show cancers initiated by certain enriched populations for

CSCs, homogeneity has not been reached. In fact, data revealing that CSCs can originate from either stem cells or progenitors (Table 1) raise the possibility that multiple CSC populations

may be formed during cancer progression and even co-exist in advanced cancers. The stem cell population is a logical candidate as a target for oncogenic transformation because of the

inherent abilities of self-renewal and multilineage differentiation (Fig. 1, left panel). Using the hematopoietic system as an example, it has been known for some time that an oncogenic

event can initiate at HSC level. It is well accepted that the t(9;22) chromosomal translocation (or the Philadelphia chromosome), which leads to the formation of the p210 BCR-ABL1

oncoprotein, is present in the HSCs of patients with chronic myelogenous leukemia (CML) (18,19). In a subset of acute lymphoblastic leukemia (ALL), this t(9;22) breakpoint was detected in

the CD34+CD38−CD19− HSCs (13). The transcripts of another leukemic fusion oncogene, _AML1-ETO_, were also detected in the CD34+Thy+CD38−Lin− HSCs of patients with acute myelogenous leukemia

(AML) in long-term remission (10). Consistent with the observations in human leukemia, only the murine _JunB__−/−_ HSC population was capable of transplanting myeloproliferative disorder

(MPD) to recipients (20). These lines of evidence underscore the stem cell origin of CSC. However, in most of the cases described above, additional mutations appear to be required for their

malignant transformation. In addition to stem cell origin, recent findings point out that CSC can also arise from committed progenitors that acquire self-renewal capacity (Fig. 1, right

panel). Such progenitors are normally derived from self-renewable HSC but have no or very limited self-renewal capacity. With progressive proliferation and differentiation, these progenitor

cells are capable of producing terminally differentiated functional cells. The oncogenic fusion genes, such as _ETV6-RUNX1_ or p190 _BCR-ABL_, could only be detected in CD34+CD38−CD19+ B

progenitor population of some ALL patients (13). From these patients, the purified CD19+ B cells, but not the CD34+CD38− CD19− HSC, exclusively reconstituted CD19+ leukemia in

immunodeficient nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice (13), providing conclusive evidence of a B progenitor origin for CSC. In the case of acute promyelocytic

leukemia (APML), the fusion gene PML-RARα, resulting from the t(15;17) translocation, was detected only in CD34−CD38+ progenitors, but not in CD34+CD38− HSC (9). The progenitor origin of CSC

in APML is supported by the transgenic mouse model of PML-RARα under the control of a human myeloid-specific promoter of MRP8, which is expressed in common myeloid progenitors (CMP) and

granulocyte/monocyte progenitors (GMP). These PML-RARα transgenic mice recapitulated human APML (21). In contrast, the transgenic mice expressing PML-RARα in more differentiated CD11b+

myelomonocytic cells failed to develop leukemia (22). Results from these studies of hematopoietic malignancies suggest that CSC can also originate from lineage-committed and stage-specific

progenitors (Fig. 1, right panel). In addition to differentiation stage-dependent origin, a study of ependymoma, a CNS (CNS) tumor, adds regional difference to the origin of CSC. Taylor _et

al._ reported that histologically identical ependymomas from the supratentorial, the posterior fossa and the spinal cord region might be initiated from altered radial glia cells (RGC,

CD133+Nestin+RC2+BLBP+ progenitors). However, these tumors maintained different chromosomal abnormalities and only recapitulated the gene expression profiles of the progenitors from their

respective anatomic sites (16). Although CSCs are generally considered to be derived from mutated stem cells or progenitors of corresponding tissues or organs, some surprisingly originate

from cells recruited from other tissues. This was shown in a mouse model of gastric cancer induced by chronic infection with _Helicobacter felis_, analogous to human _H. pylori_ infection.

In lethally irradiated mice transplanted with _LacZ_-positive bone marrow (BM) cells, these _LacZ_+ BM-derived cells could home to and repopulate the gastric mucosa and contribute to

metaplasia, dysplasia and intraepithelial cancer after _H. felis_ infection (23). _In vitro_ culture further suggested that BM-derived mesenchymal stem cells (MSC) may be a candidate origin

for CSC, as they, but not HSC, can acquire a gastric mucosa gene expression pattern when exposed to primary gastric cell cultures (23). However, it remains to be elucidated how the

