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There is increasing evidence suggesting that stem cells are susceptive to carcinogenesis and, consequently, can be the origin of many cancers. Recently, the ...

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Road for understanding cancer stem cells: model cell lines Nedime Serakinci1,2† & Can Erzik3 †Author

for correspondence Denmark University, Institute for Regional Health Research (IRS), Telomere and Aging Group, Biopark Vejle, Tysklandsvej 77100 Vejle, Denmark Tel.: Office: +45 3693 8864, Lab: +45 3693 8863; Fax: +45 7573 5509; E-mail: [email protected] 2Department of Clinical Genetics, S100.0800, Vejle Sygehus, Kabbeltoft 25, 7100 Vejle, Denmark 3Marmara University, School of Medicine, Department of Medical Biology, Tibbiye Cad.no: 49 Haydarpasa, 34668 Istanbul, Turkey Tel.: +90 216 414 4737 Fax: +90 216 348 0848 E-mail: [email protected] marmara.edu.tr 1Southern

Keywords: cancer stem cells, model lines, stem cells part of

There is increasing evidence suggesting that stem cells are susceptive to carcinogenesis and, consequently, can be the origin of many cancers. Recently, the neoplastic potential of stem cells has been supported by many groups showing the existence of subpopulations with stem cell characteristics in tumor biopsies such as brain and breast. Evidence supporting the cancer stem cell hypothesis has gained impact due to progress in stem cell biology and development of new models to validate the self-renewal potential of stem cells. Recent evidence on the possible identification of cancer stem cells may offer an opportunity to use these cells as future therapeutic targets. Therefore, model systems in this field have become very important and useful. This review will focus on the state of knowledge on cancer stem cell research, including cell line models for cancer stem cells. The latter will, as models, help us both in the identification and characterization of cancer stem cells and in the further development of therapeutic strategies including tissue engineering.

Stem cells are defined as cells with extensive selfrenewal capacity and ability for multilineage differentiation into a wide variety of cell types. Due to their broad lineage potential, stem cells are regarded as ideal candidates to be used in regenerative medicine, tissue engineering and cell replacement therapies. An increasing amount of evidence has been reported suggesting that stem cells are susceptive to carcinogenesis and consequently can be the origin of many cancers. Hematologists have known the neoplastic potential of stem cells for decades. Recently, this knowledge has been expanded to solid tissue tumors where the existence of subpopulations of cells carrying stem cell characteristics have been shown in different tumors by many groups [1–3]. Currently, conventional treatment for cancer relies on the ability to nondiscriminately kill proliferating cells. However, if an agent spares the tumor-initiating cell, which may be a cancer stem cell, the tumor will most likely re-occur after therapy. Thus, identification and better understanding of the cancer stem cell will increase the opportunity to use these cells as future therapeutic targets and thereby spare the normal stem cell population. This is where the model systems become very important and useful. Another important point in stem cell biology is to expand our understanding on the mechanisms that regulate cell renewal ability. This ability is crucial for stem cell function because it ensures that stem cells can persist for

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a lifetime through regulating the balance between self-renewal and differentiation in various organs. Cancer stem cell hypothesis Until very recently, initiation and expansion of cancer was regarded as a multistep process that was a reflection and accumulation of the genetic and epigenetic alterations that transformed normal cells into a malignant phenotype [4]. Current evidence indicates that in many tumors, cancers arise from a single cell that undergoes several genetic mutations, which will constitute the driving force for malignant transformation [5,6]. At the same time it has been suggested that many tumors contain cells that display stem celllike features. Since stem cells and cancer cells have the extensive ability to self-renew, it is logical to assume that cancer-initiating cells have adopted the regulation of self-renewal cell division that normal stem cells possess. At present, there is evidence indicating that cancer resembling stem cells exist and these cells are thought to have accumulated cellular and molecular changes leading to tumor initiation [1,6,7]. Links between cancer & stem cells Stem cells are cells with extensive self-renewal capacity, whereas cancer can be considered as a disease of cellular self-renewal capacity. An increasing amount of evidence indicates that several pathways, which have been shown to be Regen. Med. (2007) 2(6), 957–965

