Translational potential of cancer stem cells: A review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment.

E XP ER I ME NTAL C E LL RE S E ARCH

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Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/yexcr

Review Article

Translational potential of cancer stem cells: A review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment Farhadul Islama, Vinod Gopalana, Robert A. Smitha,b, Alfred K.-Y. Lama,c,n a

Cancer Molecular Pathology, School of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Qld, Australia Genomics Research Centre, Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Brisbane, Qld, Australia c Department of Pathology, Gold Coast University Hospital, Gold Coast, Qld, Australia b

article information

abstract

Article Chronology:

Cancer stem cells (CSCs) are a subpopulation of cancer cells with many clinical implications in

Received 31 January 2015

most cancer types. One important clinical implication of CSCs is their role in cancer metastases, as

Received in revised form

reflected by their ability to initiate and drive micro and macro-metastases. The other important

22 April 2015

contributing factor for CSCs in cancer management is their function in causing treatment

Accepted 25 April 2015

resistance and recurrence in cancer via their activation of different signalling pathways such as Notch, Wnt/β-catenin, TGF-β, Hedgehog, PI3K/Akt/mTOR and JAK/STAT pathways. Thus, many

Keywords:

different therapeutic approaches are being tested for prevention and treatment of cancer

Cancer stem cell

recurrence. These may include treatment strategies targeting altered genetic signalling pathways

Treatment

by blocking specific cell surface molecules, altering the cancer microenvironments that nurture

Metastases

cancer stem cells, inducing differentiation of CSCs, immunotherapy based on CSCs associated

Resistant to therapy

antigens, exploiting metabolites to kill CSCs, and designing small interfering RNA/DNA molecules

Targeted therapy

that especially target CSCs. Because of the huge potential of these approaches to improve cancer management, it is important to identify and isolate cancer stem cells for precise study and application of prior the research on their role in cancer. Commonly used methodologies for detection and isolation of CSCs include functional, image-based, molecular, cytological sorting and filtration approaches, the use of different surface markers and xenotransplantation. Overall, given their significance in cancer biology, refining the isolation and targeting of CSCs will play an important role in future management of cancer. & 2015 Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 n

Correspondence to: Griffith Medical School, Gold Coast Campus, Gold Coast, Qld 4222, Australia. Fax: þ61 7 56780303. E-mail address: a.lam@griffith.edu.au (A.-Y. Lam).

http://dx.doi.org/10.1016/j.yexcr.2015.04.018 0014-4827/& 2015 Elsevier Inc. All rights reserved.

Please cite this article as: F. Islam, et al., Translational potential of cancer stem cells: A review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment, Exp Cell Res (2015), http://dx.doi.org/10.1016/j.yexcr.2015.04.018

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E XP E RI ME N TAL CE L L R ES E ARC H

Clonal verses CSC model of cancer pathogenesis . . Detection and isolation of CSC . . . . . . . . . . . . . . . . CSC markers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CSC and metastasis . . . . . . . . . . . . . . . . . . . . . . . . . CSCs and resistance to Cancer therapy . . . . . . . . . . Signalling pathways involved in therapy resistance Approaches in targeting CSCs . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncited references . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

...... ...... ...... ...... ...... of CSC ...... ...... ...... ...... ......

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Introduction The ability of cancer stem cells (CSCs) to contribute to resistance to chemo-radiation based therapies has been associated with multiple factors that are unique to CSCs, including increased expression of drug transporters (such as ATP-binding cassette transporters), intracellular detoxification enzymes (that mediate drug efflux and metabolism), up-regulation of anti-apoptotic proteins, increased capacity for DNA damage repair, alteration in cell-cycle kinetics and tumour micro-environmental factors [1]. Also, several signalling pathways such as Notch, Wnt, and Hedgehog have been shown to be involved in the chemo-resistance displayed by CSCs in various cancers [2,3]. Evidence from preclinical and clinical studies have demonstrated that most of the currently utilised chemotherapeutic agents effectively destroy the highly proliferating and relatively differentiated cells that form the bulk of the tumour rather than the more quiescent CSCs [4,5]. Paradoxically, the elimination of nonCSCs by such treatment may allow more space for CSCs to expand and evolve into a more aggressive malignancy with higher self-renewal potential [6–10]. In this review, we aim to present the latest developments in detection of cancer stem cell research and illustrate the current clinical implications of CSCs.

