Review ArticleReviewsR

Application of Cancer Cell Reprogramming Technology to Human Cancer Research

XIU-YANG PAN, MING-HO TSAI, KENLY WUPUTRA, CHIA-CHEN KU, WEN-HSIN LIN, YING-CHU LIN, SHOTARO KISHIKAWA, MICHIYA NOGUCHI, SHIGEO SAITO, CHANG-SHEN LIN and KAZUNARI K. YOKOYAMA
Anticancer Research July 2017, 37 (7) 3367-3377;

Abstract

The cancer stem cell (CSC) hypothesis is an evolving concept of oncogenesis that has recently gained wide acceptance. By definition, CSCs exhibit continuous proliferation and self-renewal, and they have been proposed to play significant roles in oncogenesis, tumor growth, metastasis, chemoresistance, and cancer recurrence. The reprogramming of cancer cells using induced pluripotent stem cell (iPSC) technology is a potential strategy for the identification of CSC-related oncogenes and tumor-suppressor genes. This technology has some advantages for studying the interactions between CSC-related genes and the cancer microenvironment. This approach may also provide a useful platform for studying the mechanisms of CSCs underlying cancer initiation and progression. The present review summarizes the recent advances in cancer cell reprogramming using iPSC technology and discusses its potential clinical use and related drug screening.

Cancer stem cells (CSCs) have been recognized as a small subset of cells within a tumor that are endowed with stem cell-like properties, including the abilities of self-renewal, pluripotency, cancer generation and drug resistance (1-7). The primary strategy used for inducing CSCs is to enrich the cells using classical stem cell markers such as CD13, CD24, CD44, CD47, CD90 and CD133, followed by other techniques including side-population analysis, sphere formation, and so on (8-11). This cell population is then transplanted into immunodeficient SCID mice to examine its in vivo tumorigenic potential (7-9). Such cells are examined further according to their cancer markers such as WNT, Notch, Hedgehog, transforming growth factor β, epithelial–mesenchymal transition (EMT)/mesenchymal–epithelial transition (MET) signaling proteins, and epigenetic factors (12-15). Putative CSC subpopulations that are capable of initiating tumor development at a lower cell number are tested for self-renewal capacity using serial dilutions of cells to identify the CSCs. In addition to these classical techniques, some techniques, such as reprogramming, are now a research focus, although the driver and the passenger mutation are present in the genome (12-15).

Current cancer cell-reprogramming techniques such as somatic cell nuclear transfer (16) and the generation of induced pluripotent stem cells (iPSCs) (17-19), are used to identify oncogenes, anti-oncogenes and epigenomes. The breakthrough came in 2006, when Takahashi and Yamanaka introduced the concept of iPSCs by generating stem cells with properties related to those of embryonic stem cells (ESCs) (17, 18). 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 well before 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 plasticity of cancer cells and origin of CSCs, and for achieving cancer type-specific drug discovery (Figure 1).

However, these reprogramming methods remain a challenge because of two problems: the cancer-specific epigenetic state and the chromosomal aberrations or genetic mutations present in cancer cells. The epigenetic memory of the original cell type is critical for reprogramming and is related to the inefficient reprogramming that is caused by a failure to reset the epigenome to an ESC-like state (20). The epigenetic state attempts to reprogram cancer cells that may have produced incomplete resetting of the cancer-associated epigenome because of tumor heterogeneity and further accumulation of oncogenic mutations.

In 2014, the first-in-human clinical trial of iPSC-based cell therapy was conducted. A Japanese elderly woman with exudative age-related macular degeneration received implantation of a retinal pigment epithelial cell sheet that had been differentiated from iPSCs generated from fibroblasts from her own skin. Although this sheet did not improve the patient's vision, it did halt disease progression (21, 22). In 2015, in a second clinical trial using such sheet, the genetic mutations invoIved were identified. However, there was no clear confirmation that these mutations could lead directly to advanced effects of diseases (23, 24). In order to advance iPSC-based novel therapies, it is critical to determine how and when these mutations occur and whether they actually lead to harmful effects. In the above trials, the patients were elderly individuals; thus, the occurrence of mutations might have been facilitated. In order to avoid these difficulties, Yamanaka's group used human leucocyte antigen (HLA)-matched young patients in subsequent trials of iPSC-based cell therapy, which is expect to be more successful (22).

Therefore, cancer cell reprogramming is currently limited to certain cancer types and cancer-specific markers in the epigenome; this impedes successful reprogramming. Moreover, the underlying mechanisms have not been fully elucidated. Thus, further elucidation of these issues may help prevent these alterations. Nevertheless, we expect that this iPSC-based technology and therapy will be a breakthrough in the prevention of cancer generation and progression. In this review, we summarize the features of the iPSC-like cells derived from human cancer for cell therapy and discuss both their merits and demerits regarding clinical and pharmaceutical applications.

The Bilateral Character of Cancer-specific iPSC-Iike Cells

The difficulties encountered in the reprogramming of cancer cells include cancer-specific genetic mutations, chromosomal rearrangements, accumulation of DNA damage, and reprogramming-triggered cellular senescence (25-27). Despite these obstacles, many studies have reported the generation of iPSCs from cancer cells, as summarized in Table I. This has covered a range of cancer cells, including melanoma (28, 29), prostatic (28), gastrointestinal (30), chronic myeloid leukemia (CML) (31), lung (32), breast (33), glioblastoma (34), and sarcoma (35).

The initial success in this field consisted in the successful reprogramming of colon metastatic cells and PC-3 prostate metastatic cells via the expression of intronic miR-302 (28). Subsequently, Miyoshi et al. performed a series of reprogramming studies with different methods using 20 gastrointestinal cancer cell lines, and obtained successful results for eight of them (30). Transduction by a combination of retroviral- or lentiviral-based Octamer-binding protein 4 (OCT4), SRY (sex determining region Y)-box 2 (SOX2), Krüppel-like factor (KLF4), Cellular myelocytomatosis viral oncogene homolog (c-MYC) (OSKM), B cell lymphoma-2 (BCL2), Kirsten rat sarcoma viral oncogene homolog (kRAS), Lin 28 homolog (LIN28), Nanog homeobox (NANOG), then transforming growth factor was added, and shRNA for tumor-suppressor genes for each cell line was used initially to obtain iPSC-like cells that re-expressed NANOG. The eight cell lines from which iPSCs were generated were derived from cholangiocellular carcinoma (HuCCT-1), colorectal (DLD1, HT29), hepatocellular (PLC), gastric (TMKN45), esophageal (YE10), and pancreatic (MIAPPaCa-2, PAV-1). The resultant iPSC-like cells were less tumorigenic as compared with their parental cell lines. Similarly, Noguchi et al. found that PANC1 cells were easily reprogrammed, while three other cell lines, MIAPaCa-2, PSN-1, and AsPC-1, were not (36). Iskender et al. also reported the generation of iPSCs derived from bladder carcinoma T24 cells, but another bladder carcinoma cell line, HTB-9, could not be induced to reprogram (37). Thus, the success of the generation of iPSCs from cancer cells seems to be cell-type specific. This is one of the problems with this technology.

