title: Increased dosage of tumor suppressors limits the tumorigenicity of iPS cells without affecting their pluripotency.
abstract: Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent a promising therapeutic tool for many diseases, including aged tissues and organs at high risk of failure. However, the intrinsic self-renewal and pluripotency of ES and iPS cells make them tumorigenic, and hence, the risk of tumor development hinders their clinical application. Here, we present a novel approach to limit their tumorigenicity and increase their safety through increased copy number of tumor suppressors. iPS containing an extra copy of the p53 or Ink4a/ARF locus show normal pluripotency, as determined by in vitro and in vivo differentiation assays. Yet, while retaining full pluripotency, they also possess an improved engagement of the p53 pathway during teratocarcinoma formation, which leads to a reduced tumorigenic potential in various in vitro and in vivo assays. Furthermore, they show an improved response to anticancer drugs, which could aid in their elimination in case tumors arise with no adverse effects on cell function or aging. Our system provides a model for studying tumor suppressor pathways during reprogramming, differentiation, and cell therapy applications. This offers an improved understanding of the pathways involved in tumor growth from engrafted pluripotent stem cells, which could facilitate the use of ES and iPS cells in regenerative medicine.
authors: Center for Regenerative Medicine in Barcelona, Spain.
authors: Sergio
authors: S
authors: Menendez
authors: Suzanne
authors: S
authors: Camus
authors: Aida
authors: A
authors: Herreria
authors: Ida
authors: I
authors: Paramonov
authors: Laura B
authors: LB
authors: Morera
authors: Manuel
authors: M
authors: Collado
authors: Vlad
authors: V
authors: Pekarik
authors: Iago
authors: I
authors: Maceda
authors: Michael
authors: M
authors: Edel
authors: Antonella
authors: A
authors: Consiglio
authors: Adriana
authors: A
authors: Sanchez
authors: Han
authors: H
authors: Li
authors: Manuel
authors: M
authors: Serrano
authors: Juan C I
authors: JC
authors: Belmonte
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D054278:Embryonal Carcinoma Stem Cells / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018628:Gene Dosage; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53