Clonal verses CSC model of cancer pathogenesis Most cancers are composed of a variety of cell types with distinct genetic, epigenetic and morphologic make-up as well as behaviours. The two most common concepts which can explain this heterogeneity and cancer pathogenesis are cancer stem cell hypothesis and clonal evolution model [11]. Among these, the clonal evolution model of carcinogenesis dominated among cancer researchers in the second half of 19th century. This model states that the cancer cells over time acquire various combinations of mutations within a cancer [11]. This genetic drift and stepwise natural selection for the fittest, most aggressive cells ultimately drives cancer progression. According to this concept, cancer initiation takes place once multiple mutations occur in a random single cell, which is called a transformed cell [11]. This transformed cell has a selective growth advantage over adjacent normal cells. As cancer progresses, genetic instability and uncontrolled proliferation allow the production of cells with additional genetic alterations and hence new behavioural characteristics. These cells may leave a large number of offspring by chance. Alternatively, the new mutations may provide a growth advantage over the other cancer cells such as resistance to therapies and

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insensitivity to apoptotic signals [12]. In either case, new subpopulations of variant cells will be formed, and other subpopulations may contract, resulting in cancer heterogeneity. Through this process, any cancer cell can potentially become invasive and cause metastasis or become resistant to therapies and cause recurrence [13–16]. On the other hand, the cancer stem cell hypothesis is a progressive concept to account for several factors related to the cellular biology of human cancers [17]. The cancer stem cell hypothesis describes that a particular subset of cancer cells with stem cell-like properties, called “cancer stem cells” (CSCs), can leads to cancer initiation, progression and recurrence. By definition, these cells have the abilities to self-renew indefinitely and to differentiate into different lineages of cells, characteristics of normal adult stem cells. These self-renewal and differentiation will in turn leads to the production of all cancer cell types and thereby generating cancer heterogeneity [18,19]. Simultaneously, the other differentiated tumour cells in a cancer do not have unlimited self-renewal capacity and cannot differentiate to produce all cancer cell types [20].

Detection and isolation of CSC It is important to identify and isolate CSC for the accurate study of their properties. Different analytical methods and techniques have been used to detect the traits of CSCs. Commonly used methodologies for detection and isolation of CSCs include functional, image-based, molecular, cytological sorting, filtration approaches and xenotransplantation [21–24]. These approaches have been developed on the basis of unique features of CSCs. For example, assays including colony formation, sphere formation, side population (SP) analysis, aldehyde dehydrogenase (ALDH) activity and therapy resistance assays are routinely used to discriminate CSCs from non-CSCs on the basis of their functional properties [24]. Cell sorting methods like flow-cytometry and magnetic activated cell sorting (MACS) separate CSCs from nonCSCs on the basis of different cell surface and intracellular molecules with high performance and reliability [25,26]. Similarly, multiplex reverse-transcription PCR (RT-PCR) and highly sensitive multiplex reverse-transcription quantitative PCR (RTqPCR) are molecular methods used to detect CSCs in cancer patients with great target specificity [27–31]. In addition, techniques such as immunocytochemistry, immunofluorescence and immunohistochemistry are used to identify cancer stem cells based on the level and site of expression of protein markers [21]. The gold standard functional assay for detection and isolation of


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Table 1 – Approaches used to detect and isolation of cancer stem cells. Approach

Method

Advantages

Disadvantages

References

Cytological sorting

Flow cytometry

Able to isolate and quantify rare cell, multi-parameter separation Easy and fast

Processing may cause artefact and bias cell analysis, limited to cell suspension Isolate the cells on basis of single parameter, suitable for cell suspension only

