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Stem Cells and Cancer: the Cancer Stem Cell (CSC) Model

Aniruddha Banerji, Aheli Majumder, Amitava Chatterjee

Aniruddha Banerji, Aheli Majumder, Post Graduate Department of Biotechnology, St Xavier’s College (Autonomous), 30 Mother Teresa Sarani, Kolkata, 700016, India.
Amitava Chatterjee, Faculty Centre for Integrated Rural Development and Management (IRDM), Ramakrishna Mission Vivekananda University, Narendrapur, Kolkat, 700103, India.

Correspondence to: Aniruddha Banerji, PhD, Post Graduate Department of Biotechnology, St Xavier’s College (Autonomous), 30 Mother Teresa Sarani, Kolkata: 700016, West Bengal, India.
Email: aniruddha_banerji@yahoo.co.in
Telephone: +91-33-22551275
Fax: +91-33-22879966
Received: July 11, 2015
Revised: September 25, 2015
Accepted: September 30, 2015
Published online: December 10, 2015

ABSTRACT

Cancer stem cells (CSCs) can be defined as cells within the tumour which are tumour-initiating and which possess the capacity to self renew and generate the heterogenous lineages of cancer cells that comprise the tumour. They are functionally characterized by their abilities to self-renew, differentiate and form tumours in immunocompromised mice. Only a certain subpopulation of cells within the tumour possesses these abilities. CSCs have been isolated from a variety of cancers and are believed to play pivotal roles in tumour initiation, tumour progression and metastasis as well as in tumour recurrence. CSCs may arise from normal stem cells in tissue, which undergo a loss of regulation of proliferation; alternatively, they can arise from normal somatic cells which acquire stem cell like characteristics. At the molecular level, intracellular signalling pathways involved in normal stem cell self-renewal and proliferation often show dysregulation or aberrant activation in CSCs. Inherent mechanisms present in CSCs appear to render them comparatively more resistant to conventional anti-cancer approaches like chemotherapy and radiotherapy. Thus, for maximal effectiveness, anti-cancer therapies would probably need to target critical molecular pathways essential for CSC self-renewal, proliferation and survival. This review provides an overview of CSCs, their roles in various cancers and discusses their probable origins, molecular pathways involved in their functions and some possible molecular methods for targeting CSCs which may hold promise for developing therapies for alleviation of cancer.

© 2015 ACT. All rights reserved.

Key words: Neoplastic Stem Cells; Cancer Stem Cells; Metastasis; Antineoplastic Agents

Banerji A, Majumder A, Chatterjee A. Stem Cells and Cancer: the Cancer Stem Cell (CSC) Model. Journal of Tumor 2015; 3(3): 320-355 Available from: URL: http://www.ghrnet.org/index.php/JT/article/view/1504

Introduction

Stem cells comprise a variety of unspecialized cells characterized by an extensive capacity for self-renewal and an ability to differentiate into a variety of cell types[1,2,3]. Stem cells differ from each other both in their intrinsic capability to self-renew and to differentiate. They are usually classified based on potency or origin. In mammals, stem cells are primarily divided into embryonic stem cells (ESCs) which are isolated from the inner cell mass (ICM) of blastocysts, adult (somatic) stem cells, which are found in various tissues and cord stem cells derived from the umbilical cord[3].

Cancer covers a plethora of conditions characterized by uncontrolled cellular proliferation. The causes of cancer are many and varied and include genetic predisposition, environmental influences, infectious agents and ageing. These can transform normal cells into cancerous cells by hampering a wide range of regulatory pathways[4]. Stem cells and cancerous cells appear to have a number of common characteristics including rapid proliferation, the ability to express telomerase and the possession of an indefinite replicative life span[2,5]. The possible involvement of stem cells in cancer generation and tumour growth and metastasis has been discussed by scientists for many years. However, only recently, following some success in isolation of malignant stem cells and a more comprehensive understanding of stem cell behaviour, has serious attention been given to the role of stem cells in cancer and the consequences which arise from retention of stem cell behaviour in malignancy[1,6-9].

