Open Access

Cancer cell reprogramming to identify the genes competent for generating liver cancer stem cells

  • Kenly Wuputra1,
  • Chang-Shen Lin1, 2,
  • Ming-Ho Tsai1,
  • Chia-Chen Ku1,
  • Wen-Hsin Lin1,
  • Ya-Han Yang3, 4,
  • Kung-Kai Kuo3, 4 and
  • Kazunari K. Yokoyama1, 3, 5, 6, 7, 8Email author
Contributed equally
Inflammation and Regeneration201737:15

https://doi.org/10.1186/s41232-017-0041-x

Received: 16 February 2017

Accepted: 25 April 2017

Published: 18 May 2017

Abstract

The cancer stem cell (CSC) hypothesis postulates that cancer originates from the malignant transformation of stem/progenitor cells and is considered to apply to many cancers, including liver cancer. Identification that CSCs are responsible for drug resistance, metastasis, and secondary tumor appearance suggests that these populations are novel obligatory targets for the treatment of cancer. Here, we describe our new method for identifying potential CSC candidates. The reprogramming of cancer cells via induced pluripotent stem cell (iPSC) technology is a novel therapy for the treatment and for the study of CSC-related genes. This technology has advantages for studying the interactions between CSC-related genes and the cancer niche microenvironment. This technology may also provide a useful platform for studying the genes involved in the generation of CSCs before and after reprogramming, and for elucidating the mechanisms underlying cancer initiation and progression. The present review summarizes the current understanding of transcription factors involved in the generation of liver CSCs from liver cancer cell-derived iPSCs and how these contribute to oncogenesis, and discusses the modeling of liver cancer development.

Keywords

c-JUN oncogeneInduced pluripotent stem cellsLiver cancerOCT4Reprogramming

Background

The cancer stem cell (CSC) hypothesis initially proposed for leukemia by J. Dick is now accepted [13]. CSCs represent a small subset of cells within a tumor that are endowed with stem-like properties such as the ability for (i) self-renewal, (ii) pluripotency, (iii) tumor formation, and (iv) drug resistance [4, 5]. Importantly, CSCs are thought to be responsible for tumor initiation, recurrence, and metastasis through the reduced sensitivity of cancer cells to chemotherapy compared with that of the original tumor cells [6]. Growing evidence about liver CSCs confirmed their resistance to therapeutic drugs such as cisplatin, 5-fuluorouracil, and so on [7].

The primary strategy for inducing liver CSCs is to first enrich the cells using classical stem cell markers of stem cells such as CD13, CD24, CD44, CD47, CD90, CD133, epithelial cell adhesion molecule, and OV6, and then to apply functional methodologies such as side-population analysis, the ALDEFLUORTM assay, the sphere formation, and so on [811]. This cell population is then transplanted into immuno-deficient mice to examine its in vivo tumorigenic potential [79], and the cells are studied further according to their expression of various genes or signals such as Wnt, Notch, Hedgehog, Transforming growth factor β, epithelial mesenchymal transition (EMT)/mesenchymal epithelial transition (MET) signaling, epigenetic regulators, and microRNAs. The putative CSC subpopulation capable to initiating tumor development at lower cell numbers are tested further for self-renewal capacity using serial dilution of cells to identify the CSCs. Cancers are also generated as a consequence of transformation of the “driver” mutation at initiation [1215], and then positive selection and clonal progression lead to the accumulation of “passenger” mutations required for additional growth advantages. It is generally accepted that a novel strategy is needed for the functional evaluation of both putative driver and passenger mutations, and for studying their molecular dynamics underlying cancer development.

Current cancer cell-reprogramming techniques such as somatic cell nuclear transfer [16] and the generation of induced pluripotent stem cells (iPSCs) [1719] are used to identify oncogenic genes. In 2006, Yamanaka et al. [17] reported on the reprogramming of somatic cell into induced pluripotent stem cell-like cells (iPSLCs). The success in reprogramming a somatic cell into a stem cell-like state has led to the idea of reprogramming malignant cells back to their original state, which is well before the oncogenic transformation occurs. The generation of iPSCs from cancer cells may provide tools for exploring the mechanisms of tumor initiation and progression in vitro, for studying the heterogeneity and origin of CSCs, and for producing cancer type-specific drug discovery. However, these reprogramming methods remain a challenge because of the cancer-specific epigenetic state and chromosomal aberrations of cancer cells.