[26,133,134]

Colony formation assay Microsphere assay

Easy and able to quantitate CSCs Simple and easy

ALDH assay SP assay

Highly stable Easy and simple

PKH retention assay Therapy resistance assay Xenotransplantation

Easy and widely useful Fast and simple

Reliability is controversial Unable to detect quiescent CSCs and has potential to be biased Low specificity Condition dependent, costly, low specificity, lack of purity Low specificity Low specificity, sensitivity

[22,140] [22]

Widely accepted

Potential to be biased

[32]

RT-PCR

Flexible, multiplex assay, sample, time and cost effective High sensitivity and multiplex analysis

Does not allow accurate CSC detection in sample morphological analysis No morphological analysis

[141,142]

Time consuming, has potential to be biased

[21,143]

Cross-reactivity, background, qualitative only Limited to tissue sample, need well trained pathologist

[144]

Immunohistochemistry

Multi-parameter separation, Highly effective Broad-based and powerful method, relatively inexpensive, very specific Inexpensive, highly specific

Micro-filter

Time effective and specific

[146,147]

Micro-chips

Time and sample effective

No morphological analysis and needs more clinical validation Needs more clinical validation

Magnetic-Activated Cell Sorting (MACS) Functional

Molecular

RT-qPCR Imagebased

Image microscopy Immunocytochemistry

Filtration

CSCs is xenotransplantation into immune-deficient animals [32]. As these methods have advantages and disadvantages based on their experimental setup, a combination of these methods would be more reliable to detect and isolate of CSCs. Table 1 summarises the comparative merits and drawbacks of methods available for CSC detection and isolation.

CSC markers CSCs have been identified in different cancers in a variety of frequencies using combinations of cell-surface antigens as well as soluble proteins. The ability of these markers to physically isolate distinct subpopulations of neoplastic cells with differing biological features further represents the most compelling evidence that tumour cells can reside in multiple, alternative phenotypic states within a given cancer and explains the phenotype of intra-tumour heterogeneity. Several cell-surface molecules which are used for the isolation of CSCs represent cell-surface antigens that are expressed by their corresponding adult stem cells. CD133 for example, has been used as a CSC marker in different cancers, including brain [33], lung [34], pancreas [35], and prostate [36]. In addition to cell-surface markers, certain intracellular proteins molecules have also been used for isolating and detecting CSCs. For example, aldehyde dehydrogenase 1 (ALDH1), a soluble protein is used detect CSCs in various cancers, including leukaemia [37], breast cancer [38], colon cancer [39], liver cancer [40], lung cancer [41] and pancreatic cancer [42]. SP-cells, are a

[135]

[24,136] [137] [135,138] [135,139]

[27–29,31]

[145]

[148,149]

population of cells which are capable of efflux of Hoechst 33,342 dye, which is another non-cell-surface marker that has also been used for detection of normal stem cells as well as CSCs [43,44]. Bio-molecules used for the detection and isolation of CSCs in different cancers to date are summarised in Table 2 along their functions in normal tissues. The similarity of antigens, regardless of whether they are cellsurface or soluble (cytoplasmic/nuclear), displayed by normal stem cells and CSCs from corresponding neoplastic tissues has demonstrated further support to the notion that CSCs are, at least in certain respects, true stem cells. Accordingly, this sharing of markers indicates that CSCs are likely to directly originate from normal tissue stem cells through the accumulation of different degrees of epigenetic and genetic alteration.

CSC and metastasis The CSC model is in perfect agreement with the classical ‘seed and soil’ hypothesis of cancer distribution and spread by Paget et al. [45]. In this hypothesis, a CSC seed is fed by reaching a fertile soilthe metastatic site, where the local microenvironment promotes the growth of the CSC which bears some defined genetic and/or epigenetic alterations. The altered genotype in CSC, in turn drives the differentiation process in a specific fashion which corresponds to the phenotype of the primary cancer from which the CSC derives. CSCs are capable of initiating and driving cancer growth and metastases are believed to be started from CSCs [46].


