title: Induction of cells with cancer stem cell properties from nontumorigenic human mammary epithelial cells by defined reprogramming factors.
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(+)/CD24(low) 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.
authors: Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.
authors: M
authors: M
authors: Nishi
authors: Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.
authors: Y
authors: Y
authors: Sakai
authors: Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: H
authors: H
authors: Akutsu
authors: Department of Molecular Pathology, Yokohama City University School of Medicine, Yokohama, Japan.
authors: Y
authors: Y
authors: Nagashima
authors: Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.
authors: G
authors: G
authors: Quinn
authors: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
authors: S
authors: S
authors: Masui
authors: Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan.
authors: H
authors: H
authors: Kimura
authors: The Commonwealth Scientific and Industrial Research Organisation (CSIRO), Dickson, Australian Capital Territory, Australia.
authors: K
authors: K
authors: Perrem
authors: Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors: A
authors: A
authors: Umezawa
authors: Department of Microbiology, National University of Singapore, Singapore.
authors: N
authors: N
authors: Yamamoto
authors: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors: S W
authors: SW
authors: Lee
authors: Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.
authors: A
authors: A
authors: Ryo
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D051927:CD24 Antigen / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009285:Naphthoquinones / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000166:cytology*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D051927:CD24 Antigen; D019941:Cyclin-Dependent Kinase Inhibitor p16; D003609:Dactinomycin; D018960:Hyaluronan Receptors; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009285:Naphthoquinones; D050814:Octamer Transcription Factor-3; D017239:Paclitaxel; D016271:Proto-Oncogene Proteins c-myc; D011714:Pyrans; D055748:SOXB1 Transcription Factors; C417743:Cdkn2a protein, mouse; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C489427:MYC protein, human; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; C010327:salinomycin; D000095662:Polyether Polyketides; C005134:juglone