The epigenetic memory of the original cell type is important to reprogramming and is closely related to the inefficient reprogramming caused by failure of reset the epigenome to an embryonic stem cell (ESC)-like state [20]. The epigenetic state is reversible, but attempts to reprogram cancer cells have produced incomplete resetting of the cancer-associated epigenome because of tumor heterogeneity and further accumulation of oncogenic mutations. Therefore, cancer cell reprogramming is currently limited to certain cancer types and cancer-specific marks in the epigenome, which impede successful reprogramming, and the underlying mechanism has not been fully elucidated. The technique of cancer cell reprograming is one possible approach for identifying the committed genes of CSCs and for studying the mechanisms underlying the transcriptional, translational, and epigenetic inheritance of cancer development. The characterization of epigenome and tumor suppressor gene complexes, such as p53, p21Cip1, p27Kip1, the Ink4 family, and the polycomb repressive complex (PRC) might identify the possible candidates for genes for reprogramming of cancer cells to CSCs.

Obstacles to cancer cell reprogramming

The reprogramming of cancer cells is less successful than the reprogramming of somatic cells [2123]. Despite the presence of genetic alterations, melanoma cells can be reversed to the pluripotent state, such as that of the ESC, by nuclear transfer [24] (Table 1). However, the cells involved in other malignant cancer types, including breast cancer, leukemia, and lymphoma, cannot be reprogrammed, which suggests the presence of unknown barriers to reprogramming [23, 25, 26]. Similarly, embryonic carcinoma (EC) cell lines can be reprogrammed by nuclear transfer and exhibit normal preimplantation development. However, abnormal phenotypes of the clones occur, which suggests that EC cell lines possess a unique set of modifications in the epigenetic state that cannot be reprogrammed by altering the developmental potential [27]. The limited number of studies that have reported successful derivation of iPSCs from cancer cells supports the notion that the existence of cancer-specific genetic and epigenetic states hinders successful reprogramming independently of the complexity of the techniques used for reprogramming. Reprograming studies using patient-derived cancer cells have produced solid evidence of the capacity for reversal of the malignant phenotype, and this method holds great promise for breaking the seemingly irreversible state associated with cancer.
Table 1

Summary of studies of reprogramming of cancer cells from induce pluripotent stem cell technology. We have modified the summary of the table reported by Camare et al. [25, 26]

CSCs examples

Original cells

Methods of reprogramming

Karyotype

Chimeras

Teratoma/tumor formation

Drug sensitivity

Utikal et al. (2009) [65]

Mice melanoma R454 (rasinduce cells)

Lentivirus OKM

Trisomy chromosomes 8 and 11

Yes

Yes

No tumor in the absence of Dox

Carette et al. (2010) [42]

Human leukemia KBM7 (CML)

Retrovirus OSKM

Tetraployd, chromosomes 9 and 22 Ph(+)

Not applied

Yes

Cell type specific drug sensitivity

Retrovirus OSK (incomplete reprogramming)

Miyoshi et al. (2010) [43]

Human gastrointestinal cancer cells

Retrovirus and lentivirus + lipofectamine OSKM

Abnormal

Not applied

Yes

Post iPSC cells—more sensitive to 5-Fu and differentiation inducing drug

Kuo et al. (2016) [59]

Human HepG2 liver cancer cells and mouse hepatocytes-iPSCs

Lentivirus OSKM + shp53RNA (lentivirus O + c-JUN for direct reprogramming)

Abnormal

Not applied

Yes

Yes

Stemness characteristics and oncogenic functions of CSCs

Generation of iPSCs from cancer cells requires the identification of genes that regulate stem cell self-renewal and pluripotency such as OCT4, SOX2, and NANOG. CSCs require oncogenes or tumor suppressor genes to express oncogenic functions. Both expression states of stemness genes and oncogenes/tumor suppressor genes should be reorganized at the chromatin state by their regulators of epigenetic modification. Thus, three classes of gene sets might provide clues for understanding the reprogramming of cancer cells.

OCT4 is known to be overexpressed in hematological cancers, seminomas, and cancers of the bladder, brain, lung, ovary, pancreas, prostate, kidney, and testicle [28]. OCT4 works synergistically with SOX2 via direct binding to transactivate the target genes [29]. Both SOX2 and OCT4 are activators of genes involved in pluripotency, including themselves and NANOG [30], and repressors of genes involved in differentiation [31, 32]. Both SOX2 and OCT4 regulate their own transcription by binding the composite elements of SOX–OCT in their enhancers [33].