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Table 2 – Commonly used CSC markers in different cancers type. Name of Marker

Normal Functions

Reported Cancers

References

ALDH

CD26 CD29 CD133

T cell signal transduction Cell adhesion, epithelial to mesenchymal transition Regulates cell membrane topology

CD166 LGR5/ GPR49 CD15 Nestin CD13 ABCG2

Cell adhesion and cell-cell interactions Cell adhesion Cell adhesion, migration, phagocytosis and chemotaxis Remodelling of the cell Regulate peptides and lipid turnover transport various molecules across extra- and intracellular membranes Regulates B cell differentiation Regulates neuronal cell differentiation and survival Regulates invasive growth Regulates chemotactic activity of lymphocytes Cell differentiation and signal transduction Signal transduction Membrane transporter regulate amino acid transport Structural framework of keratinocytes Transactivation, regulate apoptosis Cell division and stem cell renewal

Breast, colon, head and neck, liver, pancreas, skin (melanoma) Breast, colon, stomach, head and neck, liver, ovary, pancreas, prostate Brain, liver, breast, and lung Breast, stomach, pancreas Breast, colon Haematological Breast, prostate, brain (glioma) Colon, skin (melanoma), Colon, liver, ovary, breast, lung, brain (glioblastoma) Colon, leukaemia Breast, colon Brain, colon, endometrium, liver, lung, ovary, pancreas, prostate and breast Colon, lung Colon Brain (glioma), Hodgkin's lymphoma Brain (glioma), prostate Liver Lung, breast, brain

[37–42]

CD90 CD24 Hedgehog-Gli activity CD38 α6-Integrin ABCB5 β-Catenin activity

Conversion of aldehyde to carboxylic acid involved in ester hydrolysis and retinoic acid signalling pathway Cell adhesion and migration, cell-cell interactions, cell signalling, leucocyte attachment and rolling Cell adhesion and signal transduction in T cells B cell proliferation and maturation Signal transduction, tissue regeneration and maintenance Signal transduction, calcium signalling and cell adhesion Cell adhesion, cell-surface mediated signalling Transmembrane transport of molecules Cell-cell adhesion, transcriptional regulator

CD44

CD20 CD271 C-met CXCR4/CD184 Nodal activity Trop2 CD98 Keratin 5(K5) P63 BMI-1 OCT-4 OCT-3/4 Ep-CAM KIT/CD117 CD34 Side-population (Hoechst 33342 dye exclusion)

Maintenance of stem cell pluripotency Regulates stem cell identity and cell fate Cell adhesion, migration, signalling Cell signal transduction Regulation of cell adhesion Efflux of dye via ABC transporter

Although, in CSCs, the inherent features may reflect a transient state, which are regulated by tumour micro-environment rather than by intrinsic factors [47]. Cellular plasticity of CSCs allows the conversion of non-CSC to CSC and a phenotypically differentiated cell can de-differentiate to acquire the stem cell characteristics [20]. This plasticity of CSC compartment is often debatable. However, the de-differentiation of differentiated tumour cells into CSC exists and many studies supports this hypothesis and this bring closure to the clonal and CSCs model of cancer pathogenesis [48–51]. The number of circulating cancer cells in peripheral blood is correlated with cancer progression and patient prognosis [52]. Approximately 106 cancer cells are shed into the bloodstream per gram of tumour tissue per day, which is not reflected in the extent of distant metastasis [53]. This also indicates the metastatic inefficiency of the great bulk of cancer cells and reinforced the

Skin (melanoma) Skin (melanoma), head and neck Pancreas, Breast Lung, ovarian Pancreatic Prostate Head and neck Bladder, lung Bladder Bladder, skin, prostate, ovary, breast, colon Bladder, breast Liver, breast Colon, pancreas, liver Ovary Haematological Brain (glioma), gastrointestinal tract, liver, lung, thyroid