Cancer stem cells (CSCs) can be defined as cells within the tumour which are tumour-initiating and which possess the capacity to self renew and generate the heterogenous lineages of cancer cells that comprise the tumour[7,10]. CSCs are functionally defined by their abilities to self-renew, differentiate (i.e. produce cells with non-stem cell characteristics) and form tumours in immunocompromised mice[6]. A number of observations have indicated that only a limited subset of cells within the tumour, the CSCs, can initiate and promote tumour formation. Only 1-4% of lymphoma cells were found to form colonies in vitro or initiate carcinomas in mouse spleen; thus, not all cells within the tumour were tumour initiating[11]. The cells from various types of acute myeloid leukaemia (AML) which could lead to initiation of haematopoietic malignancies upon injection into severe combined immunodeficiency (SCID) mice were found to be CD34++CD38- regardless of the heterogeneity in maturation of blasts. This subpopulation of cells also possessed the abilities of self-renewal and proliferation[12]. Experiments demonstrating that CD44+CD24−/lowLin− cells from breast cancer patients had significantly greater tumour forming ability when injected into SCID mice first indicated the presence of CSCs in solid tumours. This tumorigenic subpopulation could be serially passaged and would generate new tumours containing CD44+CD24−/lowLin− tumorigenic cells as well as the phenotypically diverse populations of non-tumorigenic cells present in the initial tumour[13]. CSCs have subsequently been isolated from a number of other solid tumours including cancers of the colon[14], brain[15], ovary[16], prostate[17], lung[18] and melanomas[19]. A fraction of cells with stem cell properties have been shown to be present in established cell lines like HeLa (cervical cancer), C-6 (glioma), MCF-7 (breast cancer) and A549 (non-small cell lung cancer)[2,20].

This review seeks to provide an overview of CSCs and their roles in various cancers and discusses their probable origins, molecular pathways involved in their functions and some possible methods for targeting and removal of CSCs which may hold promise for developing therapies for alleviation of cancer.

The Cancer Stem Cell (CSC) Hypothesis

Two models have been proposed to explain why only a limited number of cells within a tumour are capable of initiating and propagating tumour growth. The clonal evolution model (CE model) postulates that the cellular heterogeneity within a tumour is primarily caused by subclonal differences that result from genetic and epigenetic changes during cancer development. All tumour cells can contribute to tumour maintenance and any cell, having accumulated sufficient genetic changes, can potentially become invasive and cause metastasis or become resistant to therapies and cause recurrence. Stem or differentiated cell characteristics are thus phenotypes and may change over time[7,21,22].

The cancer stem cell model (CSC model) states that a specific subset of tumour cells, the CSCs, play a pivotal role in tumour initiation, progression and recurrence (Figure 1). These CSCs can self-renew indefinitely and also differentiate, leading to the production of the various heterogeneous cell types which make up a tumour. However, the majority of these cell types lack the capacity for unlimited self-renewal and the ability to produce the varied cell populations present in the tumour. Thus, the heterogeneity of the cells within a tumour result from asymmetric division of CSCs and tumours are highly hierarchical with a self-renewing population of CSCs at the top of the hierarchy[7,9,21,23]. During this process, metastasis and malignancy may occur. It has been suggested that the lower the degree of CSC differentiation, the more malignant is the tumour initiated by CSCs[24,25].

Although much of the currently available evidence appears to support the CSC model, certain findings seems to indicate that the CE model cannot be completely rejected. In metastatic sites, cell subpopulations with the capacity for self-renewal appear to display a cell surface marker profile different from the CSC that caused the origin of the primary tumour[26]. Studies on BCR-ABL1 lymphoblastic leukaemia indicate that many clinical samples contain a number of genetically distinct leukaemia-initiating subclones, linking clonal diversity with leukaemia-initiating-cell function[27]. On the other hand, in addition to the previously mentioned evidence, clinical studies of breast cancer indicate that, despite patients having thousands of single disseminated cancer cells circulating in their bloodstream, only a small percentage of cells ultimately form macroscopic metastases and secondary tumours produced by metastasis often possess heterogeneity similar to the primary tumour. Such heterogeneity could arise as a result of patterns of regeneration of CSCs[21,28]. A possible explanation, which would combine the hypothesis of both models, could be that while CSCs play important roles in tumour initiation and progression, they might undergo clonal evolution over time (Figure 2).

The Origin of CSCs

CSCs can presumably arise from a number of potential pathways. CSCs may arise from normal stem or progenitor cells present within the tissue which generate tumours due to genetic mutations or environmental alterations. Alternatively, CSCs may arise from normal somatic cells which manage to acquire stem cell like characteristics and malignant behaviour through genetic or other alterations.