Overexpression of SOX2 is detected in recurrent prostate cancer, head and neck squamous cell carcinoma, glioblastoma, small-cell lung cancer, and cancers of the breast, liver, pancreas, and stomach [33]. Overexpression of SOX2 increases cell proliferation via cyclin D3, and represses cell cycle regulators such as p21Cip1 and p27Kip1 [34]. SOX2 promotes the invasion, migration, and metastasis of melanoma, colorectal cancer, glioma, and cancers of the stomach, ovary, and liver through the activation of matric metalloproteinases family, and phosphatidylinositol 3-kinase (PI3K)–RAC-α serine/threonine kinases (AKT)–mammalian target of the rapamycin signaling pathway [3537].

NANOG is overexpressed in oral squamous cell carcinoma and other types of cancers [38]. NONOG is capable of maintaining pluripotency of ESCs independently of the leukemia inhibitory factor-signal transducers and activator of transcription pathway, which is different from the case of OCT4 [38, 39]. NANOG also controls the cell cycle and proliferation by directly binding to the cyclin D1 promoter for transactivation [40]. NANOG induced the expression of cancer-related genes like CD133 and aldehyde dehydrogenase 1A1 [41]. These stemness transcription factors of SOX2, OCT4, and NANOG co-occupy the promoter regions of about 350 genes in the genome, and OCT4 occupies more than 90% of the promoter regions bound by the OCT4 and SOX2 in human ESCs. These findings suggest that the OCT4–SOX2–NANOG axis is the key cascade for stemness [31].

Reprograming of cancer cells using iPS technology

It has been proposed that oncogenes and tumor suppressor genes should be activated or repressed to generate CSCs. However, the actual oncogenes that can generate CSCs have not been characterized.

Carette et al. [42] reprogrammed a cell line derived from chronic myeloid leukemia (CML) by infecting them with a retrovirus that induced the expression of OCT4, SOX2, KLF4, and MYC (OSKM) followed by the subcutaneous injection of the CML-iPSCs into nonobese/diabetic severe combined immunodeficient (NOD-SCID) mice [Table 1]. They found that the teratomas produced contained differentiated cells in three germ layers, which indicated pluripotency. Whereas the parental CML cell lines were dependent on the BCR–ABL pathway, by contrast, the CML iPSCs were independent of this BCR–ABL signaling and showed resistance to imatinib. However, Cratte et al. did not identify the signaling pathway involved in the suppression of this BCR–ABL cascade. Miyoshi et al. [43] reported on the reprogramming of gastrointestinal cancer cell lines into iPSCs through the OSKM method [Table 1]. Tumors were generated by parenteral injection of gastrointestinal cancer cells into NOD-SCID mice, but not by injection of differentiated cells arising from the iPSCs. These iPSCs expressed increased levels of tumor suppressor genes such as p16Ink4a and p53 upon differentiation.

Striker et al. [44] reported the reprogramming of glioblastoma (GBM) cells to neural stem cells (NSCs) by PiggyBac transposon vectors that expressed OCT4 and KLF4. In these GBM iPSCs, the widespread resetting of epigenetic methylation occurred in cancer-specific methylation variable positions, the GBM tumor suppressor gene CDKN1C (p57Kip2), and testin LIM domain protein (TES). The neural progenitor cells (NPCs) differentiated from GBM iPSCs resembled aggressive GBM cells when transplanted into the adult mouse brain [44]. By contrast, non-neural mesodermal progenitors from GBM iPSCs with sustained expression of TES and CDKN1C formed benign tumors, and failed to infiltrate the surrounding regions. These findings suggest that DNA methylation is critical to the expression of these particular genes. Kim et al. [45] generated the iPSC-like cells from pancreatic ductal adenocarcinoma (PDACs) by introducing the genes encoded OSKM. One cancer iPS-like clone harbored classical PDAC mutations, including kRAS and p16Ink4a heterozygous deletions and decreased SMAD copy number, and retained the chromosomal alterations seen in the parental cells, and differentiated into all three germ layers during in vitro differentiation in the descendants, although the neural lineages were underrepresented. An in vivo teratoma showed that the iPSC-like cells generated multiple germ layers tissues but preferred to generate endodermal ductal structures.

DNA methylation is another critical epigenetic change. However, the reprogramming of cancer cells into iPSCs shows that only about 50% of cancer-associated epigenetic defects, as defined by a comparison between normal and tumor cells, are stably reset, which suggests that locus-specific changes in the epigenome are required. Reconfiguration of the network of cell-fate transcription factors and downstream developmental epigenetic mechanisms, may effectively silence the cancer-promoting pathways essential for uncontrolled proliferation and infiltration. However, the reciprocal interaction of epigenetic changes and driver mutations of cancer need to be explored in greater detail.