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associated with cancer might also be active in the development of normal stem cells. Common mechanisms such as Notch [8,9], Sonic hedgehog (Shh) [10,11], Wnt [12] and phosphatase and tensin homologue (PTEN) [13] signaling pathways that are associated with cancer development are also associated with stem cell selfrenewal. Deregulation of these pathways has been shown to be associated with tumorigenesis. Mutations in these pathways have been demonstrated in various human tumors such as colon carcinoma, epidermal tumors [14,15], basal cell carcinoma, medulloblastoma, T-cell leukemia, cervical cancers and breast cancers [16–19]. Overexpression of the bcl-2 oncogene, which prevents apoptosis, results in an increased number of hematopoietic stem cells in vivo [20]. In many cancers, the cancer-initiating cell, which is the target cell for a transforming mutation, remains unknown. However, it is well known that certain types of cancers arise from the mutations that developed and accumulated in tissue-specific stem cells. One of the best examples is the leukemia that arises from mutations in hematopoietic stem cells, such as human acute myeloid leukemia and its subtypes [21]. Thus, it is important to understand the regulation of self-renewal pathways for stem cells. However, more than one pathway is known to be involved in stem cell proliferation and differentiation. Notch pathway

Notch proteins are transmembrane receptors. Notch 1–4, the mammalian homologues, are activated through ligand binding and cleavage by proteases and γ-secretase. After being cleaved, the intracellular domain of Notch is translocated into the nucleus to act [22]. Overexpression of the active form of Notch4 was shown to inhibit differentiation of normal breast epithelial cells [23]. In transgenic mice that express the active Notch4 protein, mammary tumors developed instead of normal breast tissue. These studies suggest the involvement of Notch signaling in both normal breast development and breast cancer development [24,25]. Notch has also been shown to play a role in epithelial self-renewal and cancer development in intestines [26]. In a recent study by Fan et al., it was shown that blockade of the Notch pathway in medullablastoma cell lines led to apoptosis and differentiation [27]. It has also been shown that Notch pathway targeting could have a promising role in prostate cancer treatment [28]. 958

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Hedgehog pathway

There are three hedgehog (Hh) ligands for mammals; sonic, desert (Dhh) and indian hedgehog (Ihh). These peptides interact with transmembrane receptors, patched (Ptch) and hedgehog interacting protein 1 (Hip1). Ptch interacts in the absence of Hh ligands with smoothened (Smo) protein to prevent it activating transcription factors Gli1, 2 and 3, which are known to regulate transcription of myelocytomatosis (Myc), cyclin D and E, PDGF and VEGF [29]. The Hh signaling components PTCH1, Gli1, and Gli2 have been shown by Liu et al. to be highly expressed in normal human mammary stem/progenitor cell cultures and that these genes are downregulated when those cells are induced to differentiate. Furthermore, the Hh signaling pathway is activated in human breast ‘cancer stem cells’ characterized as CD44+CD24–/low–30. Also in other tissues the Hh pathway was shown to have renewal effects and promote tumor expansion by transforming progenitor cells [31–34]. Wnt pathway

The Wnt proteins bind to the Frizzled receptors which if activated lead to cytoplasmic accumulation of β-catenin. When the Wnt pathway is active, β-catenin refrains from being phosphorylated, becomes stabilized and enters the nucleus to activate T-cell factor/lymphoid enhancer factor (TCF/LEF). TCF/LEF in turn acts on target genes [35]. The Wnt pathway has been shown to have a role in the hematopoietic stem cell renewal process [36]. In mice, Wnt was shown to be involved in inhibition of self-renewal capacity of mouse cortical neural progenitor cells (NPCs), promoting their neuronal differentiation [37]. Bmi-1

Bmi-1 belongs to the polycomb group of transcription factors. Recently, Bmi-1 was shown to be an important regulator in normal and cancer stem cells. It has been shown that Bmi-1-induces downregulation of p16 has an important role in the regulation of hematopoietic and neuronal stem cell self-renewal [38–40]. Its overexpression is also thought to be a regulatory factor for breast cancer aggressiveness [41]. Kelly and Gilliland demonstrated that in purified hematopoietic progenitor cell populations, acute myeloid leukemia 1/ETO protein (AML-ETO) may induce transformation of myeloid progenitors by enabling the cells to acquire the self-renewal property [42]. future science group

Road for understanding cancer stem cells: model cell lines – REVIEW

The cancer biology field has focused on molecular and biochemical pathways that lead to or are involved in carcinogenesis. While the researchers have focused on understanding the molecular biology of cancer development, the cellular biology and the understanding of self-renewal has lagged behind. Although the effect of mutations on proliferating cells such as fibroblasts and model cell lines may be known, the actual effect of the mutations on the cancer initiating cells is still lacking. The ability of extensive proliferation in cancer cells was first extensively documented in hematological cancers and then in solid cancers. Both cancer and stem cells show an unlimited proliferation; however, evidence for the existence of cancer stem cells first came with the analysis of tumor biopsy systems from hematological, breast and brain tumors that provide the cellular and molecular evidence that the neoplastic process involves cancer cells resembling stem cells. Evidence of cancer stem cells The first conclusive evidence for cancer stem cells was published in 1997 in Nature Medicine. Bonnet and Dick isolated a subpopulation of