(a) Origin from Stem Cells Present in Tissue

Many CSCs show similarities to normal stem/progenitor cells in phenotype, function and cell surface markers; for example, CD44+CD24−/low mammary gland progenitor cells resemble CD44+CD24−/lowLin− CSC cells in breast cancer[29]. With an increase in age, most adult stem cells appear to increase the expression of gate-keeping tumour suppressors like p16Ink4a, p19ARF and p53[4,30]. These suppressors negatively regulate cell survival and regeneration. This may reduce incidence of cancer in aging tissues while simultaneously downregulating proliferative capacity. Transformation of normal cells into cancer cells often requires a series of mutations in oncogenes and tumour suppressor genes; these may accumulate over a period of years[4]. While somatic cells are periodically replaced by cellular turnover, stem cells may persist in tissues long enough to accumulate the multiple mutations required for cancer initiation. Inactivation of the retinoblastoma (Rb) gene in retinoblasts can cause their transformation into CSCs that ignore growth regulatory signalling cascades which would normally have caused proliferation to cease. As the pRb protein is crucial in maintaining quiescence in cells (including adult stem cells), loss of pRb function in CSCs may cause cancer initiation[2,4,31]. Other childhood cancers such as Wilm’s tumour and some forms of leukaemia are presumed to arise from stem cells in the kidney and haematopoietic system respectively and appear to require relatively few genetic modifications for neoplastic transformation[2,4]. Chronic tissue damage, as may occur after long-term tobacco usage or prolonged UV irradiation, could lead to an increased proliferation of stem cells within the affected tissues as the body seeks to repair the damage. These constitutively proliferating stem cells could be targets for further carcinogen induced mutations leading to tumorigenesis[2,32]. Loss of ten-eleven-translocation-2 (Tet2) gene has been reported to increase self-renewal in stem cells, contributing to progressive defects in haematopoiesis and myeloid transformation in vivo[33].

(b) Origin from Somatic (Non-Stem) Cells

The ability of a differentiated cell to acquire the property of self renewal and become a CSC has been shown by transfection studies using oncogenes[2]. Reports indicate that Src, an inducible oncogene, can cause transformation of MCF10A cells and generate CSC-like cells within 16-24 hours of its activation[6,34]. Epithelial-to-mesenchymal transition (EMT) occurs during normal morphogenesis and development and is also involved in metastasis of cancer cells[4]. Induction of EMT in normal human mammary epithelial (HMLE) cells by expression of Snail, Twist or treatment with transforming growth factor beta1 (TGFβ1) caused a number of cells to exhibit the CD44+CD24−/low expression profile of CSCs. These cells also exhibited an increased ability to form mammospheres; EMT thus appears to result in the enrichment of CSCs in HMLE cells[6,29,35,36]. The mechanism by which EMT induces CSC formation may involve transcription factors like Forkhead box protein C2 (FOXC2). FOXC2 was upregulated in immortalized HMLE cells in response to EMT inducing stimuli and its suppression led to downregulation of CSC characteristics[6,37].

Molecular Pathways Involved in CSC Function

Intracellular signalling pathways essential for normal stem cell self-renewal and proliferation often show dysregulation or aberrant activation in CSCs. Molecular pathways involved in modulating stem cell self-renewal, like Wnt, Notch and phosphatase and tensin homolog (PTEN) are deregulated in a number of tumours. Other intracellular signalling pathways involving phosphatidylinositol-3-kinase (PI3K)/ Akt, nuclear factor kappa beta (NF-kβ), mitogen activated protein kinase (MAPK) and phospholipase C (PLC)/ protein kinase C (PKC) may also be involved[10,38-40].

The Wnt/ β-catenin pathway has been reported to be involved in modulation of CSC self-renewal in a number of cancers including leukaemia, melanoma, and breast, lung, and liver cancers[41-44]. Signalling through the Wnt pathway involves mediation by β-catenin which translocates to the nucleus and coordinates with lymphoid enhancer-binding factor (LEF) resulting in the activation of genes such as CCND1 (cyclin D1), c-Jun and c-Myc[41,45]. Notch signalling also plays an important role in activation of c-Myc, CCND1 and NF-κB genes. Cross-talk between Notch and Wnt signalling pathways has been reported[41,46]. Signalling through the Hedgehog (Hh) pathway plays a crucial role in mammalian embryonic development and appears to be essential for maintenance of normal stem cells as well as CSCs in various human cancers including breast cancer[10,47]. NF-κB may also be involved in modulation of signalling through the Hh pathway by activation of sonic hedgehog[41,48]. Experiments indicate that CSCs from various cell lines including C-6 (glioma), MCF-7 (breast cancer) and A549 (non-small cell lung cancer) appear to proliferate efficiently via epidermal growth factor receptor (EGFR) mediated signalling cascades even in the absence of growth factors[20]. Tumour microenvironment may also play a role in regulation of CSC self renewal and proliferation[49] with CSCs being possibly able to reciprocally modulate their microenvironment via secretion of paracrine factors or via cell-cell contact. In human brain cancers, CD133+Nestin+ CSCs in medulloblastomas, glioblastomas and oligodendrogliomas have been found to interact closely with endothelial cells promoting angiogenesis[50].