BM-derived cells are transformed to CSC. MOLECULAR MECHANISMS UNDERLYING CSC FORMATION Recent studies suggest that both cell intrinsic and environmental factors can control the normal stem

cells and thus may contribute to the formation of CSCs. As for cell intrinsic effects, studies of human hematopoietic malignancies in murine models indicate the existence of a hierarchy

among oncogenic fusion proteins in their ability of endowing a self-renewal capacity to committed progenitors and blocking cell differentiation (24,25). _MOZ-TIF2_ and _MLL-ENL_ are

AML-associated oncogenes that are capable of conferring a self-renewal capacity to myeloid progenitors and blocking cell differentiation. These oncoproteins alone are sufficient to transform

committed progenitors to CSC (24,26). On the other hand, the oncoprotein p210 BCR-ABL1 in human CML, which provides HSC proliferation and survival advantage but not self-renewal activity,

is not sufficient to trigger leukemic transformation on committed myeloid progenitors (24,27). This class of oncoproteins usually requires additional alteration(s), or a 2nd hit in the

self-renewal pathways, _e.g._ Bmi-1 or Wnt/β-catenin, for complete transformation. The differences in cellular transformation potency between these oncogenic fusion proteins remain to be

further confirmed in human diseases. Since disease-specific chromosomal translocations are generally rare in epithelial tumors (28,29), multi-step mutational mechanisms are likely to be

required for CSC formation in most of them. Based upon the above observations, alteration of self-renewal pathways seems to be an important mechanism underlying CSC formation. It is known

that the signaling pathways required for normal stem cell self-renewal are also involved in cancer development, such as Hox genes, Wnt, Sonic Hedgehog, and Notch signaling pathways (30,31).

Recently, we have demonstrated that the PTEN tumor suppressor appears to negatively regulate the self-renewal of neural stem cells (NSC) (32) by modulating their G0-G1 cell cycle entry (33).

The roles for these genes/pathways in normal and cancer stem cells have drawn an increased attention from both developmental and cancer biologists. It is hypothesized that the self-renewal

and differentiation of stem cells are maintained by asymmetric division, through which a stem cell gives rise to two unequal daughter cells: one resembling the parental stem cell in the

niche and the other proceeding toward differentiation. Any change in the control of asymmetric division may result in aberrant self-renewal activity of stem cells. Support for this

hypothesis came from _Drosophila_ studies. Aberrations in the stem cell asymmetric division, caused by mutations in polarity-controlling genes, _e.g. raps_, _mira_, _numb_, or _pros_,

resulted in enhanced self-renewal activity and altered neuroblasts to form neuroblastoma-like tumors in adult hosts (34). It is suggested that the human tumor suppressor gene _LKB1_, which

is reported to regulate polarity and is lost in the Peutz-Jeghers cancer syndrome, may contribute to tumorigenesis in mammalian systems via a similar mechanism (35). Of those self-renewal

regulators, the polycomb family transcriptional repressor Bmi-1 and Wnt/β-catenin signaling pathway have recently been studied in the regulation of CSC self-renewal (25,36). Bmi-1 has been

shown to be required for the self-renewal of adult HSC and NSC (37–39). Park _et al._ demonstrated that the number of HSC was normal in the fetal liver of _Bmi-1_−/− mice but markedly

reduced in postnatal BM. Moreover, _Bmi-1_−/− fetal liver and bone marrow cells were only able to transiently reconstitute hematopoiesis (37). The studies of Bmi-1 in NSC further confirmed

that NSC self-renewal is also dependent on Bmi-1, distinct from the Bmi-1-independent proliferation of restricted progenitors (39). Intriguingly, Bmi-1 plays an essential role in the

self-renewal of CSC. Although introduction of _Hoxa9_ and _Meis1_ into _Bmi-1__−/−_ fetal liver cells resulted in AML in host mice, leukemic cells from _Bmi-1__−/−__Hoxa9–Meis1_ recipients

failed to reconstitute AML in any of secondary recipient mice (36). Besides Bmi-1, Wnt/β-catenin signaling is reported to regulate _HoxB4_ and _Notch1_, two critical regulators of HSC

self-renewal activity (40). The ectopic expression of _Axin_ or a frizzled ligand-binding domain, inhibitors of Wnt/β-catenin signaling, led to inhibition of HSC growth _in vitro_ and

reduced reconstitution _in vivo_. This self-renewal role for Wnt/β-catenin signaling appears to be conserved in self-renewing CSC. For example, committed myeloid progenitors or GMP, putative