Another problem encountered in this field of research is the lower efficiency of cancer cell reprogramming. This low efficiency in iPSC generation from cancer cells suggests the presence of multiple mechanisms that might be involved in the regulation of reprogramming (37, 38). Mathieu et al. reported that reprogramming factors and Hypoxia-inducible factor 1 alpha (HIF1α) accelerated the induction of iPSCs from the A549 lung carcinoma cell line, suggesting that reprogramming is enhanced by a cumulative effect of environmental hypoxia (32). Moreover, Mohyeldin et al. showed that low oxygen levels promote the self-renewing capacity of stem cells (39). Hypoxia activated the expression of stemness genes, such as OKM and NANOG, and stem-cell-associated miRNAs, in different cancer cell lines that shared an overlapping gene expression signature with human ESC lines (32).

Figure 1.
Figure 1.

Schematic representation of use of cancer-derived induced Pluripotent stem cell (iPSC)s for cancer biology. Tissue resources may be used to develop human cancer specific iPSCs lines and generate cancer stem cell (CSC)s mechanistic studies of cancer remodeling and drug screening or develop cell-based therapy of human cancer using genomic editing and induced differentiation from organoid 3D cells.

Hematopoietic malignancy with chromosome rearrangement is another challenging issue; disease-specific iPSCs possessing the genetic abnormalities of hematological malignancies would provide an efficient platform for studying pathogenesis. Carette et al. generated iPSCs derived from the CML cell line KBM7 carrying the fusion gene of the breakpoint cluster region protein (BCR)-breakpoint cluster region protein (BCR) (BCR–ABL) via defined factors OSKM (31). An acute myeloid leukemia (AML) mouse model was also generated by retroviral overexpression encoded the human mixed-lineage leukemia-AF9 (MLL–AF9) fusion gene in hematopoietic cells from transgenic mice that carried deoxycycline-inducible four OSKM genes. Upon deoxycycline addition, the MLL–AF9-expressing leukemia cells were efficiently converted into iPSCs that were capable of forming teratomas and producing chimeras. Most of the chimeric mice developed AML spontaneously (40).

Moreover, reports of the generation of iPSCs generated from human primary malignant cells are scarce and are limited to cancers such as leukemia (41-44) and pancreatic cancer (45). Hu et al. (41) used the transgene-free iPSC technology to express OSKM, NANOG, LIN28, and Simian vacuolating virus 40 large T antigen (SV40 LT) genes in primary human lymphoblasts from a BCR–ABL-positive patient with CML (41). Kumano et al. produced iPSCs from samples from imatinib-sensitive patients with CML that became resistant to imatinib despite the expression of the BCR–ABL oncogene (42). Gandre-Babbe et al. (43) and Kotini et al. (44) reported that the reprogramming of cancer cells was feasible despite the presence of genomic alterations in the parental cells, and that iPSCs derived from patients with juvenile myelomonocyte leukemia and with myelodysplatic syndrome recapitulated the disease-associated phenotype. Similarly, pancreatic-cancer-derived iPSC-like cells were also successfully generated from a parental pancreatic ductal adenocarcinoma with a kRASG12D mutation (45). Therefore, a similar concept is found in the reprogramming of normal somatic cells, in which reprogramming-induced multiple genetic/epigenetic abnormalities did not interfere with the differentiation capacity of the resulting iPSCs (46-48). Although expression of reprogramming genes was found to be successful in various primary patient samples of hematological malignancies, Liu et al. reported that NOTCH1-induced T-acute lymphoblastic leukemia could not be reprogrammed into a pluripotent state (40). Therefore, the reprogramming of cancer cells needs to be optimized for each cancer type. For example, Utikal et al. showed that the R545 melanoma cell line could be reprogrammed into iPSCs by introducing OCT4-KLF4-c-MYC (OKM), without ectopic SOX2 requirement (29). The resultant iPSCs were used to generate higher-degree chimeric mice that exhibited competent germline transmission. In contrast, Oshima et al. showed the induction of CSC features in colon cancer cells upon the introduction of OCT4-SOX2-KLF4 (OSK), and found that a subset of colon cancer cells gained cancer properties expressed defined colon CSC markers but not to teratomas in vivo (49). This different reprogramming might be caused by heterogeneity in plasticity or epigenesis.

View this table:
Table I.

Summary of studies of reprogramming of human cancer cells to induce pluripotent stem cells (iPSC). Recent reports also demonstrated the success in reducing the tumorigenicity of cancer cells (51, 80-82), or not changing the plasticity of cancer cells (80, 81, 83-85), even exhibiting strong cancerous features such as cancer stem cells (81), even these heterogeneous outputs are due to the status of p53 (86). Modified from the Table in Izgi et al. (87).

Interestingly, Jaenisch's group examined reprogramming activity using nuclear transplantation techniques (transplantation of nuclei from melanoma, leukemia, lymphoma, and breast cancer cells into enucleated oocytes) (50). In fact, all nuclei from primary leukemia and lymphoma cells cannot be reprogramed. A modest percentage of the transplanted nuclei from all cancer cells and transplanted tumors were reprogrammed, and the surviving oocytes went on to develop into blastocysts. By contrast, only blastocysts derived from the melanoma yielded ESCs, indicating that not all cancer genomes can be epigenetically reprogrammed to full pluripotency using the nuclear transplantation. Moreover, chimeras were generated only by using the melanoma nuclear-transferred ESCs. However, the chimeras developed earlier and exhibited higher expansion into tumor cells compared with the original nucleus-donor mouse model. These studies indicate that reprogramming of a primary tumor cells is more difficult in mouse models, and that further technological progress is needed to be able to generate reliable iPSC models of cancer.

Epigenetic Remodeling of Cancer Cells

Epigenetic changes in cancer cells result in reduced or increased aggressive phenotypes of partially reprogrammed iPSCs or iPSC-like cells. Regarding DNA methylation, Moore et al. reported that iPSCs from cancer cells exhibited distinct hypomethylation of the densely methylated regions of the genome, which are specific for cancer cells (51). Stricker et al. showed that glioblastoma cell lines derived from patients with high aneuploidy exhibited erasure of cancer-specific DNA methylation and could be reprogrammed (34). Moreover, reprogramming antagonized the DNA methylations that are significant for non-small cell lung cancer (NSCLC) cell lines, and differentiation of NSCLC-derived iPSCs in vitro did not restore the tumor-specific epigenetic modification (52). iPSCs from glioblastoma-derived neural stem cells exhibited reduced ability to infiltrate into surrounding tissues, suggesting suppression of their aggressive character upon reprogramming (34). Zhang et al. reprogrammed cells from three osteosarcoma, two liposarcoma, and a sarcoma of unknown origin, which altered the epigenetic feature of oncogenes (35). Tumor-suppressor genes render cells with a less aggressive tumor phenotype. However, some studies have suggested the acquisition of sensitivity to anticancer agents in the reprogramming of iPSCs, which is not necessarily an indicator of repression of the malignancy, but shows increased drug sensitivity compared with the parental cells (30). The reactivation of some tumor-suppressor genes, such as p16Ink4a, in iPSCs might lead to increasing chemosensitivity as well as the repressing proliferation and invasiveness in reprogrammed cancer cells (30). Although not all cancer reprogramming studies have analyzed the tumorigenic potential or drug responsiveness of the resulting iPSCs (31, 42, 53), the results of studies contradict the outcomes of Miyoshi et al. (30).