[150–152] [153–157] [158,159] [160,161] [162] [160,163] [160,164,165] [160,203] [160,166,167] [168] [169–172] [173] [174] [160,175] [176] [177] [171] [163,164] [160,180] [160,181] [171] [160,182] [160] [183] [184,185] [184,186] [184,204] [184,187] [188,189,205] [190] [191] [192–194] [195–199]

prevailing idea that there is only a small fraction of cells (specifically CSCs) present in a cancer which have the capacity to make a successful distant metastasis. It is worth mentioning that CSCs are the only cells capable of forming a metastasis following injection of cancer cells into the tail vein of mice, whereas non-CSCs are defined by their failure to form tumours in this circumstance [46,54]. More experimental evidence, however, is needed to determine the capacity for stemness, especially when considering the potential for non-CSCs to revert to a CSC state, depending on their microenvironment or following genetic alteration. Furthermore, current evidence suggests that CSCs capable of metastasising are themselves a subset of the entire CSC population that is endowed with a migratory ability [55]. This migratory subpopulation of CSCs can be detected using specific markers such as CD26, CXCR4 and CD44v6 or experimentally using lentiviral barcode tracing [35,56–58].


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CSCs and resistance to Cancer therapy Chemotherapy and radiotherapy have been the choice for treating cancer for the past 50 years and afford notable reductions in tumour burden. Nonetheless, despite the continuous improvements of therapeutic set-up, cancer recurrence and therapy resistance still occur in most patients. Studies from a multitude of observations in cell culture, animal models and cancer patients in different cancers have determined that CSCs are responsible for therapy resistance and tumour relapses [59–64]. Colak et al. reported that cultured CSCs in colon cancers were selectively resistant to chemotherapy induced apoptosis whereas differentiated colon cancer cells underwent the process of apoptotic cell death in response to such treatment [65]. This study has also found that the surviving CSCs can re-establish the culture, confirming that CSCs are responsible for therapy resistance [65]. Several studies have demonstrated that CSCs isolated from different cancers such as liver cancer, lung cancer, pancreatic cancer, breast cancer, leukaemia and glioblastoma were resistant to conventional chemotherapeutic drugs such as gemcitabine, cisplatin, 5-fluouracil and imatinib [66–71]. CSCs and their evasion from therapy were also demonstrated in animal models by different research groups. These studies have observed that xenotransplanted CSC numbers were remarkably increased in mice after exposure to chemotherapy compared to differentiated non-CSCs [68,72–74]. CSCs also confer resistance to radiotherapy in various cancers [63,75]. Bao et al. for instance described that irradiated mice with gliomas presented with increased numbers of CD133þ (CSCs) cells compared to those with non-irradiated tumours [76]. In addition, Diehn et al. reported that CSCs of breast cancer (Thy1þ CD24þ Lin- cell) and head & neck cancer (CD44þ Lin- cell) increased up to two fold after irradiation in comparison to non-irradiated mice [77]. Thus, it is evident that therapy resistance of CSCs is a generic or common feature and further research to uncover the delicate mechanisms involved in this phenomenon have significant potential in cancer research. Therefore, it is essential to develop novel treatment strategies in future targeting CSCs to overcome their resistance to chemo-radiation therapies.