leukemic cells that express a specific surface marker CD34, but lack the CD38 marker. The authors established that the CD34+/CD38- subpopulation is capable of initiating tumors in NOD/SCID mice that are histologically similar to those of the donor. The existence of leukemic stem cells prompted further research into other types of cancer. Cancer stem cells were later isolated from breast and brain tumors [1,43–45]. Recently, further evidence of cancer cells with stem cell properties have been obtained in prostate and lung cancers also. Richardson et al. demonstrated that a normal prostate stem cell expresses CD133. Moreover, they found a subpopulation in prostate cancer cells that was characterized as CD44+/α2βhi1/CD133+ [46]. In another study Kim et al. demonstrated the presence of bronchial alveolar stem cells that could be transformed in vitro by K-ras and could form tumors in mice [2]. Stem cells have considerable clinical potential, therefore characterization and identification of a cell that is capable of sustaining the growth of a neoplastic clone within a tumor still remains an important issue in cancer research [7,47,48]. In this

Figure 1. Extrinsic and intrinsic factors in stem cells or progenitor cells can give rise to cancer stem cells.

It might be that cancer stem cells can be derived from differentiated cells or tissue-derived stem cells simply because many factors in the microenvironment can trigger the initial step of cancer development.

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way the capacity for self-renewal of stem cells is linked to the neoplastic growth [5,49]. Recently the stem cell origin of malignancy has also been reported in hepatic tissue and head and neck squamous cell carcinoma [50,51]. All these findings support the existence of cancer stem cells. The identification of cancer stem cells strongly suggests that these cells could be a key target for future therapeutic development as they fuel the replicative capacity of the cancer. Besides these in vivo findings, Setoguchi et al. showed that four established cancer cell lines contain a small side population [52]. Hirschmann-Jax et al. demonstrated a distinct side population of cells within neuroblastoma tumor samples from 15 out of 23 patient samples, as well as a range of other tumors such as small-cell lung cancer and breast adenocarcinoma. These cells were capable of sustained ex vivo proliferation and demonstrated evidence for asymmetric division [53]. These examples support the cancer stem cell hypothesis and suggest that cancers originate from tissue stem cells and/or progenitor cells possibly through dysregulation of selfrenewal pathways which leads to expansion of this cell that may undergo further genetic and epigenetic changes to become fully transformed. Currently there are many standard cell lines that, as immortalized primary stem cells, show evidence of cancer stem cell characteristics. Serakinci et al. have demonstrated that prolonged culture of telomerase immortalized human mesenchymal stem cells leads to a malignant phenotype [54]. The extended life span acquired a genetic change that unmasked the malignant phenotype. Thus, the authors underlined the importance of phenotypic screening of genetically modified stem cells for clinical applications. This phenomenon has also been demonstrated in other immortalized cell line models. Wei et al. [55] have shown similar findings in immortalized human fibroblasts. At the same time, Milyavsky et al. [56] also demonstrated that immortalized and long life span fibroblasts are favoring potential malignant alterations. Tissue-specific stem cells, for example, bone marrow-derived stem cells and neural stem cells, show remarkable plasticity in vitro and in vivo, indicating that the developmental limitations of tissue-specific stem cells are regulated by the microenvironment that keeps the cells under certain conditions [57–60]. In addition, bone marrow cells have been shown to contribute to an important part of the endothelium in mouse tumors [61–64] and recent work has shown that 960

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inflammatory cells can also promote tumors through the production of growth-stimulating proteins and DNA-damaging chemicals that can trigger cancer-causing mutations [65,66]. However, it is not clear whether the cancer stem cells are stem cells that obtained the regulatory defects during the development or are derived from true tissue stem cells or mature progenitor cells that have acquired differentiation defects during the process (Figure 1). Normal stem cells are currently being investigated as potential targets for treatments for different types of diseases including neurodegenerative, cardiovascular and autoimmune diseases. Increased understanding of stem cell biology might allow development of markers for stem cell identity that could also be used as early markers for cancer. One of the important steps is to figure out what makes the cancer stem cell different from other cancer cells and normal stem cells. Currently, researchers exploit different techniques such as microarrays and gene chips to identify the genes that are active in cancer causing cells, compared with both normal stem cells and other cells from tumors, and some of which may be the ones controlling the cells ability to proliferate and metastasize. The identification of cancer stem cells strongly suggests that these cells are key targets for therapeutic development, as they fuel the replicative capacity of the cancer. The experimental systems to support this important proposal have been lacking for a long time. Recently, several groups have described useful model systems [67]. Ponti et al. have succeeded in isolating and establishing long-term in vitro cultures of breast tumorigenic cells with stem/progenitor cell properties [3]. The cells were isolated as CD44+/CD24-/low fraction from breast carcinomas, as first described by Al-Hajj et al., who found that as few as 100 cells with this phenotype were able to form tumors in mice [1]. This cellular model may be a helpful tool in eradicating the tumorigenic subpopulation within breast cancer. Cancer stem cells in clinics: targets for cancer therapy Hopes for improved cancer therapies are stimulating research to develop approaches with increased specificity on targeting and lower toxicity. Therefore, the answer to the question ‘What is the target cell for carcinogenesis?’ is needed desperately. With the current knowledge the answer is that the target cells should be the future science group