CSC from CML patients in accelerated phase or blast crisis, showed increased nuclear β-catenin activity and self-renewal in a replating assay. Correspondingly, their replating capacity was

reduced by the lentiviral introduction of _Axin_ (25). PI3 K/AKT signaling is reported to positively regulate Wnt/β-catenin signaling through AKT-mediated phosphorylation of GSK-3β (41). In

a murine MPD model carrying a conditional deletion of _Pten_, a potent negative regulator of PI3 K/AKT signaling, we also observed elevated cytosolic and nuclear β-catenin in leukemic blasts

(W.G., J.L.L., and H.W., unpublished data). Interestingly, these two self-renewal pathways appear to play important roles in the regulation of metastasis. Brabletz _et al._ observed that a

high level of β-catenin was detected in mesenchyme-like colorectal tumor cells at the invasive fronts, implicating Wnt/β-Catenin signaling in the epithelial-to-mesenchymal transition (EMT)

or dissemination process of primary tumors (42). They proposed that low-level activation of β-catenin in the nucleus may be enough to confer self-renewal capacity, but its higher activation

is required to trigger EMT, an essential step for metastasis (43). This phenomenon appears to hold true for the Bmi-1 pathway. Expression profiling on metastatic versus primary prostate

tumors from human patients and the murine TRAMP transgenic model revealed substantial elevation of Bmi-1 and its associated molecular signature of 11 genes in metastatic cancer (44).

Furthermore, this metastasis/stem cell signature was used to predict the risk of metastatic recurrence and poor clinical outcomes using samples from 1,153 cancer patients with 11 different

types of cancer (44). Future studies are required to investigate the link between stem-ness and metastatic potential and the dual roles that Wnt/β-catenin or Bmi-1 pathway may play. As stem

cell niches control normal stem cells, it is currently unknown how extrinsic or environmental factors control CSC formation. Studies on the development of _Drosophila_ germ cells suggest

that stem cell faith is determined by the instructive signals from their microenvironment—the “stem-cell niche” (45). In _Drosophila_ germ cell niches, instructive signals are reported to be

comprised of _dpp_ and _Yb/Piwi/hh_ in ovary or Unpaired (Jak-Stat signaling) in testis (45). In mammalian systems, signaling pathways conserved in niche-mediated stem cell control are

reported to include TGFβ/BMP, NOTCH, JAK-STAT, and context-dependent WNT (46,47). Furthermore, the size of a stem cell niche determines the number of stem cells in this niche. In

_Drosophila_, the number of germline stem cells is positively correlated with the number of cap cells, a component of germline niches (48). Consistently, an increased number of murine

osteoblasts, a component of HSC niches, leads to an increase in the number of HSCs (49,50). Although the role of the stem cell or CSC-specific niches in CSC formation remains unclear, some

indirect evidence underscores their importance. For example, _dpp_ overexpression induced by heat shock in _Drosophila_ germaria resulted in stem cell-like germline tumors (51). CLINICAL

IMPLICATIONS The introduction of the CSC concept has provided exciting insights into the roots of carcinogenesis and sheds light on the future cure of cancer. The impact from current and

future studies of CSC will revolutionize clinical practice with regards to both cancer diagnosis and therapy. Two of the implicated changes will be the re-classification of human tumors and

development of novel therapeutic strategies targeting CSC. The current diagnosis and classification of human cancer is mainly based on pathologic characterization of the entire tumor.

However, we now understand that a rare CSC population(s) initiates and maintains cancer. As indicated by the above cases (13,16), although tumors are histologically identical, their CSC may

be derived from different stem cell or progenitor populations, depending on where the transformation occurs. This difference at the level of CSC will likely be very important for diagnosis

and therapy, especially for future therapies targeting CSC. Once CSC isolation approaches are established and verified, it will be critical to characterize human cancers based on both CSC

and bulk tumor and establish a new system of cancer classification. However, since the current identification of CSC is fully dependent on _in vivo_ reconstitution assays, a more practical

and quicker approach to identify CSC will be essential for diagnosis. Both molecular signatures for altered self-renewal pathways, _e.g._ Bmi-1 (39) and β-catenin (25) in CSC, and _in vitro_

replating capacity may serve as biomarkers for diagnosis based on CSC. In most cases, current therapeutic strategies are developed to target the bulk of cancer and likely do not eradicate