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Notch pathway by inhibitors or siRNA treatment increased the sensitivity to platinum based therapy [85]. The Hedgehog pathways transmit signals to embryonic cells required for appropriate development [86]. Hyper-activation of Hedgehog signalling pathways has been found in stem cells in various cancers including basal cell carcinoma, prostate adenocarcinoma, gastric adenocarcinoma, meduloblastoma, glioma, oral squamous cell carcinoma and ovarian adenocarcinomas [87–91]. Ma et al. reported that elevated expression of Hedgehog target genes such as glioma-associated oncogene homolog 1 (gli1) or human patched gene 1 occurred in gastric adenocarcinomas and was responsible for resistance in therapy. Treatment of these cancer cells with cyclopamine (a Hedgehog inhibitor) caused increased cell growth inhibition and apoptosis [88]. Also, Qiang and co-workers noted that CD133þ stem cell in glioblastoma overexpressed Hedgehog target genes like gli1 and Bmi1 and these cells have been shown to be more resistant to hypoxia, irradiation and chemotherapy than CD133- cells [87]. Wnt signalling is involved in a wide spectrum of important biological phenomena, ranging from embryonic development to cell behaviours in several diseases, especially cancers [92]. Aberrant Wnt signalling pathways have been found to be involved in pathogenesis in different cancers and their resistance to chemoradiation therapies [93–97]. Heidel and colleagues demonstrated that genetic inactivation or pharmacologic modulation of βcatenin (a target of Wnt pathway) remarkably increased the sensitivity of hematopoietic stem cells to a chemotherapy drugimatinib (a tyrosine kinase inhibitor) [96]. Similarly, Yeung et al., reported that intervention in the Wnt pathways (by β-catenin deletion) in mixed lineage leukaemia stem cells will make the leukaemia become non-oncogenic [98]. Also, this deletion makes the leukaemia highly sensitive to chemotherapy (glycogen synthase kinase-3 inhibitor) [98]. In addition, other pathways like PI3K/Akt/mTOR and JAK/STAT, also contribute to the therapy resistant properties of CSCs [78–81]. Thus, CSCs can be regulated by the modulation of different genetic pathways and this in turn contributes to the therapeutic resistance of CSCs.

Approaches in targeting CSCs Signalling pathways involved in therapy resistance of CSC Activation of different signalling pathways such as Notch, Wnt/βcatenin, TGF-β and Hedgehog has been reported in the attribution of therapy resistance of CSCs during or after treatment [78–82]. Many studies have demonstrated that chemical intervention or downregulation of these signalling pathways increased the therapy sensitivity of CSCs in various cancers [83–85]. Ulasov et al. reported that CD133þ glioblastoma stem cells increase the expression of the genes involved in Notch and Hedgehog pathways, making the glioblastoma insensitive to chemotherapy (temozolomide) [83]. Also, inhibition of components of theses pathways with gamma-secretase inhibitors and cyclopamine, respectively, increased the sensitivity of CSCs to the treatment [83]. In addition, treatment of non-small cell lung cancer stem cells (CD133þ cell) with gamma-secretase inhibitors or Notch1 shRNA increased their sensitivity against doxorubicin and paclitaxel [84]. Similarly, in ovarian cancer, down regulation of the

In addition to intervention of signalling pathways, CSCs can be eliminated by targeting specific cell surface molecules. Using this approach, targeting of CSCs can be achieved by blocking their interactions with the tumour microenvironment, inducing them to become terminally differentiated cells, killing them selectively with immunotherapy or targeting CSCs metabolism directly. As CSCs can be identified on the basis of their cell surface molecules, developing specific antibodies/immunotoxins against these antigens will be a useful way to eradicate CSCs selectively [99–104]. Swaminathan and colleagues developed polymeric nanoparticles (CD133NPs) consisting of a monoclonal antibody against CD133, paclitaxel (a conventional chemo-agent) and a fluorescence probe [99]. They investigated the effectiveness of CD133NPs as anti-CSCs agents by examining mammosphere formation and soft-agar colony formation as well as in a xenograft model [99]. Treatment of cells (Caco-2, which express abundant of CD133) with CD133NPs showed remarkable reduction in the ability of mammosphere and colony formation compared to the untreated control or paclitaxel-only treated cells. Also, in vivo tumour