Funato et al. [46] used the pluripotent stem cells to study the role of driver mutations in modeling pediatric brain tumors. Differentiation of human ESCs into NPCs and induced cellular transformation through the overexpression of a constitutively active PDGFRA, TP53 knockdown, or expressing the K27M mutant of histone H3.3 found in pediatric gliomas. Moreover, induced NPC transformation was induced by the combination of different mutations typically observed in human gliomas that collectively affect the signaling of the PI3K, MAPK, and p53 pathways [47].

BMI1 of PRC1 has been shown to be involved in the maintenance and/or self-renewal of many types of stem cells, including embryonic, neural, hematopoietic, and prostate stem cells [48]. BMI1 promotes the proliferation of leukemic stem cells in a mouse model [49], and activates the self-renewal ability of NSCs [50]. BMI1 is known to be directly responsible for the regulation of multiple targets such p16Ink4a and p14Arf [51] and to bind directly to the promoter of PTEN gene, which results in the activation of the PI3K–AKT signaling and subsequent stabilization of SNAIL to induce the EMT [52]. BMI1 also occupies the cadherin promoter, which causes E-cadherin repression [52] and cooperates with TWIST1 to promote cancer dedifferentiation and metastasis [53]. In endometrial cancer cells, the loss of BMI1 results in the reduced expression of SOX2 and KLF4 [54]. Overexpression of BMI1 correlates with overexpression of NANOG, high tumor grade status, and increased self-renewal in breast adenocarcinomas [55].

Recently, Kaufhold et al. [56] reported the association of Yin Yang 1 (YY1) and CSC transcription factors and that YY1 might be a transcriptional repressor that acts on CSC-associated transcription factors such as BMI1, SOX2, and OCT4. They also proposed the existence a regulatory loop involving crosstalk between the nuclear factor kB–PI3K–AKT pathway and the downstream controls of target gene products such as YY1, OCT4, SOX2 and BMI1. Taken together, these findings suggest that most of the genes critical for cancer reprogramming belong to the families of (i) stemness genes, (ii) oncogenes/tumor suppressor genes, and (iii) epigenetic-related genes of DNA or histone modification, and (iv) the INK4 locus mediated by PRC family.

Thus, we hypothesized a “two-hit” theory for the generation of CSCs. The first hit introduces stemness and the second hit induces oncogenic features or repression of tumor suppressor function. Both are required for induction and maintenance of CSCs by epigenetic alterations induced by both genes. In this model, the reprogramming can be used as a platform for identification of the functional driver or passenger mutations, and modifications under the activation of stemness genes and the activation of oncogenes (or the repression of tumor suppressor genes) (Fig. 1).
Fig. 1

Schematic representation of hypothetical two-hit theory for crosstalk to generate cancer stem cells by reprogramming. Hypothetical two-hit theory for induction of cancer stem cells was represented. Stemness factors (OCT4, SOX2, and NANOG) and oncogene/tumor suppressor genes (oncogenes such as Myc, KLF4, c-JUN, kRAS, etc.; antioncogenes such as p53, Rb, PTEN, BMI1, EZH2, INK4 family, etc.) and epigenetic modification of DNA methylation and histone modification are required for generation of cancer stem cells by reprogramming. We have reported the feedback control of c-JUN and OCT4 is critical for generation of cancer stem like cells [59]. The oncogene c-JUN transactivated genes encoding OCT4, SOX2, and NANOG [60], and the genes of OCT4, SOX2, and NANOG formed the molecular circuitry for stemness and pluripotency [64], and then OCT4 upregulated the expression of c-JUN gene to form the feedback circuit [59]. Taken together, we hypothesize that these feedback circuit might be regulated by the family of the stemness genes and the family of cancer-related oncogenes or tumor suppressor genes

Selective plasticity of CSCs

Cell plasticity is a key issue for the reprogramming of CSCs. Mu et al. [57] and Ku et al. [58] independently reported the role of cell plasticity in cell identity, which allows cancers to thrive. It has been known that hormone deprivation therapy that suppresses androgen receptor (AR) signaling is one of the treatments for metastatic prostate cancer. However, prostate cancers can become resistant to these drugs by losing hormone dependence on androgen. Because androgen stimulates the growth of prostate cancer cells, decreased production of androgen and/or inhibition of the hormone’s action on prostate cancer cells can make a tumor shrink or grow more slowly. Mu et al. [57] reported that the induction of SOX2 expression subsequent to loss of RB1 and TP53 contributes to neuroendocrine differentiation and androgen independence of prostate cancer cells. Ku et al. [58] examined the effects of RB1 and TP53 deletion in a mouse model of metastatic prostate cancer (PTEN loss) and found that EZH2 inhibition restored enzalutamide responsiveness in RB1- and TP53-depleted and AR expressing LNCaP cells. The cell lineage plasticity was determined by the E2F-regulating genes such as SOX2 and EZH2. These data suggest that both tumor suppressor genes, such as RB1, TP53, and PTEN, and the cell cycle regulator E2F-controlled genes, such as SOX2 and EZH2, might be critical for determination of cell lineage plasticity.