The tumor-suppressor gene products are known to play a critical role in reprogramming to generate iPSCs (54); however, more evidence is needed to draw a conclusion in terms of the role of the suppressor proteins in cancer-specific reprogramming. BMI1 in polycomb repressive complex 1 was demonstrated to increase reprogramming efficiency by replacing the function of KLF4 and c-MYC (55, 56). Another member of the polycomb repressive complex 2, EZH2, is also critical for reprogramming; forced expression of EZH2 enhances, while knockdown of EZH2 impairs, the generation of iPSCs (57-59). The epigenetic study of cancer cells exhibited aberrant epigenetic regulation of the p53-Inhibitors of cyclin-dependent kinase (INK) family network. Thus, the absence or reduced expression of p53 and p21CIP1 favored the generation of iPSCs (60-62). Epigenetic silencing of tumor-suppressor genes, such as though aberrant methylation of the p16INK4A promoter, has been shown to be reversed by reprogramming (63). Therefore, the reprogramming of cancer cells and overcoming of the barriers to pluripotency remain to be solved.

Common epigenetic processes might be involved in reprogramming and in the development of certain cancer types. In fact, global changes in epigenetic modifications that occur in normal cells and cancer cells were demonstrated to be bidirectional rather than unidirectional. Therefore, the application of reprogramming techniques to cancer cells might promote our understanding of the cancer-specific epigenome and elucidate the overlapping mechanisms shared by cancer-initiating and pluripotent cells.

Is it possible to reprogram cells via modification of the epigenetic state? A few authors have reported such reprogramming in the mouse. Hou et al. showed that a combination of small molecules is sufficient for pluripotency and is dispensable for reprogramming in mouse somatic cells (64). Growing evidence suggests that a combination of small molecules in mouse cells could compensate for exogenous reprogramming factors and generated iPSC-like cells with expression profiles and epigenesis similar to those of ESCs (65). Thus, for certain cell types, epigenomic editing could replace the ectopic expression of transcription factors for reprogramming, while for most cell types, the overcoming of epigenetic obstacles warrants a combination of mechanisms induced by forced expression of reprogramming factors and other modifications.

Reprogramming efficiency has been shown to be improved upon treatment with small molecules including inhibitors of DNA methyltransferase, histone deacetylase, WNT signal modulators, modulators of cell senescence, and metabolism (66). Cell origin thoroughly affects reprogramming efficiency, as iPSC induction does not reset the epigenetic memory completely, and the memory of the donor cell may be retained in the iPSCs (67). Incomplete reprogramming with inherited epigenetic memory generates iPSCs that have a tendency to differentiate toward the original lineage (68). Although reprogramming efficiency was further increased after combinational treatment with small molecules, transcription factors, and signaling pathway regulators, efforts should be focused on elucidating the mechanisms that direct terminally differentiated cells to erase their somatic epigenetics and gain pluripotency (69-71). Moreover, some of these observations were made in the mouse, not in humans. Thus, human iPSCs from human cancer cells need to be examined further, and additional information regarding the molecular relationship between epigenetic control and reprogramming should be collected.

Potential Application in Biomedical Research

Human cancer-derived iPSCs can be used to preserve unique genotypes by banking cells that can be differentiated into many cell types. The cancer-derived iPSC model is used for studying the mutation of cancer-related genes and epigenetic alterations in the genome in order to understand the molecular mechanisms underlying tumorigenesis in humans. The use of iPSC technologies has both advantages and disadvantages compared with traditional approaches using cancer cell lines and animal models. High-throughput drug screening using patient-specific iPSCs has been receiving growing attention. Chemotherapy takes a huge toll on patients with cancer because of its undesirable side-effects. A differentiated cytotoxicity screen could lead to the development of drugs that are more specific to their target cells.

Efforts to harness the merits of iPSC technology have been carried out for various neurological disorders (72) and diabetic cardiomyopathy (73). Current recombinant technologies enable precise genomic manipulation in diseased cells. For example, the efficiency of iPSC production can be improved through use of techniques including episomal plasmids, lentivirus-, adenovirus-, or sendai virus-mediated gene transfers. Moreover, the feasibility of genetic manipulation in iPSCs has been demonstrated using several technologies such as knockdown, knockout, and gene correction using homologous recombination, combined with genome-editing tools such as zinc-finger nucleases, Transcription activator-like effector nuclease (TALEN)s, and the Clustered regularly interspaced short palindromic repeats (CRISPER)- CRISPR associated protein 9 (CAS9) system (74, 75). Genetically defective cells could be corrected in vitro and reintroduced into patients. The autologous transplantation approach has been shown to be effective in principle using a humanized mouse model of sickle cell anemia (76). Human iPSCs are a potential source of cells for tissue reconstruction in the long term (77). Saki et al. reported that transplanted hematopoietic precursor cells can be generated from iPSCs, potentially offering new cell sources for cell reconstitution in patients with hematological cancer after treatment (78). Recently, AML patient-derived dermal fibroblasts were reprogrammed into normal iPSCs that did not carry any chromosomal aberrations of the patient's bone marrow cells, and they differentiated into normal hematopoietic progenitor cells (78). The HLA-matched iPSC sources at the iPSC bank of Kyoto University or the RIKEN Cell Bank are now prepared for clinical use (http://www.cira.kyoto-u.ac.jp/e/research/stock.html and http://cell.brc.riken.jp/en/, respectively). The use of three-dimensional (3D) organoid technologies to engineer tissues, such as stomach, small intestine, colon, pancreas and liver, are expected to bring about great advances regarding how we can model human disorders, perform drug screenings, and engineer replacement tissues or organs (79). Human organoid cultures are useful for studies in regenerative medicine and for the therapeutic screening of drugs and small molecules. These engineered 3D tissues can replace intact tissues in the cancer research because they are histologically and functionally more faithful to their in vivo counterparts.

Conclusion

The generation of patient-specific iPSCs from various tissues is revolutionizing the way in which we approach human disease modeling, novel drug development, and autologous/allogenic cell therapy of disorders. In particular, cancer iPSCs offer a new paradigm in cancer modeling and tissue regeneration. Cancer-derived iPSCs may enhance our understanding of the features of tumorigenesis, the effects of microenvironments, and how epigenetic events contribute to the development of various cancer types. This information could be expected to enable the establishment of drug screening platforms, the development of more targetable and less toxic therapies, and effective tissue reconstitution. The study of the reprograming of cancer cells and efforts to harness the versatility of iPSCs for cancer remodeling and for screening effective drugs should contribute to further progress in our understanding of cancer biology.