Detection of CSCs Using Specific Markers

The most widely used method for identifying CSCs is based on specific cellular markers, especially cell surface markers. These include CD133, CD24, CD44, epithelial-specific antigen (ESA) and aldehyde dehydrogenase1 (ALDH1)[10,13,29,51]. ALDH activity has been shown to enrich haematopoetic stem cells and cells with increased stem-like properties in solid malignancies[29,52]. Stem cells including hESCs and CSCs also express the octamer-4 (Oct-4) transcription factor while normal differentiated adult cells do not express Oct-4[53]. However, the expression of many specific-CSC markers have been found to vary in a tissue specific and even in a tumour subtype-specific manner[10,29]. For instance, the lung carcinoma cell marker SP-C has been reported to show variable expression in lung cancer spheres, possibly reflecting the phenotypic variability in human CSCs[54]. A number of CSC markers which have been reported in human cancers have been enumerated in Table 1.

Cancer Stem Cell Therapeutics

As tumour cells tend to proliferate rapidly, most conventional cancer treatment strategies, including radiotherapy and chemotherapy, are targeted at relevant molecules which direct them to inhibit rapidly dividing cells[4]. Evidence indicates that inherent mechanisms present in CSCs render them more resistant to chemotherapy and radiotherapy; thus, conventional anti-cancer approaches might fail to eradicate the CSC subset that initiates and perpetuates tumorigenesis[2,50,68]. Stem cells possess a wide variety of transporters, including ATP-binding cassette (ABC) transporters such as ABCG2, ABCB1/ multi-drug resistance-1 (MDR-1), ABCC1 and ABCA2, as a possible defense against xenobiotic toxins[2,69,70]. Several of these transporters play important roles in drug efflux and resistance to chemotherapeutic drugs. For example, leukaemic progenitor stem cells can efflux mitoxantrone and daunorubicin, two agents commonly used in treatment of AML[71]. Drug-resistant variants of CSCs can also produce a population of DNA-repairing tumour cells. CD133+ CSCs in gliomas express 30-fold higher levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) than CD133− cells and, due to increased DNA repair capacity, are more resistant to radiotherapy[41,59]. Overexpression of certain enzymes involved in catalyzing xenobiotic substrates, e.g. ALDH1 (which catalyses oxidation of acetaldehydes produced from ethanol) may provide some resistance against chemotherapeutic drugs like cyclophosphamide[41,72]. Cell cycle kinetics may also explain why CSCs are comparatively resistant. As mentioned previously, rapidly dividing cells are more sensitive to cytotoxic therapies. Experiments indicate that a particular subset of leukaemia CSCs remain quiescent. Similar phenomena may also occur in CSCs in other cancers[68,73]. Thus, CSCs appear to employ a combination of mechanisms to increase their resistance to cancer therapy. These mechanisms might vary between tumour types.

A number of methods have been proposed for dealing with CSC proliferation and self-renewal. Support for the potential therapeutic utility of targeting CSCs has been provided by the observation that selective killing of CSCs identified by ABCB5 expression in human melanoma inhibits experimental tumour growth[67]. Some of these proposed methods are discussed in the following sections. However, these are still mainly at an experimental or pre-clinal stage and further research is necessary to fully develop and explore the therapeutic potential of such methods in the treatment of human cancers.

(a) Targeting CSCs using surface markers

Surface markers used to identify or isolate CSCs may serve as attractive targets for monoclonal antibody based or siRNA based therapies. In human glioma cells and breast cancer, CSCs exhibit reduced 26S proteasome activity and increased resistance to ionizing radiation compared with other cell subpopulations within the tumour. Targeted killing of CSCs via a proteasome-dependent thymidine kinase suicide gene was reported to cause tumour regression[74]. Conjugating an anti-human CD133 antibody to mono-methyl auristatin F, a potent cytotoxic drug, inhibited growth and induced apoptosis in Hep3B hepatocellular and KATO III gastric cancer cells in vitro[10,75]. In vitro apoptosis of CD133+ glioma CSCs has been reported to be induced by shRNA mediated knockdown of L1 cell adhesion molecule (L1CAM) which is preferentially expressed on these CD133+ cells[76]. Thus, conjugating drugs to antibodies directed against specific cell surface markers might be a potential method for targeted therapy of CSCs. Salinomycin, a potassium ionophore has been reported to induce breast CSC specific toxicity and downregulate expression of certain CSC associated genes[77]. However, although such approaches appear promising, one potential shortcoming of such targeting is that many CSC surface antigens may also be overexpressed by stem cells in normal tissue[68] and targeting approaches using such markers can have toxic side effects[7,10]. Also, as CSCs generally comprise only a small minority of cells within cancer cell populations, most high-throughput cell viability assays, when applied to populations of cancer cells in vitro, often fail to identify agents with CSC specific toxicity[77].

