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Induction of cells with cancer stem cell properties from nontumorigenic human mammary epithelial cells by defined reprogramming factors

Oncogene volume 33, pages 643–652 (2014)Cite this article

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Abstract

Cancer stem cells (CSCs), a small and elusive population of undifferentiated cancer cells within tumors that drive tumor growth and recurrence, are believed to resemble normal stem cells. Although surrogate markers have been identified and compelling CSC theoretical models abound, actual proof for the existence of CSCs can only be had retrospectively. Hence, great store has come to be placed in isolating CSCs from cancers for in-depth analysis. On the other hand, although induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine, concern exists over the inadvertent co-transplantation of partially or undifferentiated stem cells with tumorigenic capacity. Here we demonstrate that the introduction of defined reprogramming factors (OCT4, SOX2, Klf4 and c-Myc) into MCF-10A nontumorigenic mammary epithelial cells, followed by partial differentiation, transforms the bulk of cells into tumorigenic CD44+/CD24low cells with CSC properties, termed here as induced CSC-like-10A or iCSCL-10A cells. These reprogrammed cells display a malignant phenotype in culture and form tumors of multiple lineages when injected into immunocompromised mice. Compared with other transformed cell lines, cultured iCSCL-10A cells exhibit increased resistance to the chemotherapeutic compounds, Taxol and Actinomycin D, but higher susceptibility to the CSC-selective agent Salinomycin and the Pin1 inhibitor Juglone. Restored expression of the cyclin-dependent kinase inhibitor p16INK4a abrogated the CSC properties of iCSCL-10A cells, by inducing cellular senescence. This study provides some insight into the potential oncogenicity that may arise via cellular reprogramming, and could represent a valuable in vitro model for studying the phenotypic traits of CSCs per se.

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Article 01 December 2022

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Acknowledgements

We thank A Kondo, T Taniguchi, Y Kojima, Y Watanabe, M Tanaka and N Sakurai for technical assistance and discussion. This work was in part supported by Grant-in-Aid for Scientific Research on Innovative Areas and the Japan Health Sciences Foundation, and grants from the Uehara Memorial Foundation and Takeda Science Foundation to AR.

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Authors and Affiliations

  1. Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan

    M Nishi, Y Sakai, G Quinn & A Ryo

  2. Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan

    H Akutsu & A Umezawa

  3. Department of Molecular Pathology, Yokohama City University School of Medicine, Yokohama, Japan

    Y Nagashima

  4. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan

    S Masui

  5. Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan

    H Kimura

  6. The Commonwealth Scientific and Industrial Research Organisation (CSIRO), Dickson, Australian Capital Territory, Australia

    K Perrem

  7. Department of Microbiology, National University of Singapore, Singapore

    N Yamamoto

  8. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    S W Lee

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Correspondence to A Ryo.

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Nishi, M., Sakai, Y., Akutsu, H. et al. Induction of cells with cancer stem cell properties from nontumorigenic human mammary epithelial cells by defined reprogramming factors. Oncogene 33, 643–652 (2014). https://doi.org/10.1038/onc.2012.614

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