CSC completely, although they may have some effects on CSC, _e.g._ inhibition of CSC proliferation, and so reduce CSC number. For example, imatinib administration for CML can achieve

complete remission, but the _BCR-ABL1_ fusion gene is often detected in HSC of patients in remission, suggesting a potential risk of CML relapse. Thus, the complete eradication of CSC is

likely the key to the cure of cancer. For clinical elimination of CSC, the cellular and molecular properties described below need to be taken into account. The rarity of CSC will require

therapeutic strategies different from conventional ones. Specific recognition of CSC from the tumor mass will be the first challenge. The identification of CSC-specific antigens may help

develop specific targeting. Since the origins of CSC vary from cancer to cancer, the development of therapeutic strategies targeting different CSC population(s) will also be necessary. For

stem cell-derived CSC which usually require additional mutations to generate malignancy, the use of inductive differentiation (_i.e._ trans-retinoic acid therapy for APML) or replacement

with normal stem cells may be required, if it is hard to distinguish between normal stem cells and CSC. For progenitor-derived malignant CSC, eradication therapies targeting CSC and

progenitors can be applied as long as a normal stem cell pool is still available for reconstitution in cancer patients (13). Finally, multiple pathways/mechanisms will likely need to be

targeted together for effective elimination. CSC may have or acquire stem cell properties that are more resistant to therapies, such as survival advantage with increased anti-apoptotic

activities and drug resistance due to increased levels of drug efflux pumps such as BCRP (breast cancer resistance protein) and MDR (multiple drug resistance) complexes. Future therapeutic

strategies will need to integrate inhibition of these resistant mechanisms with CSC killing components. Moreover, combination therapies will help to prevent the generation of resistant CSC

colonies due to mutations (52). PROSPECTIVE Despite recent progress in CSC research, our knowledge of these rare populations is still limited and many questions remain to be answered.

Certain types of cancer are known to be multi-stage diseases, which generally progress into more malignant forms with the sequential accumulation of genetic and molecular alterations. For

instance, hematological malignancies, such as CML, are often found to have two distinct phases: chronic phase and blast crisis (or leukemia). Similarly, some epithelial tumors, _e.g._ colon

tumors, are thought to progress through at least five stages: pretumor patches/fields, hyperplasia, carcinoma _in situ_, invasive carcinoma and metastasis (30). One of the central questions

in the CSC research is: how to link CSC to cancer progression in these tumors? Given sequential requirements of genetic and molecular alterations and distinct pathologic abnormalities

associated with different stages of cancer progression, one may postulate that there could be multiple CSC populations, either intrinsically linked or generated independently, responsible

for different stages of cancer progression. To advance CSC research, we need to first understand the normal stem cells and critical pathways controlling stem cell properties. For this,

identification of cell surface molecules for prospective stem cell isolation and biologically relevant stem cell assays are essential. In addition, technical improvement will expedite the

studies of these rare and heterogeneous population(s). We should investigate the molecular mechanisms for the CSC formation and maintenance, especially their self-renewal regulation, which

holds the key for the development of effective therapeutic strategies against CSC. Although stem cell niches have been shown to play an instructive and pivotal role in the regulation of stem

cells, their implication in the CSC formation remains to be elucidated. Ultimately, with further improvements in our understanding of CSC, we will be able to develop better diagnostic and

therapeutic methodologies, with which to classify, treat, and cure cancer. ABBREVIATIONS * ALL: acute lymphoblastic leukemia * AML: acute myelogenous leukemia * APML: acute promyelocytic

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Bangyan Stiles and Shunyou Wang for comments and suggestions, and Bahram Valamehr for proofreading. AUTHOR INFORMATION Author notes * Joseph L Lasky: J.L.L. is a fellow of NCI Scholar for

Oncology and Molecular Imaging Training Program. AUTHORS AND AFFILIATIONS * Department of Molecular and Medical Pharmacology, University of California, Los Angeles, 90095, CA Wei Guo, Joseph

L Lasky & Hong Wu * Department of Pediatrics, University of California, Los Angeles, 90095, CA Joseph L Lasky Authors * Wei Guo View author publications You can also search for this

author inPubMed Google Scholar * Joseph L Lasky View author publications You can also search for this author inPubMed Google Scholar * Hong Wu View author publications You can also search

for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Wei Guo. ADDITIONAL INFORMATION This work is supported by grants from DOD PC031130 and NCI UO1 CA84128-06 and

RO1 CA107166 (H.W.). RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Guo, W., Lasky, J. & Wu, H. Cancer Stem Cells. _Pediatr Res_ 59 (Suppl 4), 59–64

(2006). https://doi.org/10.1203/01.pdr.0000203592.04530.06 Download citation * Received: 02 December 2005 * Accepted: 28 December 2005 * Issue Date: 01 April 2006 * DOI:

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