Instead of direct killing, another approach could involve increasing sensitivity of CSCs to chemotherapy or radiotherapy. ABCB5 mediates resistance to the chemotherapeutic drug doxorubicin in malignant melanoma. Such drug resistance can be overcome using targeted monoclonal antibodies to inhibit ABCB5-dependent drug efflux[50,78]. siRNA-mediated ABCB5 gene silencing also overcomes doxorubicin resistance and increases the sensitivity of melanoma cells to the chemotherapeutic drugs 5-fluorouracil (5-FU) and camptothecin[50,79]. Enhanced resistance of HNSCC CSCs to radiotherapy can be reduced by knockdown of the transcriptional repressor Bmi-1[52]. Inhibiting Chk1 and Chk2 checkpoint kinases has been reported to reduce resistance of CD133+ glioma CSCs to ionizing radiations[50]. Curcumin (diferuloyl methane), a major component of the rhizome of Curcuma longa L., has also been reported to exert its anti-cancer activity by targeting CSCs in colorectal, pancreatic, breast, brain and head and neck cancers[80].

(b) Targetting molecular pathways involved in CSC self-renewal and proliferation

Potential signalling pathways that may serve as therapeutic targets for controlling CSC self-renewal and proliferation include Wnt/ β-catenin, Hh, Notch, NF-κB, PTEN and bone morphogenetic protein (BMP) mediated signalling cascades[41,68,70,81]. Inhibition of the Notch pathway with γ-secretase inhibitors can potentially be of use in downregulating CSC self-renewal; however, clinical use could be restricted by high hydrophobicity and side effects including possibly goblet cell metaplasia[41,70]. Cyclopamine, a Hh signalling inhibitor is also under study as a therapeutic against CSCs but again, clinical use could be limited by high hydrophobicity and systemic toxicity[41,82]. Silencing H-Ras in a tumour initiating cell (i.e. CSC) enriched breast cancer cell line has been reported to downregulate self renewal without affecting cell differentiation[83]. Treatment with miR145 incorporated with polyurethane-short branch polyethylenimine (PU-PEI) has been found to block key signal transduction pathways and effectively downregulate Oct-4 and Sox2, transcription factors which control pluripotency in stem cells including CSCs[84].

(c) Differentiation therapy

As promoting differentiation of CSCs within a tumour would lead to tumour degeneration and might also increase susceptibility to conventional chemotherapies, potential therapeutic strategies could include modulation of specific signalling cascades and alteration of specific gene expression[50]. Modulation of cellular signalling cascades by Notch pathway inhibitors in medulloblastoma and modulation of BMP signalling in experimental models of human glioblastoma have been shown to promote CSC differentiation[15,85]. Enforced expression of let-7 miRNA in breast cancer has been reported to induce differentiation of CD44+CD24−/low CSCs[81]. Administration of a monoclonal antibody directed against the cell adhesion molecule CD44 to nonobese diabetic SCID mice transplanted with human AML has been reported to induce differentiation and appreciably reduce leukaemic repopulation[86].

(d) Use of nanomedicine in targeting CSCs and drug delivery

Some recent therapeutic approaches for targeting CSCs involve the use of nanomedicine. Imetelstat decreases telomerase activity, suppresses breast CSC self-renewal potential and inhibits tumorigenicity of PANC1 and MDA-MB-231 cells in vivo. Delivery of such inhibitors to CSCs by nanotechniques may allow efficient targeting for therapeutic purposes[70,87]. Even conventional chemotherapeutic drugs can be promising for CSC therapy if efficient targeting methods can be developed. Doxorubicin-tethered gold nanoparticles have been reported to mediate potent drug delivery to breast CSCs and reduce cancer initiation and tumour growth in murine models[88].

Conclusion

CSCs appear to be play pivotal roles in tumour initiation, development, metastasis and development of therapeutic resistance. Thus, modern cancer treatments would need to target self-renewal or other critical molecular pathways in CSCs as their eradication could possibly lead to tumour regression and a better prognosis in cancer afflicted patients. The challenge, for effective alleviation of the disease cancer, lies in devising therapies which can cause destruction of CSCs while causing minimal damage to normal cells.

Acknowledgements

We are thankful to Rev. Fr. Dr. J. Felix Raj, SJ, Principal, St. Xavier’s College (Autonomous), Kolkata for providing facilities, support and encouragement.