Acknowledgements

This work was supported in part by MOST 104-2320-B-037-033-My2, and MOST 104-2314-B-037-002, MOST 104-2314-B-037-043 from the Ministry of Science and Technology; NHRI-EX106-10416S1, from the National Health Research Institutes in Taiwan; and KMU-TP105G01, KMU-TP105E21, and KMU-DT106006 from Kaohsiung Medical University in Taiwan. The Authors also thank Wen-Hsin Lin for drawing the Figure and preparing the Table.

Footnotes

  • This article is freely accessible online.

  • Competing Interests

    The Authors declare that they have no competing interests.

  • Received May 19, 2017.
  • Revision received May 29, 2017.
  • Accepted June 2, 2017.

References

  1. ↵
    1. Lapidot T,
    2. Sirard C,
    3. Vormoor J,
    4. Murdoch B,
    5. Hoang T,
    6. Caceres-Cortes J,
    7. Minden M,
    8. Paterson B,
    9. Caligiuri MA,
    10. Dick JE
    : A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367: 645-648, 1994.
    OpenUrlCrossRefPubMed
    1. Shibue T,
    2. Weinberg RA
    : EMT, CSCs and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol, 2017. doi:10.1038/nrclinonc.2017.44. [Epub ahead of print]
    1. Laplane L,
    2. Beke A,
    3. Vainchenker W,
    4. Solary E
    : Concise Review: Induced Pluripotent Stem Cells as New Model Systems in Oncology. Stem Cells 33: 2887-2892, 2015.
    OpenUrl
    1. Friedmann-Morvinski D,
    2. Verma IM
    : Dedifferentiation and reprogramming: origins of cancer stem cells. EMBO Rep 15: 244-253, 2014.
    OpenUrlAbstract/FREE Full Text
    1. Medema JP
    : Cancer stem cells: the challenges ahead. Nature Cell Biol 15: 338-344, 2013.
    OpenUrlCrossRefPubMed
    1. Visvader JE,
    2. Lindeman GJ
    : Cancer stem cells: current status and evolving complexities. Cell Stem Cell 10: 717-728, 2012.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Magee JA,
    2. Piskounova E,
    3. Morrison SJ
    : Cancer stem cells: impact, heterogeneity and uncertainty. Cancer Cell 21: 283-296, 2012.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Ishiguro T,
    2. Ohata H,
    3. Sato A,
    4. Yamawaki K,
    5. Enomoto T,
    6. Okamoto K
    : Tumor-derived spheroids: Relevance to cancer stem cells and clinical applications. Cancer Science 108: 283-289, 2017.
    OpenUrl
  9. ↵
    1. Chiba T,
    2. Kita K,
    3. Zheng YW,
    4. Yokosuka O,
    5. Saisho H,
    6. Iwama A,
    7. Nakauchi H,
    8. Taniguchi H
    : Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 44: 240-251, 2006.
    OpenUrlCrossRefPubMed
    1. Ma S,
    2. Chan KW,
    3. Lee TK,
    4. Tang KH,
    5. Wo JY,
    6. Zheng BJ,
    7. Guan XY
    : Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res 6: 1146-1153, 2008.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Cardinale V,
    2. Renzi A,
    3. Carpino G,
    4. Torrice A,
    5. Bragazzi MC,
    6. Giuliante F,
    7. DeRose AM,
    8. Fraveto A,
    9. Onori P,
    10. Napoletano C,
    11. Franchitto A,
    12. Cantafora A,
    13. Grazi G,
    14. Caporaso N,
    15. D'Argenio G,
    16. Alpini G,
    17. Reid LM,
    18. Gaudio E,
    19. Alvaro D
    : Profiles of cancer stem cell subpopulations in cholangiocarcinomas. The Am J Pathol 185: 1724-1739, 2015.
    OpenUrl
  12. ↵
    1. Chen J,
    2. McKay RM,
    3. Parada LF
    : Malignant glioma: lessons from genomics, mouse models and stem cells. Cell 149: 36-47, 2012.
    OpenUrlCrossRefPubMed
    1. Vogelstein B,
    2. Papadopoulos N,
    3. Velculescu VE,
    4. Zhou S,
    5. Diaz LA Jr..,
    6. Kinzler KW
    : Cancer genome landscapes. Science 339: 1546-1558, 2013.
    OpenUrlAbstract/FREE Full Text
    1. Pon JR,
    2. Marra MA
    : Driver and passenger mutations in cancer. Ann Rev Pathol 10: 25-50, 2015.
    OpenUrl
  15. ↵
    1. De S,
    2. Ganesan S
    : Looking beyond drivers and passengers in cancer genome sequencing data. Ann Oncol 28: 938-945, 2017.
    OpenUrl
  16. ↵
    1. Gurdon JB,
    2. Wilmut I
    : Nuclear transfer to eggs and oocytes. Cold Spring Harb Perspect Biol 3: a002659, 2011.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Takahashi K,
    2. Yamanaka S
    : Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-676, 2006.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Takahashi K,
    2. Tanabe K,
    3. Ohnuki M,
    4. Narita M,
    5. Ichisaka T,
    6. Tomoda K,
    7. Yamanaka S
    : Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861-872, 2007.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Yu J,
    2. Vodyanik MA,
    3. Smuga-Otto K,
    4. Antosiewicz-Bourget J,
    5. Frane JL,
    6. Tian S,
    7. Nie J,
    8. Jonsdottir GA,
    9. Ruotti V,
    10. Stewart R,
    11. Slukvin II,
    12. Thomson JA
    : Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917-1920, 2007.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Papp B,
    2. Plath K
    : Reprogramming to pluripotency: stepwise resetting of the epigenetic landscape. Cell Res 21: 486-501, 2011.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Kamao H,
    2. Mandai M,
    3. Okamoto S,
    4. Sakai N,
    5. Suga A,
    6. Sugita S,
    7. Kiryu J,
    8. Takahashi M
    : Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application. Stem Cell Reports 2: 205-218, 2014.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Mandai M,
    2. Watanabe A,
    3. Kurimoto Y,
    4. Hirami Y,
    5. Morinaga C,
    6. Daimon T,
    7. Fujihara M,
    8. Akimaru H,
    9. Sakai N,
    10. Shibata Y,