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growth was reduced significantly in the CD133NP treated animal groups [99]. Similarly, Yao and colleagues established a drug delivery system (SAL-SWNT-CHI-HA) having salinomycin (SAL, a chemo-agent) and chitosan (CHI, a linear polysaccharide to help in drug delivery) coated single wall carbon nanotubes (SWNT) conjugated with hyaluronic acid (HA, for drug delivery) [102]. Treatment of gastric cancer cells with this complex selectively eradicated gastric CSCs (CD44þ cells) and decreased mammosphere and colony formation of such cells [102]. Another complex (ctd-Mab), developed by Damek-Poprawa et al. (containing genetically modified cyto-lethal distending toxin [ctd] and monoclonal antibody against CD133 [-Mab]) selectively killed CD133þ cells in cultured primary head and neck cancer cells [100]. Another study by Bach et al. reported the selective elimination of CD133þ cells from tumour of NOD/SCID mice with treatment using an oncolytic measles virus [101]. Heterogeneous signals from fibroblasts, myofibroblasts, adipocytes, mesenchymal cells, infiltrating immune cells and endothelial cells of tumour microenvironments nurture cancer stem cells [105,106]. Pharmacological interruptions of these paracrine signalling systems thus have therapeutic potential to eradicate CSCs in the tumour bulk. Ma and colleagues reported that the blocking of stroma-derived signals using a prostaglandin E2 receptor antagonist (RQ-15986) in breast cancer cells resulted in complete protection from the immunosuppressive effects of the tumour microenvironment [107]. They also found that such treatment reversed the tumour-promoting effects of mesenchymal stem cells on carcinoma cells [107]. Lin and his colleagues have demonstrated that the blocking of immune cell activated interleukin-6/STAT3 signalling pathways can inhibit the self-renewal and proliferation of CSCs [108]. Similarly, the inhibition of CXCL12/CXCR4 (chemokine and its receptor) autocrine/paracrine signalling using a CXCR4 antagonist (AMD3100) reduced the CSCs of glioblastoma [109]. Thus therapeutic approaches to disrupt

] (]]]]) ]]]–]]]

stromal signals can target CSCs and might in turn improve the clinical outcomes of cancer management. Induced differentiation of CSCs to shift them into terminal epithelial phenotypic cells is an emerging strategy in making CSCs sensitive to conventional therapies. An all-trans retinoic acid was combined with conventional chemotherapy and used to treat patients with acute promyelocytic leukaemia, with successful induction of differentiation [110,111]. Recent studies have demonstrated that induction of differentiation of hepatic carcinoma stem cells by down-regulation of BC047440 (a gene involved in cancer growth and proliferation) suppressed the tumorigenic potential of hepatic carcinoma stem cells both in vivo and in vitro [112,113]. Also, Zieker and co-workers reported the induced differentiation of gastric carcinoma stem cells (CD44þ cells) by knocking-down phosphoglycerate kinase 1 (a metabolic enzyme responsible for cancer cell invasion and dissemination) using shRNA. They noted reduced tumour growth in culture and mice after this phenotypic change of CSCs [114]. In addition, Dong et al., described the differentiation of glioblastoma stem cells by blocking platelet derived growth factor receptor and c-kit (a stem cell factor) with imatinib and also with siRNAs for c-kit and platelet derived growth factor receptor. They found that cells treated with imatinib and siRNA showed reduced expression of stem cell markers (CD133, Oct3/4, nestin and Bmi1) and increased expression of terminal neuronal markers at the mRNA level [115]. Other compounds used as differentiating agents in different cancer include hexamethylamine bisacetamide, dimethylsulphoxide and suberoylanilide hydroxamic acid, among others [116–120]. CSCs can also be eliminated selectively by developing immunotherapies based on tumour specific and CSCs associated antigens in cancer [121–125]. Vik-Mo and colleagues reported a vaccination against autologous cancer stem cells with dendritic cells in glioblastoma cancer patients. They noted a three-fold increase of cancer free survival of vaccinated patients in com-

Table 3 – Therapeutic strategies targeting cancer stem cells. Therapeutic approach

Potential Targets

Possible Outcome

References

Signalling pathways Cell-surface molecules Microenvironment

Notch1, Wnt, Hedgehog, TGF-β, PI3K/Akt/mTOR and JAK/ STAT etc. CD44, CD133, Lrg5, CD26, CD271, CD90 EpCAM etc.