Clone selection of CSCs from iPSC-like cells

In an attempt to isolate the CSCs, we have used a new strategy to isolate the clone responsible for generating CSCs among the heterogeneous clones of iPSC-like cells derived from human hepatocyte cell lines [59]. Using the original four Yamanaka’s factors plus small hairpin TP53 plasmid, we have generated iPSC-like clones. To identify the possible CSC clones, we have reduced the number of cells that remain competent after tumor formation, as determined by the transplantation of colonies of xenograft-derived iPSC-like cells. One colony comprising about 200 cells finally generated tumors in more than 40% of transplants. We then characterized this colony to determine its tumor-forming capacity. This clone exhibited greater tumor-forming activity and other cancer-related activities such as sphere formation, colony formation, invasion activity, and drug resistance compared with the original liver cancer cells.

To gain further insight into the acquired CSC characteristics of this CSC colony, RNA sequencing was performed and showed that OCT4 and c-JUN expression was greater in this clone than in the original cancer cells. This experiment suggests that both OCT4 and c-JUN are key factors required for the feedback control of each other. Moreover, the two genes—one a stemness gene and the other an oncogene—were also competent in inducing CSCs derived from iPSCs from mouse hepatocytes infected with lentivirus that encoded OCT4 and c-JUN. This combination is interesting because c-JUN is an oncogene and OCT4 is a stemness gene. By themselves, OCT4 and c-JUN showed less transformation activity, but the feedback between OCT4 and c-JUN increased the likelihood of cancer induction. Therefore, we hypothesize that both genes are required to generate liver cancer and that the feedback regulation of OCT4 and c-JUN might be critical for triggering CSCs.

Future perspectives

This strategy of cancer reprograming is one possible approach for generating CSCs. Chang et al. [60] reported that c-JUN is activated in pluripotent stemness gene promoters such as OCT4, SOX2, and NANOG and promotes the EMT in head and neck cancer cells. We have introduced OCT4 and c-JUN into mouse iPSCs from normal hepatocytes to generate tumor formation [59]. These approaches to induce the feedback regulation of the stemness gene family and oncogene family might provide a novel approach to generate CSC-like clones. Elevated expression of OCT4 and c-JUN was observed in specimens taken from patients with liver cancers. These findings suggest that both genes are possible candidates as future therapeutic targets.

Conclusions

In this review, we have described the methods for generating CSC-like cells from iPSCs from liver cancer cells. The critical point is to isolate the clone with strongest tumor-inducing activity. We have identified the genes of stemness and oncogenes as possible CSC target genes. This approach can now be extended to isolate CSCs and to generate disease- or cancer-specific models with distinct features. However, the efficiency of cell reprogramming from iPSCs to CSCs is lower and each CSCs has been shown to be heterogeneous. Moreover, oncogene induced plasticity including the CSC markers, and the microenvironments controlling this process have still not been elucidated, especially in the cases of the solid tumors [23, 6163]. Further work is needed to identify and characterize CSC-like cells in other cancers and diseases, which will help to detect the driver and passenger mutations for generating cancers and genetic diseases. The study of the reprogramming of cancer cells should be encouraged to further progress the understanding of cancer and disease biology.

Abbreviations

CSC: 

Cancer stem cell

EC: 

Embryonic carcinoma

EMT: 

Epithelial mesenchymal transition

ESC: 

Embryonic stem cell

GMB: 

Glioblastoma

iPSC: 

Induced pluripotent stem cell

MET: 

Mesenchymal epithelial transition

MMP: 

Matrix metalloproteinase

NOD SCID: 

Nonobese diabetic/severe combined immunodeficient

OSKM: 

OCT4, SOX2, KLF4 and MYC

PRC: 

Polycomb repressive complex

YY1: 

Yin Yang 1

Declarations

Acknowledgements

We thank CC Ku for drawing the figure and table.