    11. Terada M,
    12. Nomiya Y,
    13. Tanishima S,
    14. Nakamura M,
    15. Kamao H,
    16. Sugita S,
    17. Onishi A,
    18. Ito T,
    19. Fujita K,
    20. Kawamata S,
    21. Go MJ,
    22. Shinohara C,
    23. Hata KI,
    24. Sawada M,
    25. Yamamoto M,
    26. Ohta S,
    27. Ohara Y,
    28. Yoshida K,
    29. Kuwahara J,
    30. Kitano Y,
    31. Amano N,
    32. Umekage M,
    33. Kitaoka F,
    34. Tanaka A,
    35. Okada C,
    36. Takasu N,
    37. Ogawa S,
    38. Yamanaka S,
    39. Takahashi M
    : Autologous induced stem-cell-derived retinal cells for macular degeneration. New Engl J Med 376: 1038-1046, 2017.
    OpenUrlCrossRef
  23. ↵
    1. Chakradhar S
    : An eye to the future: Researchers debate best path for stem cell-derived therapies. Nature Med 22: 116-119, 2016.
    OpenUrlPubMed
  24. ↵
    1. Garber K
    : RIKEN suspends first clinical trial involving induced pluripotent stem cells. Nat Biotechnol 33: 890-891, 2015.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Banito A,
    2. Gil J
    : Induced pluripotent stem cells and senescence: learning the biology to improve the technology. EMBO Rep 11: 353-359, 2010.
    OpenUrlAbstract/FREE Full Text
    1. Banito A,
    2. Rashid ST,
    3. Acosta JC,
    4. Li S,
    5. Pereira CF,
    6. Geti I,
    7. Pinho S,
    8. Silva JC,
    9. Azuara V,
    10. Walsh M,
    11. Vallier L,
    12. Gil J
    : Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev 23: 2134-2139, 2009.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Ramos-Mejia V,
    2. Fraga MF,
    3. Menendez P
    : iPSCs from cancer cells: challenges and opportunities. Trends Mol Med 18: 245-247, 2012.
    OpenUrlCrossRefPubMed
  28. ↵
    1. Lin SL,
    2. Chang DC,
    3. Chang-Lin S,
    4. Lin CH,
    5. Wu DT,
    6. Chen DT,
    7. Ying SY
    : Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. RNA 14: 2115-2124, 2008.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Utikal J,
    2. Maherali N,
    3. Kulalert W,
    4. Hochedlinger K
    : Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J Cell Sci 122: 3502-3510, 2009.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Miyoshi N,
    2. Ishii H,
    3. Nagai K,
    4. Hoshino H,
    5. Mimori K,
    6. Tanaka F,
    7. Nagano H,
    8. Sekimoto M,
    9. Doki Y,
    10. Mori M
    : Defined factors induce reprogramming of gastrointestinal cancer cells. Proc Natl Acad Sci USA 107: 40-45, 2010.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Carette JE,
    2. Pruszak J,
    3. Varadarajan M,
    4. Blomen VA,
    5. Gokhale S,
    6. Camargo FD,
    7. Wernig M,
    8. Jaenisch R,
    9. Brummelkamp TR
    : Generation of iPSCs from cultured human malignant cells. Blood 115: 4039-4042, 2010.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Mathieu J,
    2. Zhang Z,
    3. Zhou W,
    4. Wang AJ,
    5. Heddleston JM,
    6. Pinna CM,
    7. Hubaud A,
    8. Stadler B,
    9. Choi M,
    10. Bar M,
    11. Tewari M,
    12. Liu A,
    13. Vessella R,
    14. Rostomily R,
    15. Born D,
    16. Horwitz M,
    17. Ware C,
    18. Blau CA,
    19. Cleary MA,
    20. Rich JN,
    21. Ruohola-Baker H
    : Long-term culture following ES-like gene-induced markers in cancer cells. Cancer Res 71: 4640-4652, 2011.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Corominas-Faja B,
    2. Cufi S,
    3. Oliveras-Ferraros C,
    4. Cuyas E,
    5. Lopez-Bonet E,
    6. Lupu R,
    7. Alarcon T,
    8. Vellon L,
    9. Iglesias JM,
    10. Leis O,
    11. Martin AG,
    12. Vazquez-Martin A,
    13. Menendez JA
    : Nuclear reprogramming of luminal-like breast cancer cells generates Sox2-overexpressing cancer stem-like cellular states harboring transcriptional activation of the mTOR pathway. Cell Cycle 12: 3109-3124, 2013.
    OpenUrlCrossRefPubMed
  34. ↵
    1. Stricker SH,
    2. Feber A,
    3. Engstrom PG,
    4. Caren H,
    5. Kurian KM,
    6. Takashima Y,
    7. Watts C,
    8. Way M,
    9. Dirks P,
    10. Bertone P,
    11. Smith A,
    12. Beck S,
    13. Pollard SM
    : Widespread resetting of DNA methylation in glioblastoma-initiating cells suppresses malignant cellular behavior in a lineage-dependent manner. Genes Dev 27: 654-669, 2013.
    OpenUrlAbstract/FREE Full Text
  35. ↵
    1. Zhang X,
    2. Cruz FD,
    3. Terry M,
    4. Remotti F,
    5. Matushansky I
    : Terminal differentiation and loss of tumorigenicity of human cancers via pluripotency-based reprogramming. Oncogene 32: 2249-2260, 2013.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Noguchi K,
    2. Eguchi H,
    3. Konno M,
    4. Kawamoto K,
    5. Nishida N,
    6. Koseki J,
    7. Wada H,
    8. Marubashi S,
    9. Nagano H,
    10. Doki Y,
    11. Mori M,
    12. Ishii H
    : Susceptibility of pancreatic cancer stem cells to reprogramming. Cancer Sci 106: 1182-1187, 2015.
    OpenUrl
  37. ↵
    1. Iskender B,
    2. Izgi K,
    3. Canatan H
    : Reprogramming bladder cancer cells for studying cancer initiation and progression. Tumour Biol 37: 13237-13245, 2016.
    OpenUrl
  38. ↵
    1. Saito S,
    2. Lin YC,
    3. Tsai MH,
    4. Lin CS,
    5. Murayama Y,
    6. Sato R,
    7. Yokoyama KK
    : Emerging roles of hypoxia-inducible factors and reactive oxygen species in cancer and pluripotent stem cells. Kaohsiung J Med Sci 31: 279-286, 2015.
    OpenUrl
  39. ↵
    1. Mohyeldin A,
    2. Garzon-Muvdi T,
    3. Quinones-Hinojosa A
    : Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 7: 150-161, 2010.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Liu Y,
    2. Cheng H,
    3. Gao S,
    4. Lu X,
    5. He F,
    6. Hu L,
    7. Hou D,
    8. Zou Z,
    9. Li Y,
    10. Zhang H,
    11. Xu J,
    12. Kang L,
    13. Wang Q,
    14. Yuan W,
    15. Gao S,
    16. Cheng T
    : Reprogramming of MLL-AF9 leukemia cells into pluripotent stem cells. Leukemia 28: 1071-1080, 2014.
    OpenUrl
  41. ↵
    1. Hu K,
    2. Yu J,
    3. Suknuntha K,
    4. Tian S,
    5. Montgomery K,
    6. Choi KD,
    7. Stewart R,
    8. Thomson JA,
    9. Slukvin II
    : Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood 117: e109-119, 2011.
    OpenUrlAbstract/FREE Full Text
  42. ↵
    1. Kumano K,
    2. Arai S,
    3. Hosoi M,
    4. Taoka K,
    5. Takayama N,
    6. Otsu M,
    7. Nagae G,
    8. Ueda K,
    9. Nakazaki K,
    10. Kamikubo Y,
    11. Eto K,
    12. Aburatani H,
    13. Nakauchi H,
    14. Kurokawa M
    : Generation of induced pluripotent stem cells from primary chronic myelogenous leukemia patient samples. Blood 119: 6234-6242, 2012.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Gandre-Babbe S,
    2. Paluru P,
    3. Aribeana C,
    4. Chou ST,
    5. Bresolin S,
    6. Lu L,
    7. Sullivan SK,
    8. Tasian SK,
    9. Weng J,
    10. Favre H,
    11. Choi JK,
    12. French DL,
    13. Loh ML,
    14. Weiss MJ
    : Patient-derived induced pluripotent stem cells recapitulate hematopoietic abnormalities of juvenile myelomonocytic leukemia. Blood 121: 4925-4929, 2013.
    OpenUrlAbstract/FREE Full Text
  44. ↵
    1. Kotini AG,
    2. Chang CJ,
    3. Boussaad I,
    4. Delrow JJ,
    5. Dolezal EK,
    6. Nagulapally AB,
    7. Perna F,
    8. Fishbein GA,
    9. Klimek VM,
    10. Hawkins RD,
    11. Huangfu D,
    12. Murry CE,
    13. Graubert T,
    14. Nimer SD,
    15. Papapetrou EP
    : Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells. Nat Biotechnol 33: 646-655, 2015.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Kim J,
    2. Hoffman JP,
    3. Alpaugh RK,
    4. Rhim AD,
    5. Reichert M,
    6. Stanger BZ,
    7. Furth EE,
    8. Sepulveda AR,
    9. Yuan CX,
    10. Won KJ,
    11. Donahue G,
    12. Sands J,
    13. Gumbs AA,
    14. Zaret KS
    : An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Rep 3: 2088-2099, 2013.
    OpenUrlCrossRefPubMed
  46. ↵
    1. Hussein SM,
    2. Batada NN,
    3. Vuoristo S,
    4. Ching RW,
    5. Autio R,
    6. Narva E,
    7. Ng S,
    8. Sourour M,
    9. Hamalainen R,
    10. Olsson C,
    11. Lundin K,
    12. Mikkola M,
    13. Trokovic R,
    14. Peitz M,
    15. Brustle O,
    16. Bazett-Jones DP,
    17. Alitalo K,
    18. Lahesmaa R,
    19. Nagy A,
    20. Otonkoski T
    : Copy number variation and selection during reprogramming to pluripotency. Nature 471: 58-62, 2011.
    OpenUrlCrossRefPubMed
    1. Lister R,
    2. Pelizzola M,
    3. Kida YS,
    4. Hawkins RD,
    5. Nery JR,
    6. Hon G,
    7. Antosiewicz-Bourget J,
    8. O'Malley R,
    9. Castanon R,
    10. Klugman S,
    11. Downes M,
    12. Yu R,
    13. Stewart R,
    14. Ren B,
    15. Thomson JA,
    16. Evans RM,
    17. Ecker JR
    : Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471: 68-73, 2011.
    OpenUrlCrossRefPubMed
  48. ↵
    1. Mayshar Y,
    2. Ben-David U,
    3. Lavon N,
    4. Biancotti JC,
    5. Yakir B,
    6. Clark AT,
    7. Plath K,
    8. Lowry WE,
    9. Benvenisty N
    : Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7: 521-531, 2010.
    OpenUrlCrossRefPubMed
  49. ↵
    1. Oshima N,
    2. Yamada Y,
    3. Nagayama S,
    4. Kawada K,
    5. Hasegawa S,
    6. Okabe H,
    7. Sakai Y,
    8. Aoi T
    : Induction of cancer stem cell properties in colon cancer cells by defined factors. PLoS One 9: e101735, 2014.
    OpenUrlCrossRefPubMed
  50. ↵
    1. Hochedlinger K,
    2. Blelloch R,
    3. Brennan C,
    4. Yamada Y,
    5. Kim M,
    6. Chin L,
    7. Jaenisch R
    : Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev 18: 1875-1885, 2004.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    1. Moore JBt,
    2. Loeb DM,
    3. Hong KU,
    4. Sorensen PH,
    5. Triche TJ,
    6. Lee DW,
    7. Barbato MI,
    8. Arceci RJ
    : Epigenetic reprogramming and re-differentiation of a Ewing sarcoma cell line. Front Cell Dev Biol 3: 15, 2015.
    OpenUrl
  52. ↵
    1. Mahalingam D,
    2. Kong CM,
    3. Lai J,
    4. Tay LL,
    5. Yang H,
    6. Wang X
    : Reversal of aberrant cancer methylome and transcriptome upon direct reprogramming of lung cancer cells. Sci Rep 2: 592, 2012.
    OpenUrlPubMed
  53. ↵
    1. Islam SM,
    2. Suenaga Y,
    3. Takatori A,
    4. Ueda Y,
    5. Kaneko Y,
    6. Kawana H,
    7. Itami M,
    8. Ohira M,
    9. Yokoi S,
    10. Nakagawara A
    : Sendai virus-mediated expression of reprogramming factors promotes plasticity of human neuroblastoma cells. Cancer Sci 106: 1351-1361, 2015.
    OpenUrl
  54. ↵
    1. Lin YC,
    2. Murayama Y,
    3. Hashimoto K,
    4. Nakamura Y,
    5. Lin CS,
    6. Yokoyama KK,
    7. Saito S
    : Role of tumor suppressor genes in the cancer-associated reprogramming of human induced pluripotent stem cells. Stem Cell Res Ther 5: 58, 2014.
    OpenUrl
  55. ↵
    1. Cao L,
    2. Bombard J,
    3. Cintron K,
    4. Sheedy J,
    5. Weetall ML,
    6. Davis TW
    : BMI1 as a novel target for drug discovery in cancer. J Cell Biochem 112: 2729-2741, 2011.