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

REFERENCES

1.Costea DE, Gammon L, Kitajima K, Harper L, Mackenzie IC. Epithelial stem cells and malignancy. J Anat 2008; 213: 45–51.

2.Dean M. Cancer stem cells: redefining the paradigm of cancer treatment strategies. Mol Interv 2006; 6: 140-148.

3.Stewart R, Stojkovic M, Lako M. Mechanisms of self-renewal in human embryonic stem cells. Eur J Cancer 2006; 42:1257-1272.

4.Weinberg RA. The Biology of Cancer.1st ed. New York: Garland Science, Taylor & Francis Group, 2006: Chapters 2, 8, 9, 14, 16.

5.Krtolica A. Stem cell: balancing aging and cancer. Int J Biochem Cell Biol 2005; 37: 935–941.

6.Owens TW, Naylor MJ. Breast cancer stem cells. Front Physiol 2013; 4: 225: doi: 10.3389/fphys.2013.00225.

7.Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin 2013; 34: 732–740.

8.Sell S. Cancer stem cells and differentiation therapy. Tumour Biol 2006; 27: 59–70.

9.Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 2003; 3: 895–902.

10.Han L, Shi S, Gong T, Zhang Z, Sun X. Cancer stem cells: therapeutic implications and perspectives in cancer therapy. Acta Pharmaceutica Sinica B 2013; 3: 65–75.

11.Bruce WR, Van Der Gaag H. A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 1963; 199: 79–80.

12.Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.

13.Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003; 100: 3983–3988.

14.O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007; 445: 106–110.

15.Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, Brem H, Olivi A, Dimeco F, Vescovi AL. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 2006; 444: 761–765.

16.Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, Dombkowski D, Preffer F, Maclaughlin DT, Donahoe PK. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian inhibiting substance responsiveness. Proc Natl Acad Sci U S A 2006; 103: 11154–11159.

17.Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 2005; 65:10946–10951.

18.Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005; 121: 823–835.

19.Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, Van Belle PA, Xu X, Elder DE, Herlyn M. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 2005; 65: 9328–9337.

20.Kim J, Jung J, Lee SJ, Lee JS, Park MJ. Cancer stem-like cells persist in established cell lines through autocrine activation of EGFR signaling. Oncol Lett 2012; 3: 607-612.

21.Casarsa C, Oriana S, Coradini D. The Controversial Clinicobiological Role of Breast Cancer Stem Cells. J Oncol 2008; 2008: 492643: doi: 10.1155/2008/492643.

22.Campbell LL, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle 2007; 6: 2332–2338.

23.Tang DG. Understanding cancer stem cell heterogeneity and plasticity. Cell Res 2012; 22: 457–472.

24.Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 2004; 51: 1-28.

25.Chen W, Wang GM. Gene expression profiling of cancer stem cells in the Du145 prostate cancer cell line. Oncol Lett 2012; 3:791-796.

26.Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 2008; 8: 755–768.

27.Notta F, Mullighan CG, Wang JC, Poeppl A, Doulatov S, Phillips LA, Ma J, Minden MD, Downing JR, Dick JE. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 2011; 469: 362-367.

28.Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer 2005; 5: 744–749.

29.Kumar D, Shankar S, Srivastava RK. Understanding the biological functions and therapeutic potentials of stem cells and cancer stem cells: Where are we? Journal of Cancer Stem Cell Research 2014; 2: e1002; DOI: 10.14343/JCSCR.2014.2e1002.

30.Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL.. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 2007; 447: 725–729.

31.Sage J. The retinoblastoma tumor suppressor and stem cell biology. Genes Dev 2012; 26: 1409–1420.

32.Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 1999; 91: 1194-1210.

33.Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, Fiqueroa ME, Vasanthakumar A, Patel J, Zhao X, Perna F, Pandey S, Madzo J, Song C, Dai Q, He C, Ibrahim S, Beran M, Zavadil J, Nimer SD, Melnick A, Godley LA, Aifantis I, Levine RL. Tet2 loss leads to increased hematopoietic stem cell self renewal and myeloid transformation. Cancer Cell 2011; 20:11–24.

34.Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci U S A 2011; 108: 1397–1402.

35.Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 2008; 3: e2888. doi: 10.1371/journal.pone.0002888

36.Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.

37.Hollier BG, Tinnirello AA, Werden SJ, Evans KW, Taube JH, Sarkar TR, Sphyris N, Shariati M, Kumar SV, Battula VL, Herschkowitz JI, Guerra R, Chang JT, Miura N, Rosen JM, Mani SA. FOXC2 expression links epithelial-mesenchymal transition and stem cell properties in breast cancer. Cancer Res 2013; 73: 1981–1992.