Funding

This work was supported in part by MOST 104-2320-B-037-033-My2, and MOST 104-2314-B-033-002 from the Ministry of Science and Technology; NHRI-Ex102-10109B1, and NHRI-Ex104-10416S1, from the National Health Research Institutes in Taiwan; and KMU-TP103G00, G01, G03, G04, G05, KMU-TP103A104, KMU-TP104A04, KMU-TP104E24, KMU-TP104PR22, and KMU-DT104001 from Kaohsiung Medical University in Taiwan.

Authors’ contributions

KW and CSL contributed to the preparation of this review. All authors KW, CSL, MHT, YHY, CCK, WHL, and KKK read and approved the final manuscript. KKY prepared and revised the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

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Authors’ Affiliations

(1)
Graduate Institute of Medicine, Kaohsiung Medical University
(2)
Department of Biological Sciences, National Sun Yat-sen University
(3)
Center of Stem Cell Research, Kaohsiung Medical University
(4)
Department of Surgery, Department of Medicine, Kaohsiung Medical University
(5)
Center of Infectious Diseases and Cancer Research, Kaohsiung Medical University
(6)
Research Center for Environmental Medicine, Department of Medicine, Kaohsiung Medical University
(7)
Faculty of Molecular Preventive Medicine, Graduate School of Medicine, the University of Tokyo
(8)
Faculty of Science and Engineering, Tokushima Bunri University