    OpenUrlCrossRefPubMed
  56. ↵
    1. Moon JH,
    2. Heo JS,
    3. Kim JS,
    4. Jun EK,
    5. Lee JH,
    6. Kim A,
    7. Kim J,
    8. Whang KY,
    9. Kang YK,
    10. Yeo S,
    11. Lim HJ,
    12. Han DW,
    13. Kim DW,
    14. Oh S,
    15. Yoon BS,
    16. Scholer HR,
    17. You S
    : Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1. Cell Res 21: 1305-1315, 2011.
    OpenUrlCrossRefPubMed
  57. ↵
    1. Villasante A,
    2. Piazzolla D,
    3. Li H,
    4. Gomez-Lopez G,
    5. Djabali M,
    6. Serrano M
    : Epigenetic regulation of Nanog expression by Ezh2 in pluripotent stem cells. Cell Cycle 10: 1488-1498, 2011.
    OpenUrlCrossRefPubMed
    1. Ding X,
    2. Wang X,
    3. Sontag S,
    4. Qin J,
    5. Wanek P,
    6. Lin Q,
    7. Zenke M
    : The polycomb protein Ezh2 impacts on induced pluripotent stem cell generation. Stem Cells Dev 23: 931-940, 2014.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Xie B,
    2. Zhang H,
    3. Wei R,
    4. Li Q,
    5. Weng X,
    6. Kong Q,
    7. Liu Z
    : Histone H3 lysine 27 trimethylation acts as an epigenetic barrier in porcine nuclear reprogramming. Reproduction 151: 9-16, 2016.
    OpenUrl
  60. ↵
    1. Yi L,
    2. Lu C,
    3. Hu W,
    4. Sun Y,
    5. Levine AJ
    : Multiple roles of p53-related pathways in somatic cell reprogramming and stem cell differentiation. Cancer Res 72: 5635-5645, 2012.
    OpenUrlAbstract/FREE Full Text
    1. Ichida JK,
    2. Tcw J,
    3. Williams LA,
    4. Carter AC,
    5. Shi Y,
    6. Moura MT,
    7. Ziller M,
    8. Singh S,
    9. Amabile G,
    10. Bock C,
    11. Umezawa A,
    12. Rubin LL,
    13. Bradner JE,
    14. Akutsu H,
    15. Meissner A,
    16. Eggan K
    : Notch inhibition allows oncogene-independent generation of iPS cells. Nat Chem Biol 10: 632-639, 2014.
    OpenUrl
  62. ↵
    1. Rasmussen MA,
    2. Holst B,
    3. Tumer Z,
    4. Johnsen MG,
    5. Zhou S,
    6. Stummann TC,
    7. Hyttel P,
    8. Clausen C
    : Transient p53 suppression increases reprogramming of human fibroblasts without affecting apoptosis and DNA damage. Stem Cell Rep 3: 404-413, 2014.
    OpenUrl
  63. ↵
    1. Ron-Bigger S,
    2. Bar-Nur O,
    3. Isaac S,
    4. Bocker M,
    5. Lyko F,
    6. Eden A
    : Aberrant epigenetic silencing of tumor suppressor genes is reversed by direct reprogramming. Stem Cells 28: 1349-1354, 2010.
    OpenUrlCrossRefPubMed
  64. ↵
    1. Hou P,
    2. Li Y,
    3. Zhang X,
    4. Liu C,
    5. Guan J,
    6. Li H,
    7. Zhao T,
    8. Ye J,
    9. Yang W,
    10. Liu K,
    11. Ge J,
    12. Xu J,
    13. Zhang Q,
    14. Zhao Y,
    15. Deng H
    : Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science 341: 651-654, 2013.
    OpenUrlAbstract/FREE Full Text
  65. ↵
    1. Kimura T,
    2. Kaga Y,
    3. Sekita Y,
    4. Fujikawa K,
    5. Nakatani T,
    6. Odamoto M,
    7. Funaki S,
    8. Ikawa M,
    9. Abe K,
    10. Nakano T
    : aPluripotent stem cells derived from mouse primordial germ cells by small molecule compounds. Stem Cells 33: 45-55, 2015.
    OpenUrl
  66. ↵
    1. Lin T,
    2. Wu S
    : Reprogramming with Small Molecules instead of Exogenous Transcription Factors. Stem Cells Int 2015: 794632, 2015.
    OpenUrlPubMed
  67. ↵
    1. Ruiz S,
    2. Diep D,
    3. Gore A,
    4. Panopoulos AD,
    5. Montserrat N,
    6. Plongthongkum N,
    7. Kumar S,
    8. Fung HL,
    9. Giorgetti A,
    10. Bilic J,
    11. Batchelder EM,
    12. Zaehres H,
    13. Kan NG,
    14. Scholer HR,
    15. Mercola M,
    16. Zhang K,
    17. Izpisua Belmonte JC
    : Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells. Proc Natl Acad Sci USA 109: 16196-16201, 2012.
    OpenUrlAbstract/FREE Full Text
  68. ↵
    1. Bar-Nur O,
    2. Russ HA,
    3. Efrat S,
    4. Benvenisty N
    : Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell 9: 17-23, 2011.
    OpenUrlCrossRefPubMed
  69. ↵
    1. Buganim Y,
    2. Faddah DA,
    3. Jaenisch R
    : Mechanisms and models of somatic cell reprogramming. Nat Rev Genet 14: 427-439, 2013.
    OpenUrlCrossRefPubMed
    1. Rais Y,
    2. Zviran A,
    3. Geula S,
    4. Gafni O,
    5. Chomsky E,
    6. Viukov S,
    7. Mansour AA,
    8. Caspi I,
    9. Krupalnik V,
    10. Zerbib M,
    11. Maza I,
    12. Mor N,
    13. Baran D,
    14. Weinberger L,
    15. Jaitin DA,
    16. Lara-Astiaso D,
    17. Blecher-Gonen R,
    18. Shipony Z,
    19. Mukamel Z,
    20. Hagai T,
    21. Gilad S,
    22. Amann-Zalcenstein D,
    23. Tanay A,
    24. Amit I,
    25. Novershtern N,
    26. Hanna JH
    : Deterministic direct reprogramming of somatic cells to pluripotency. Nature 502: 65-70, 2013.
    OpenUrlCrossRefPubMed
  71. ↵
    1. Vidal SE,
    2. Amlani B,
    3. Chen T,
    4. Tsirigos A,
    5. Stadtfeld M
    : Combinatorial modulation of signaling pathways reveals cell-type-specific requirements for highly efficient and synchronous iPSC reprogramming. Stem Cell Rep 3: 574-584, 2014.
    OpenUrlCrossRef
  72. ↵
    1. Xu XH,
    2. Zhong Z
    : Disease modeling and drug screening for neurological diseases using human induced pluripotent stem cells. Acta Pharmacol Sin 34: 755-764, 2013.
    OpenUrlCrossRefPubMed
  73. ↵
    1. Drawnel FM,
    2. Boccardo S,
    3. Prummer M,
    4. Delobel F,
    5. Graff A,
    6. Weber M,
    7. Gerard R,
    8. Badi L,
    9. Kam-Thong T,
    10. Bu L,
    11. Jiang X,
    12. Hoflack JC,
    13. Kiialainen A,
    14. Jeworutzki E,
    15. Aoyama N,
    16. Carlson C,