38.Rountree CB, Mishra L, Willenbring H. Stem cells in liver diseases and.cancer: recent advances on the path to new therapies. Hepatology 2012; 55: 298–306.

39.Ponti D, Zaffaroni N, Capelli C, Daidone MG. Breast cancer stem cells: An overview. Eur J Cancer 2006; 42: 1219–1224.

40.Fomchenko EI, Holland EC. Stem cells and brain cancer. Exp Cell Res 2005; 306: 323–329.

41.Wang K, Wu X, Wang J, Huang J. Cancer stem cell theory: therapeutic implications for nanomedicine. Int J Nanomedicine 2013; 8: 899–908.

42.Ysebaert L, Chicanne G, Demur C, De Toni F, Prade-Houdellier N, Ruidavets JB, Mansat-De Mas V, Rigal-Huquet F, Laurent G, Payrastre B, Manenti S, Racaud-Sultan C. Expression of beta-catenin by acute myeloid leukemia cells predicts enhanced clonogenic capacities and poor prognosis. Leukemia 2006; 20: 1211–1216.

43.Teng Y, Wang X, Wang Y, Ma D. Wnt/beta-catenin signaling regulates cancer stem cells in lung cancer A549 cells. Biochem Biophys Res Commun 2010; 392: 373–379.

44.Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X, Rowlands T, Egeblad M, Cowin P, Werb Z, Tan LK, Rosen JM, Varmus HE. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci U S A 2003; 100: 15853–15858.

45.Katoh M, Katoh M. WNT signaling pathway and stem cell signaling network. Clin Cancer Research 2007; 13: 4042–4045.

46.Borggrefe T, Oswald F. The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci. 2009; 66:1631–1646.

47.Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006; 66: 6063–6071.

48.Nakashima H, Nakamura M, Yamaguchi H, Yamanaka N, Akiyoshi T, Koga K, Yamaguchi K, Tsuneyoshi M, Tanaka M, Katano M. Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. Cancer Res 2006; 66: 7041–7049.

49.Bissell MJ, LaBarge MA. Context, tissue plasticity, and cancer: are tumor stem cells also regulated by the microenvironment? Cancer Cell 2005; 7: 17-23.

50.Frank NY, Schatton T,Frank MH. The therapeutic promise of the cancer stem cell concept. J Clin Invest 2010; 120: 41–50.

51.Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007; 1: 555–567.

52.Rastogi P. Emergence of cancer stem cells in head and neck squamous cell carcinoma: A therapeutic insight with literature review. Dent Res J 2012; 9: 239–244.

53.Trosko JE, Chang CC, Upham BL, Tai MH. The role of human adult stem cells and cell–cell communication in cancer chemoprevention and chemotherapy strategies. Mutat Res 2005; 591: 187–197.

54.Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, Conticello C, Ruco L, Peschle C, De Maria R. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 2008; 15: 504–14.

55.Ricardo S, Vieira AF, Gerhard R, Leitao D, Pinto R, Cameselle-Teijeiro JF, Milanezi F, Schmitt F, Paredes J. Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J Clin Pathol 2011; 64: 937–46.

56.Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM. Identification of pancreatic cancer stem cells. Cancer Res 2007; 67:1030–1037.

57.Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007; 1: 313–323.

58.Rasheed ZA, Yang J, Wang Q, Kowalski J, Freed I, Murter C, Hong SM, Koorstra JB, Rajeshkumar NV, He X, Goggins M, Iacobuzio-Donahue C, Berman DM, Laheru D, Jimeno A, Hidalgo M, Maitra A, Matsui W. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst 2010; 102: 340–51.

59.Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006; 444: 756–760.

60.Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB. Identification of human brain tumour initiating cells. Nature 2004; 432:396–401.

61.Son MJ, Woolard K, Nam DH, Lee J, Fine HA. SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell 2009; 4: 440–452.

62.O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007; 445: 106–110.

63.Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H, Fields JZ, Wicha MS, Boman BM. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res 2009; 69: 3382–3389.

64.Huang CP, Tsai MF, Chang TH, Tang WC, Chen SY, Lai HH, Lin TY, Yang JC, Yang PC, Shih JY, Lin SB. ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Cancer Lett 2013; 328: 144–151.

65.Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 2007; 104: 973–978.

66.Jordan CT. Cancer stem cell biology: from leukemia to solid tumors. Curr Opin Cell Biol 2004; 16: 708–712.

67.Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, Frank MH. Identification of cells initiating human melanomas. Nature 2008; 451: 345–349.