References

  1. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.View ArticlePubMedGoogle Scholar
  2. Medema JP. Cancer stem cells: the challenges ahead. Nat Cell Biol. 2013;15:338–44.View ArticlePubMedGoogle Scholar
  3. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10:717–28.View ArticlePubMedGoogle Scholar
  4. Yamashita T, Wang XW. Cancer stem cells in the development of liver cancer. J Clin Invest. 2013;123:1911–8.View ArticlePubMedPubMed CentralGoogle Scholar
  5. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.View ArticlePubMedPubMed CentralGoogle Scholar
  6. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.View ArticlePubMedGoogle Scholar
  7. Hashimoto N, Tsunedomi R, Yoshimura K, Watanabe Y, Hazama S, Oka M. Cancer stem-like sphere cells induced from de-differentiated hepatocellular carcinoma-derived cell lines possess the resistance to anti-cancer drugs. BMC Cancer. 2014;14:722.View ArticlePubMedPubMed CentralGoogle Scholar
  8. Marquardt JU, Raggi C, Andersen JB, Seo D, Avital I, Geller D, Lee YH, et al. Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways. Hepatology. 2011;54:1031–42.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, Nakauchi H, et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology. 2006;44:240–51.View ArticlePubMedGoogle Scholar
  10. Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, Guan XY. Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res. 2008;6:1146–53.View ArticlePubMedGoogle Scholar
  11. Cardinale V, Renzi A, Carpino G, Torrice A, Bragazzi MC, Giuliante F, DeRose AM, et al. Profiles of cancer stem cell subpopulations in cholangiocarcinomas. Am J Pathol. 2015;185:1724–39.View ArticlePubMedPubMed CentralGoogle Scholar
  12. Chen J, McKay RM, Parada LF. Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell. 2012;149:36–47.View ArticlePubMedPubMed CentralGoogle Scholar
  13. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Pon JR, Marra MA. Driver and passenger mutations in cancer. Annu Rev Pathol. 2015;10:25–50.View ArticlePubMedGoogle Scholar
  15. De S, Ganesan S. Looking beyond drivers and passengers in cancer genome sequencing data. Ann Oncol. 2016. doi: 10.1093/annonc/mdw677.
  16. Gurdon JB, Wilmut I. Nuclear transfer to eggs and oocytes. Cold Spring Harb Pespect Biol. 2011;3:1–14.Google Scholar
  17. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse cancer embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.View ArticlePubMedGoogle Scholar
  18. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.View ArticlePubMedGoogle Scholar
  19. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.View ArticlePubMedGoogle Scholar
  20. Papp B, Plath K. Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape. Cell Res. 2011;21:486–501.View ArticlePubMedPubMed CentralGoogle Scholar
  21. Kasai T, Chen L, Mizutani A, Kudoh T, Murakami H, Fu L, Seno M. Cancer stem cells converted from pluripotent stem cells and the cancerous niche. J Stem Cells Regen Med. 2014;10:2–7.PubMedPubMed CentralGoogle Scholar
  22. Volinia S, Nuovo G, Drusco A, Costinean S, Abujarour R, Desponts C, Garofalo M, et al. Pluripotent stem cell miRNAs and metastasis in invasive breast cancer. J Natl Cancer Inst. 2014;106. doi: 10.1093/jnci/dju324.
  23. Curry EL, Moad M, Robson CN, Heer R. Using induced pluripotent stem cells as a tool for modelling carcinogenesis. World J Stem Cells. 2015;7:461–9.View ArticlePubMedPubMed CentralGoogle Scholar
  24. Hochedlinger K, Blelloch R, Brennan C, Yamada Y, Kim M, Chin L, Jaenisch R. Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev. 2004;18:1875–85.View ArticlePubMedPubMed CentralGoogle Scholar
  25. Camare DA, Mambelli LI, Porcacchia AS, Herkis I. Advances and challenges on cancer cells reprogramming using induced pluripotent stem cells technologies. J Cancer. 2016;7:2296–303.View ArticleGoogle Scholar
  26. Izgi K, Canatan H, Iskender B. Current status in cancer cell reprogramming and its clinical implications. J Cancer Res Clin Oncol. 2017;143:371–83.View ArticlePubMedGoogle Scholar
  27. Blelloch RH, Hochedlinger K, Yamada Y, Brennan C, Kim M, Mintz B, Chin L, et al. Nuclear cloning of embryonal carcinoma cells. Proc Natl Acad Sci U S A. 2004;101:13985–90.PubMedPubMed CentralGoogle Scholar
  28. Schoenhals M, Kassambara A, De Vos J, Hose D, Moreaux J, Klein B. Embryonic stem cell markers expression in cancers. Biochem Biophys Res Commun. 2009;383:157–62.View ArticlePubMedGoogle Scholar
  29. Ambrosetti DC, Schöler HR, Dailey L, Basilico C. Modulation of the activity of multiple transcriptional activation domains by the DNA binding domains mediates the synergistic action of Sox2 and Oct-3 on the fibroblast growth factor-4 enhancer. J Biol Chem. 2000;275:23387–97.View ArticlePubMedGoogle Scholar
  30. Kuroda T, Tada M, Kubota H, Kimura H, Hatano SY, Suemori H, Nakatsuji N, et al. Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression. Mol Cell Biol. 2005;25:2475–85.View ArticlePubMedPubMed CentralGoogle Scholar
  31. Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell. 2005;122:947–56.View ArticlePubMedPubMed CentralGoogle Scholar
  32. Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell. 2008;133:1106–17.View ArticlePubMedGoogle Scholar
  33. Weina K, Utikal J. SOX and cancer; current research and its implication in the clinic. Clin Transl Med. 2014;3:19.View ArticlePubMedPubMed CentralGoogle Scholar
  34. Herreros-Villanueva M, Zhang JS, Koenig A, Abel EV, Smyrk TC, Bamlet WR, de Narvajas AA, et al. SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells. Oncogenesis. 2013;2:e61.View ArticlePubMedPubMed CentralGoogle Scholar
  35. Alonso MM, Diez-Valle R, Manterola L, Rubio A, Liu D, Cortes-Santiago N, Urquiza L, et al. Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas. PLoS One. 2011;6:e26740.View ArticlePubMedPubMed CentralGoogle Scholar