    17. Burcin M,
    18. Gromo G,
    19. Boehringer M,
    20. Stahlberg H,
    21. Hall BJ,
    22. Magnone MC,
    23. Kolaja K,
    24. Chien KR,
    25. Bailly J,
    26. Iacone R
    : Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells. Cell Rep 9: 810-821, 2014.
    OpenUrlCrossRefPubMed
  74. ↵
    1. Musunuru K
    : Genome editing of human pluripotent stem cells to generate human cellular disease models. Dis Model Mech 6: 896-904, 2013.
    OpenUrlAbstract/FREE Full Text
  75. ↵
    1. Chandrasekaran AP,
    2. Song M,
    3. Ramakrishna S
    : Genome editing: a robust technology for human stem cells. Cell Mol Life Sci, 2017. doi: 10.1007/s00018-017-2522-0. [Epub ahead of print]
  76. ↵
    1. Hanna J,
    2. Wernig M,
    3. Markoulaki S,
    4. Sun CW,
    5. Meissner A,
    6. Cassady JP,
    7. Beard C,
    8. Brambrink T,
    9. Wu LC,
    10. Townes TM,
    11. Jaenisch R
    : Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318: 1920-1923, 2007.
    OpenUrlAbstract/FREE Full Text
  77. ↵
    1. Doulatov S,
    2. Vo LT,
    3. Chou SS,
    4. Kim PG,
    5. Arora N,
    6. Li H,
    7. Hadland BK,
    8. Bernstein ID,
    9. Collins JJ,
    10. Zon LI,
    11. Daley GQ
    : Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors. Cell Stem Cell 13: 459-470, 2013.
    OpenUrlCrossRefPubMed
  78. ↵
    1. Salci KR,
    2. Lee JH,
    3. Laronde S,
    4. Dingwall S,
    5. Kushwah R,
    6. Fiebig-Comyn A,
    7. Leber B,
    8. Foley R,
    9. Dal Cin A,
    10. Bhatia M
    : Cellular reprogramming allows generation of autologous hematopoietic progenitors from AML patients that are devoid of patient-specific genomic aberrations. Stem Cells 33: 1839-1849, 2015.
    OpenUrl
  79. ↵
    1. Dutta D,
    2. Heo I,
    3. Clevers H
    : Disease modeling in stem cell-derived 3D organoid systems. Trends Mol Med 23: 393-410, 2017.
    OpenUrl
  80. ↵
    1. Lee DF,
    2. Su J,
    3. Kim HS,
    4. Chang B,
    5. Papatsenko D,
    6. Zhao R,
    7. Yuan Y,
    8. Gingold J,
    9. Xia W,
    10. Darr H,
    11. Mirzayans R,
    12. Hung MC,
    13. Schaniel C,
    14. Lemischka IR
    : Modeling familial cancer with induced pluripotent stem cells. Cell 161: 240-254, 2015.
    OpenUrlCrossRefPubMed
  81. ↵
    1. Kuo KK,
    2. Lee KT,
    3. Chen KK,
    4. Yang YH,
    5. Lin YC,
    6. Tsai MH,
    7. Wuputra K,
    8. Lee YL,
    9. Ku CC,
    10. Miyoshi H,
    11. Nakamura Y,
    12. Saito S,
    13. Wu CC,
    14. Chai CY,
    15. Eckner R,
    16. Steve Lin CL,
    17. Wang SS,
    18. Wu DC,
    19. Lin CS,
    20. Yokoyama KK
    : Positive feedback loop of OCT4 and c-JUN expedites cancer stemness in liver cancer. Stem Cells 34: 2613-2624, 2016.
    OpenUrl
  82. ↵
    1. Bernhardt M,
    2. Novak D,
    3. Assenov Y,
    4. Orouji E,
    5. Knappe N,
    6. Weina K,
    7. Reith M,
    8. Larribere L,
    9. Gebhardt C,
    10. Plass C,
    11. Umansky V,
    12. Utikal J
    : Melanoma-derived iPCCs show differential tumorigenicity and therapy response. Stem Cell Rep 8: 1379-1391, 2017.
    OpenUrl
  83. ↵
    1. Nagai K,
    2. Ishii H,
    3. Miyoshi N,
    4. Hoshino H,
    5. Saito T,
    6. Sato T,
    7. Tomimaru Y,
    8. Kobayashi S,
    9. Nagano H,
    10. Sekimoto M,
    11. Doki Y,
    12. Mori M
    : Long-term culture following ES-like gene-induced reprogramming elicits an aggressive phenotype in mutated cholangiocellular carcinoma cells. Biochem Biophys Res Commun 395: 258-263, 2010.
    OpenUrlPubMed
    1. Komura S,
    2. Semi K,
    3. Itakura F,
    4. Shibata H,
    5. Ohno T,
    6. Hotta A,
    7. Woltjen K,
    8. Yamamoto T,
    9. Akiyama H,
    10. Yamada Y
    : An EWS-FLI1-induced osteosarcoma model unveiled a crucial role of impaired osteogenic differentiation on osteosarcoma development. Stem Cell Rep 6: 592-606, 2016.
    OpenUrl
  85. ↵
    1. Chiou SS,
    2. Wang SS,
    3. Wu DC,
    4. Lin YC,
    5. Kao LP,
    6. Kuo KK,
    7. Wu CC,
    8. Chai CY,
    9. Lin CL,
    10. Lee CY,
    11. Liao YM,
    12. Wuputra K,
    13. Yang YH,
    14. Wang SW,
    15. Ku CC,
    16. Nakamura Y,
    17. Saito S,
    18. Hasegawa H,
    19. Yamaguchi N,
    20. Miyoshi H,
    21. Lin CS,
    22. Eckner R,
    23. Yokoyama KK
    : Control of oxidative stress and generation of induced pluripotent stem cell-like cells by JUN dimerization protein 2. Cancers 5: 959-984, 2013.
    OpenUrl
  86. ↵
    1. Hoshino H,
    2. Nagano H,
    3. Haraguchi N,
    4. Nishikawa S,
    5. Tomokuni A,
    6. Kano Y,
    7. Fukusumi T,
    8. Saito T,
    9. Ozaki M,
    10. Sakai D,
    11. Satoh T,
    12. Eguchi H,
    13. Sekimoto M,
    14. Doki Y,
    15. Mori M,
    16. Ishii H
    : Hypoxia and TP53 deficiency for induced pluripotent stem cell-like properties in gastrointestinal cancer. Int J Oncol 40: 1423-1430, 2012.
    OpenUrlPubMed
  87. ↵
    1. Izgi K,
    2. Canatan H,
    3. Iskender B
    : Current status in cancer cell reprogramming and its clinical implications. J Cancer Res Clin Oncol 143: 371-383, 2017.
    OpenUrl
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Application of Cancer Cell Reprogramming Technology to Human Cancer Research
XIU-YANG PAN, MING-HO TSAI, KENLY WUPUTRA, CHIA-CHEN KU, WEN-HSIN LIN, YING-CHU LIN, SHOTARO KISHIKAWA, MICHIYA NOGUCHI, SHIGEO SAITO, CHANG-SHEN LIN, KAZUNARI K. YOKOYAMA
Anticancer Research Jul 2017, 37 (7) 3367-3377;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section

Keywords