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cells that are capable of sustaining the growth of a neoplastic clone. This idea should cause us to focus on cancer stem cells and the relationship between cancer and normal tissue stem cells. One of the main clinical importances of cancer stem cell models are that it suggests targeting the cancer stem cells and not the tumorbulk when developing tumor-reducing treatment modalities (like chemo- and radio-therapy), since such therapies would be directed towards the source of malignancy. In a recent study, it has been reported that differences between normal hematopoietic stem cells and leukemic stem cells can be used for specific targeting [68]. The idea behind specific targeting of cancer stem cells is that these are known to exhibit resistance against conventional therapies by different mechanisms. Thus, in many cancers it has been shown that the multiple drug resistance transporter proteins are upregulated only in a limited group of tumor cells, which renders them more resistant to chemotherapy [69]. Stem cells are also known to express higher levels of antiapoptotic proteins as a resistance mechanism compared with differentiated cells [70]. The existence of cancer stem cells thus has profound implications for cancer biology and therapy, because it is likely that eradication of cancer stem cells is the critical determinant in achieving a cure. It has been proposed that cancer stem cells may be particularly resistant to chemotherapy and radiation therapy, although good evidence supporting this notion has been lacking. Phillips et al. report evidence that cells from breast cancer cell lines that resemble breast cancer–initiating cells are radioresistant compared with the remainder of breast cancer cells [71]. Similarly, a recently published report by Bao et al. suggests that glioblastoma stem cells are radioresistant and may therefore contribute to treatment failures [72]. Although the cancer stem cells make up just a tiny fraction of the entire tumor mass, they can divide to form more copies of themselves and thereby drive tumor formation. Recently, it has been shown that glioblastoma stem cells, which express a characteristic marker protein called CD133, activate a DNA repair pathway more potently than CD133-negative cancer cells. This makes them more able to survive DNA damage, and therefore, more resistant to ionizing radiation. Thus, new therapeutic strategies targeting cancer stem cells are currently being developed. The self-renewal pathways future science group

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mentioned above (Notch, Hh and Wnt) are currently being developed as new targets for therapeutic interventions. Thus, the enzyme γ-secretase of the Notch pathway was inhibited and breast tumor growth was shown to be suppressed in a subgroup of tumors by such a treatment [73]. Another self-renewal pathway inhibitor, HhAntag for Hh, has been shown to prevent medulloblasoma growth in a mouse model [74,75]. The Hh inhibitor cyclopamine, when added to pancreatic cancer cell lines, reduced the in vitro invasion capacity and significantly prevented metastasis in a mouse model [76]. The downregulating effect of cyclopamine has also been reported recently for hepatocellular, endometrial, gastric and ovarian carcinoma [77–80]. Challenges and future perspective Elucidating the genomic signature in tumor stem cells, or in cells with stem cell properties, may give important insights into understanding tumor development. Glinsky et al. reported that an 11-gene expression signature was associated with stem cell characteristics, where the expression was regulated by the Bmi-1 gene, which is also a stem cell self-renewal gene. Interestingly, the expression of this 11-gene signature associated with a poor prognosis in ten different types of cancers. The critical point in trying to define markers for cancer stem cells is that it is unknown to what extend such a marker or ‘expression signature’ is valid in different types of malignancies unless verified by functional assays. For instance, currently, surface markers such as CD44, CD133, Sca1 and Thy1 are used in stem cell isolation. In fact, many of the cells that express these markers are not stem cells. Another phenotype used to distinguish cells is their presence within the side population (SP) fraction defined by Hoechst dye efflux properties [81]. However, as with cell surface markers, possession of a SP phenotype is not a universal property of stem cells, and in some tissues, the SP fraction may not contain the stem cells. Experiments that identified normal breast stem cells by their ability to generate mammary glands in cleared fat pads showed that most of these cells are not included within the SP fraction. Possible toxicity of the dye to cells that do not exclude it should also be considered as a caveat to interpreting functional assays of SP cells. As with other markers used to identify certain types of stem cells, marker expression 961