  36. Han X, Fang X, Lou X, Hua D, Ding W, Foltz G, Hood L, et al. Silencing SOX2 induced mesenchymal-epithelial transition and its expression predicts liver and lymph node metastasis of CRC patients. PLoS One. 2012;7:e41335.View ArticlePubMedPubMed CentralGoogle Scholar
  37. Yang N, Hui L, Wang Y, Yang H, Jiang X. SOX2 promotes the migration and invasion of laryngeal cancer cells by induction of MMP-2 via the PI3K/Akt/mTOR pathway. Oncol Rep. 2014;31:2651–9.PubMedGoogle Scholar
  38. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell. 2003;113:631–42.View ArticlePubMedGoogle Scholar
  39. Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell. 2003;113:643–55.View ArticlePubMedGoogle Scholar
  40. Han J, Zhang F, Yu M, Zhao P, Ji W, Zhang H, Wu B, et al. RNA interference-mediated silencing of NANOG reduces cell proliferation and induces G0/G1 cell cycle arrest in breast cancer cells. Cancer Lett. 2012;321:80–8.View ArticlePubMedGoogle Scholar
  41. Jeter CR, Liu B, Liu X, Chen X, Liu C, Calhoun-Davis T, Repass J, et al. NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene. 2011;30:3833–43835.View ArticlePubMedPubMed CentralGoogle Scholar
  42. Carette JE, Pruszak J, Varadarajan M, Blomen VA, Gokhale S, Camargo FD, Wernig M, et al. Generation of iPSCs from cultured human malignant cells. Blood. 2010;115:4039–42.View ArticlePubMedPubMed CentralGoogle Scholar
  43. Miyoshi N, Ishii H, Nagai K, Hoshino H, Mimori K, Tanaka F, Nagano H, et al. Defined factors induce reprogramming of gastrointestinal cancer cells. Proc Natl Acad Sci U S A. 2010;107:40–5.View ArticlePubMedGoogle Scholar
  44. Stricker SH, Feber A, Engström PG, Carén H, Kurian KM, Takashima Y, Watts C, et al. Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner. Genes Dev. 2013;27:654–69.View ArticlePubMedPubMed CentralGoogle Scholar
  45. Kim J, Hoffman JP, Alpaugh RK, Rhim AD, Reichert M, Stanger BZ, Furth EE, et al. An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Rep. 2013;3:2088–99.View ArticlePubMedPubMed CentralGoogle Scholar
  46. Funato K, Major T, Lewis PW, Allis CD, Tabar V. Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science. 2014;346:1529–33.View ArticlePubMedPubMed CentralGoogle Scholar
  47. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, TCGA Research Network, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;55:462–77.View ArticleGoogle Scholar
  48. Fasano CA, Dimos JT, Ivanova NB, Lowry N, Lemischka IR, Temple S. shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell. 2007;1:87–99.View ArticlePubMedGoogle Scholar
  49. Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature. 2003;423:255–60.View ArticlePubMedGoogle Scholar
  50. Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R. Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev. 2005;19:1432–7.View ArticlePubMedPubMed CentralGoogle Scholar
  51. Park IK, Morrison SJ, Clarke MF. Bmi1, stem cells, and senescence regulation. J Clin Invest. 2004;113:175–9.View ArticlePubMedPubMed CentralGoogle Scholar
  52. Song LB, Li J, Liao WT, Feng Y, Yu CP, Hu LJ, Kong QL, et al. The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest. 2009;119:3626–36.View ArticlePubMedPubMed CentralGoogle Scholar
  53. Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH, Huang CH, et al. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol. 2010;12:982–92.View ArticlePubMedGoogle Scholar
  54. Dong P, Kaneuchi M, Watari H, Hamada J, Sudo S, Ju J, Sakuragi N. MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BM-1. Mol Cancer. 2011;10:99.View ArticlePubMedPubMed CentralGoogle Scholar
  55. Paranjape AN, Balaji SA, Mandal T, Krushik EV, Nagaraj P, Mukherjee G, Rangarajan A. Bmi1 regulates self-renewal and epithelial to mesenchymal transition in breast cancer cells through Nanog. BMC Cancer. 2014;14:785.View ArticlePubMedPubMed CentralGoogle Scholar
  56. Kaufhold S, Garbán H, Bonavida B. Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication. J Exp Clin Cancer Res. 2016;35:84.View ArticlePubMedPubMed CentralGoogle Scholar
  57. Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, Wongvipat J, et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 2017;355:84–8.View ArticlePubMedPubMed CentralGoogle Scholar
  58. Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, Goodrich MM, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science. 2017;355:78–83.View ArticlePubMedGoogle Scholar
  59. Kuo KK, Lee KT, Chen KK, Yang YH, Lin YC, Tsai MH, Wuputra K, et al. Positive feedback loop of OCT4 and c-JUN expedites cancer stemness in liver cancer. Stem Cells. 2016;34:2613–24.View ArticleGoogle Scholar
  60. Chang CC, Hsu WH, Wang CC, Chou CH, Kuo MY, Lin BR, Chen ST, et al. Connective tissue growth factor activates pluripotency genes and mesenchymal-epithelial transition in head and neck cancer cells. Cancer Res. 2013;73:4147–57.View ArticlePubMedGoogle Scholar
  61. Friedman-Morviski D, Verma IM. Dedifferentiation and reprogramming: origin of cancer stem cells. EMBO Rep. 2014;15:244–53.View ArticleGoogle Scholar
  62. Rapp UR, Ceteci F, Schreck R. Oncogene-induced plasticity and cancer stem cells. Cell Cycle. 2008;7:45–51.View ArticlePubMedGoogle Scholar
  63. Magee JS, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell. 2012;21:283–96.View ArticlePubMedPubMed CentralGoogle Scholar
  64. Jaenisch R, Young R. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell. 2008;132:567–82.View ArticlePubMedPubMed CentralGoogle Scholar
  65. Utikali J, Maherali N, Kulalert W, Hochedinger K. Sox2 is dispensable for the reprogramming of melanocytes and melanoma cell into induced pluripotent stem cells. J Cell Sci. 2009;122:3502–10.View ArticleGoogle Scholar

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