68.Diehn M, Cho RW, Clarke MF. Therapeutic implications of the cancer stem cell hypothesis. Semin Radiat Oncol 2009; 19: 78–86.

69.Clarke MF. Self-renewal and solid-tumor stem cells. Biol Blood Marrow Transplant 2005; 11: 14–16.

70.Zhang M, Rosen JM. Stem cells in the etiology and treatment of cancer. Curr Opin Genet Dev 2006; 16: 60–64.

71.Sikic BI. Multidrug resistance and stem cells in acute myeloid leukemia. Clin Cancer Res 2006; 12: 3231-3232.

72.Magni M, Shammah S, Schiró R, Mellado W, Dalla-Favera R, Gianni AM. Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood 1996; 87: 1097–1103.

73.Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, Nakamura R, Tanaka T, Tomiyama H, Saito N, Fukata M, Miyamoto T, Lyons B, Ohshima K, Uchida N, Taniguchi S, Ohara O, Akashi K, Harada M, Shultz LD. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 2007; 25: 1315–1321.

74.Vlashi E, Kim K, Lagadec C, Donna LD, McDonald JT, Eghbali M, Sayre JW, Stefani E, McBride W, Pajonk F. In vivo imaging, tracking, and targeting of cancer stem cells. J Natl Cancer Inst 2009; 101: 350–359.

75.Smith LM, Nesterova A, Ryan MC, Duniho S, Jonas M, Anderson M, Zabinski RF, Sutherland MK, Gerber HP, Van Orden KL, Moore PA, Ruben SM, Carter PJ. CD133/ prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. Br J Cancer 2008; 99: 100–109.

76.Bao S, Wu Q, Li Z, Sathornsumetee S, Wang H, McLendon RE, Hjelmeland AB, Rich JN. Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res 2008; 68: 6043–6048

77.Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009; 138: 645-659.

78.Frank NY, Margaryan A, Huang Y, Schatton T, Waaga-Gasser AM, Gasser M, Sayegh MH, Sadee W, Frank MH. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 2005; 65: 4320–4333.

79.Elliott AM, Al-Hajj MA. ABCB8 mediates doxorubicin resistance in melanoma cells by protecting the mitochondrial genome. Mol Cancer Res 2009; 7: 79–87.

80.Zang S, Liu T, Shi J, Qiao L. Curcumin: a promising agent targeting cancer stem cells. Anticancer Agents Med Chem 2014; 14: 787-792.

81.Grudzien P, Lo S, Albain KS, Robinson P, Rajan P, Strack PR, Golde TE, Miele L, Foreman KE. Inhibition of Notch signaling reduces the stem-like population of breast cancer cells and prevents mammosphere formation. Anticancer Res 2010; 30: 3853–3867.

82.Zhou Y, Yang J, Kopecek J. Selective inhibitory effect of HPMA copolymer-cyclopamine conjugate on prostate cancer stem cells. Biomaterials 2012; 33:1863–1872.

83.Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, Huang Y, Hu X, Su F, Lieberman J, Song E. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131:1109–1123

84.Lo WL, Chien Y, Chiou GY, Tseng LM, Hsu HS, Chang YL, Lu KH, Chien CS, Wang ML, Chen YW, Huang PI, Hu FW, Yu CC, Chu PY, Chiou SH. Nuclear localization signal-enhanced RNA interference of EZH2 and Oct4 in the eradication of head and neck squamous cell carcinoma-derived cancer stem cells. Biomaterials 2012; 33: 3693–3709.

85.Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM, Eberhart CG. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 2006; 66: 7445–7452.

86.Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006; 12:1167–1174.

87.Joseph I, Tressler R, Bassett E, Harley C, Buseman CM, Pattamatta P, Wright WE, Shay JW, Go NF. The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer Res 2010; 70: 9494–9504.

88.Sun TM, Wang YC, Wang F, Du JZ, Mao CQ, Sun CY, Tang RZ, Liu Y, Zhu J, Zhu YH, Yang XZ, Wang J. Cancer stem cell therapy using doxorubicin conjugated to gold nanoparticles via hydrazone bonds. Biomaterials 2014; 35: 836-845.

Peer reviewers: Zhou Yuan M.D, Department of General Surgery, The 6th Hospital Affiliated to Shanghai Jiaotong University, 600 Yishan Road,Shanghai, 200233, China; Nailing Zhang, Mouse Cancer Genetics Program, National Cancer Institute, Bldg.560, Rm.32-24, 1050 Boyles Street, Frederick, MD 21702, USA; Héctor R. Contreras, Program of Physiology and Biophysics, Institute of Biomedical Sciences, Faculty of Medicine. University of Chile, Santiago. Chile.

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