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must be linked with a functional assay. Due to this complicating factor, it is safer to first isolate stem cells using other methods and then ask whether that particular stem cell population is indeed included within the SP. Besides surface markers, identification of other genetic signatures that typify stem cells is very important. For example Bmi-1, Tie-2, Shh, Notch, and Wnt/β-catenin have been shown to have important regulatory functions for some stem cells. However, as mentioned above, these genes frequently operate in other cell types, as well as in cancer cells and therefore they cannot be regarded as ‘stemness’ genes. Bromodeoxyuridine incorporation, namely in label retention studies, have been also proposed as way of identifying stem cells [82,83]. From these studies, it is known that not all stem cells are label retaining and not all label-retaining cells are stem cells. In fact, results on both normal and malignant breast stem cells demonstrated that both cell types are cycling and much more information is needed on the regulation of cancer stem cell cycling behavior before such assays can be used for identification of stem cells. Serial colony-forming unit assay is another in vitro method that is used for identification of stem cells [84]. Furthermore, serial transplantation in animal models, as an in vivo assay, is being used to evaluate both normal stem cells and cancer stem cells in order to show both self-renewal and tumor propagation. In vivo assays are the hallmarks for demonstration of self-renewal and lineage capacity. However, each of these methods has potential pitfalls that either complicate the application of the methods or the interpretation of the results. For instance, in vivo experiments take 6 months or more, which makes high-throughput screens very difficult or impossible. Based on these technical difficulties and challenges, it is obvious that an assay that is highly specific, rapid and quantitative is needed. Recently, adult human mesenchymal stem cells were identified as a target for transformation by phenotypic screening of the key steps in adult stem cell transformation. This study was made possible through the immortalization of human mesenchymal stem cells by ectopic telomerase expression. Previous models using fibroblasts and epithelial cells, whilst valuable,

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have not specifically addressed the issue of the adult stem cell as a target for transformation. Such studies offer insight in developing new experimental model systems. The cancer stem cell model underlines a need to alter the current paradigm in drug development. Eradication of cancers may require the targeting and elimination of cancer stem cells. Thus, model systems will help to identify the molecular basis for the cancer stem cell that will help us to find the differences between normal stem cells and cancer stem cells. The cancer stem cell hypothesis in carcinogenesis suggests that cancer originate from either a tissue stem cell or a progenitor cell through the dysregulation of self-renewal pathways of the stem cell. This cell subsequently expands and undergoes further genetic and/or epigenetic changes that lead to full transformation. Approaches, producing pluripotent stem cell lines by transplantation of cancer stem cell nuclei into a normal pluripotent stem cell, will allow us to study how the genetic alterations in the progression torwards cancer modulates the generation of cancer cells from the normal cells. Furthermore, model systems will allow us to recapitulate and study the natural development of tumors in vivo and moreover provide valuable models for new drug testing and discovery to help both in the identification of such differences and in screening for successful anticancer drugs. This approach will not only lead to new therapeutic targets, it will also lead to the identification of specific markers for detection of early cancer as well as residual disease after therapy. Acknowledgements The authors wish to thank Drs Steen Kolvraa, Rikke Christensen and Finn Rasmussen for critical reading of the manuscript. Financial & competing interests disclosure Research in the authors lab was supported by European Union contracts EC-FI6R-CT-2003-508842 and LSHCCT-2004-502943. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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Executive summary Key conclusions • Tumor stem cells were isolated and identified in leukemia and various solid tumor samples. • Stem cell-related proliferation pathways were shown to be dysregulated in many cancer types – genetic and epigenetic alterations in tissue stem cells could be important in tumor development. • Immortalized primary stem cell lines that were obtained and propagated were shown to gain malignant characteristics. • Tumor stem cells were shown to be more resistant against radio- and chemo-therapy. • Specific and selective targeting of the tumor stem cells plays a key role in cancer therapy, as well as in preventing new tumor formation. • Well-established and characterized model cell lines that will help for better understanding of cancer stem cells are still needed. Questions to be addressed • • • •

Do tumor stem cells arise at developmental period or from tissue stem cells or both? Are there identifiable surface markers or different expression for tumor stem cells? Can an in vitro assay be developed to identify stem cells? Can specific markers of cancer stem cells be identified to use as therapy targets?

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