Inhibits cell proliferation and increases the sensitivity of CSCs against therapies Selectively eliminate or killed the CSCs

[83– 85,87,96] [99–104]

Cytokine network, stroma cells, immune cells, extracellular matrix, etc. Autologous CSC

Interruption of stromal signals could help to eliminate the CSCs as well as tumour bulk Selective eradication of CSCs by modified host immune response Inhibit the switching of stem cell like properties of cancer cells and prevent CSC generation Make the CSCs more sensitive to conventional therapies and killed them completely Induce CSCs to differentiated cells and make them more sensitive to conventional therapies Increased sensitivity to chemotherapies Inhibit cell proliferation and self-renewal

[107–109]

Direct immunotherapy Preventing EMT

Differentiation Metabolic pathways Side-population Intracellular molecules Preventing DNA repair Increasing apoptosis of CSCs

Signalling pathways and molecules involved in, epithelial to mesenchymal transition such as TGF- β, BMI-1 etc. Switching on metabolic pathways associated with cell maturation Metabolic enzymes and regulators like AMP-kinase Drug transporters Transcription factors, intracellular enzymes such as ALDH Enzymes and proteins involve in DNA repair Proteins regulate apoptosis

Increased apoptosis and inhibit cell proliferation Increased apoptosis

[121–125] [200–202]

[112–115] [126–132] [195–199] [39–41] [32,206] [32,207,208]


644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703


704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763

pared to the matched control group [121]. Similarly, Gammaitoni and co-workers investigated the melanoma CSC killing efficiency of cytokine induced killer cells and noted a remarkable increase in the killing of CSCs (up to 71% killing of CSCs) [122]. These cytokine induce killer cells also inhibited tumour growth and lymphatic infiltration of autologous melanoma in mice [122]. Another study by Nishio et al., demonstrated that Zoledronate (a mevalonate pathway inhibitor) sensitised neuroblastoma stem cells to cytolysis by γδ T-cells (a subpopulation of T-cells that recognise and kill target cells) [123]. This study also observed that Zoledronate activated γδT-cells inhibit in vitro colony formation and in vivo neuroblastoma outgrowth in an animal model [123]. Therefore, development of immunotherapy targeting CSC specific tumour antigens might have great potential for clinical improvements in cancer management. Despite the immense development of cancer molecular biology understanding in recent years, cancer metabolism and especially CSC metabolism remains poorly understood. According to the observation of the Warburg effect (high energy production of cancer cells using lactic acid fermentation), cancer cell generate their ATP through aerobic glycolysis rather than oxidative phosphorylation, even in the presence of non-hypoxic conditions [126]. Several studies revealed that changes/mutations in the metabolic pathways as well as the metabolites produced in cancer cells can make them resistant to cancer therapy [127–132]. Thus research to unveil the details of the metabolic changes in CSCs and possible pharmacological approaches targeting those abnormalities will further open the horizons of cancer research. Other approaches such as blocking the DNA repair capacity of CSCs, promoting apoptosis and targeting anti-apoptotic properties of CSCs, has the therapeutic potential and could be effectively sensitize CSCs to the existing therapies. Table 3 presents a summary of approaches to eradicate CSCs selectively from cancers.

Conclusion Q3 Identification and isolation of CSCs are important for the transla-

tional work in cancer research. CSCs are fundamental in giving rise to cancer metastases and thus cancer recurrence. They also directly contribute to resistance to current modes of cancer therapy. From a clinical standpoint, novel clinical trials that examine the efficacies of treatment and target of CSCs are of prime importance. Understanding the mechanisms of CSCs in cancer pathogenesis and targeting treatment to CSCs will ultimately improve survival and quality of life of patients with cancer.

Q2

Uncited references [178,179].

Acknowledgments Q4 The authors would like to thank Griffith University (Visiting

Fellowship and Higher Degree Research scholarship) and National Natural Science Foundation of China (Grant no. 81200796) for funding support for this manuscript.

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