title: Characterization of preneoplastic and neoplastic rat mesothelial cell lines: the involvement of TETs, DNMTs, and 5-hydroxymethylcytosine.
abstract: Malignant mesothelioma (MM) is one of the worst cancers in terms of clinical outcome, urging the need to establish and characterize new preclinical tools for investigation of the tumorigenic process, improvement of early diagnosis and evaluation of new therapeutic strategies. For these purposes, we characterized a collection of 27 cell lines established from F344 rats, after 136 to 415 days of induction with crocidolite asbestos administered intraperitoneally. Four mesotheliomas were distinguished from 23 preneoplastic mesothelial cell lines (PN) according to their propensity to generate tumors after orthotopic transplantation into syngeneic rats, their growth pattern, and the expression profile of three genes. PN cell lines were further discriminated into groups / subgroups according to morphology in culture and the expression profiles of 14 additional genes. This approach was completed by analysis of positive and negative immunohistochemical MM markers in the four tumors, of karyotype alterations in the most aggressive MM cell line in comparison with a PN epithelioid cell line, and of human normal mesothelial and mesothelioma cells and a tissue array. Our results showed that both the rat and human MM cell lines shared in common a dramatic decrease in the relative expression of Cdkn2a and of epigenetic regulators, in comparison with PN and normal human mesothelial cells, respectively. In particular, we identified the involvement of the relative expression of the Ten-Eleven Translocation (TET) family of dioxygenases and Dnmt3a in relation to the 5-hydroxymethylcytosine level in malignant transformation and the acquisition of metastatic potential.
authors.affiliation: CRCNA, Université d'Angers, Université de Nantes, Nantes, France.|INSERM, Université d'Angers, Université de Nantes, Nantes, France.|CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: David
authors.initials: D
authors.lastname: Roulois
authors.affiliation: CRCNA, Université d'Angers, Université de Nantes, Nantes, France.|INSERM, Université d'Angers, Université de Nantes, Nantes, France.|CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Deshayes
authors.affiliation: CEA, DSV, iRCM, LCE, BP6, Fontenay aux Roses cedex, France.
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Guilly
authors.affiliation: CRCNA, Université d'Angers, Université de Nantes, Nantes, France.|INSERM, Université d'Angers, Université de Nantes, Nantes, France.|CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: Joëlle S
authors.initials: JS
authors.lastname: Nader
authors.affiliation: CRCNA, Université d'Angers, Université de Nantes, Nantes, France.|INSERM, Université d'Angers, Université de Nantes, Nantes, France.|CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: Charly
authors.initials: C
authors.lastname: Liddell
authors.affiliation: INSERM, Université d'Angers, Université de Nantes, Nantes, France.|Cellular and Tissular Imaging Core Facility (MicroPICell), Nantes, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Robard
authors.affiliation: INSERM, Université d'Angers, Université de Nantes, Nantes, France.|Cellular and Tissular Imaging Core Facility (MicroPICell), Nantes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hulin
authors.affiliation: CRCNA, Université d'Angers, Université de Nantes, Nantes, France.|INSERM, Université d'Angers, Université de Nantes, Nantes, France.|CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: Amal
authors.initials: A
authors.lastname: Ouacher
authors.affiliation: CRCNA, Université d'Angers, Université de Nantes, Nantes, France.|INSERM, Université d'Angers, Université de Nantes, Nantes, France.|CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Le Martelot
authors.affiliation: CRCNA, Université d'Angers, Université de Nantes, Nantes, France.|INSERM, Université d'Angers, Université de Nantes, Nantes, France.|CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fonteneau
authors.affiliation: CRCNA, Université d'Angers, Université de Nantes, Nantes, France.|INSERM, Université d'Angers, Université de Nantes, Nantes, France.|CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Grégoire
authors.affiliation: CRCNA, Université d'Angers, Université de Nantes, Nantes, France.|INSERM, Université d'Angers, Université de Nantes, Nantes, France.|CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Blanquart
authors.affiliation: CRCNA, Université d'Angers, Université de Nantes, Nantes, France.|INSERM, Université d'Angers, Université de Nantes, Nantes, France.|CNRS, Université d'Angers, Université de Nantes, Nantes, France.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Pouliquen
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D017638:Asbestos, Crocidolite / Q000633:toxicity; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D000090205:DNA Methyltransferase 3A; D004847:Epithelial Cells / Q000473:pathology; D004848:Epithelium / Q000473:pathology; D006801:Humans; D059785:Karyotype; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology*; D008654:Mesothelioma / Q000139:chemically induced / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011230:Precancerous Conditions / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D017638:Asbestos, Crocidolite; D044503:5-Methylcytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: DNMTs; TETs; mesothelioma; preneoplastic mesothelial cells; rat