title: The senescent microenvironment promotes the emergence of heterogeneous cancer stem-like cells.
abstract: There is a well-established association between aging and the onset of metastasis. Although the mechanisms through which age impinges upon the malignant phenotype remain uncharacterized, the role of a senescent microenvironment has been emphasized. We reported previously that human epithelial cells that undergo telomere-driven chromosome instability (T-CIN) display global microRNA (miR) deregulation and develop migration and invasion capacities. Here, we show that post-crisis cells are not able to form tumors unless a senescent microenvironment is provided. The characterization of cell lines established from such tumors revealed that these cells have acquired cell autonomous tumorigenicity, giving rise to heterogeneous tumors. Further experiments demonstrate that explanted cells, while displaying differences in cell differentiation markers, are all endowed of enhanced stem cell properties including self-renewal and multilineage differentiation capacity. Treatments of T-CIN+ cells with senescence-conditioned media induce sphere formation exclusively in cells with senescence-associated tumorigenicity, a capacity that depends on miR-145 repression. These results indicate that the senescent microenvironment, while promoting further transdifferentiations in cells with genome instability, is able to propel the progression of premalignant cells towards a malignant, cell stem-like state.
authors.affiliation: UMR3244, Telomeres and Cancer Laboratory, "Labellisé Ligue", Institut Curie, Paris 75248, France, UPMC University, Paris 75005, France.
authors.forename: Luis Jaime
authors.initials: LJ
authors.lastname: Castro-Vega
authors.affiliation: UMR3244, Telomeres and Cancer Laboratory, "Labellisé Ligue", Institut Curie, Paris 75248, France, UPMC University, Paris 75005, France.
authors.forename: Karina
authors.initials: K
authors.lastname: Jouravleva
authors.affiliation: Cellular and Molecular Physiology Group, Instituto de Investigaciones Biomédicas, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá DC 111311, Colombia.
authors.forename: Paola
authors.initials: P
authors.lastname: Ortiz-Montero
authors.affiliation: UMR3244, Telomeres and Cancer Laboratory, "Labellisé Ligue", Institut Curie, Paris 75248, France, UPMC University, Paris 75005, France.
authors.forename: Win-Yan
authors.initials: WY
authors.lastname: Liu
authors.affiliation: Cellular and Molecular Physiology Group, Instituto de Investigaciones Biomédicas, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá DC 111311, Colombia.
authors.forename: Jorge Luis
authors.initials: JL
authors.lastname: Galeano
authors.affiliation: Department of Pathology, Hospital Universitario-Fundación Santa Fe de Bogotá, Bogotá 110111, Colombia.
authors.forename: Martha
authors.initials: M
authors.lastname: Romero
authors.affiliation: U830 Genetics and Cancer Biology, Institut Curie, Paris 75248, France and.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Popova
authors.affiliation: Department of Experimental Oncology, Istituto Regina Elena, Rome 00158, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bacchetti
authors.affiliation: Cellular and Molecular Physiology Group, Instituto de Investigaciones Biomédicas, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá DC 111311, Colombia.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Vernot
authors.affiliation: UMR3244, Telomeres and Cancer Laboratory, "Labellisé Ligue", Institut Curie, Paris 75248, France, UPMC University, Paris 75005, France, arturo.londono@curie.fr.
authors.forename: Arturo
authors.initials: A
authors.lastname: Londoño-Vallejo
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology*; D016615:Telomere / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D035683:MicroRNAs