Characterization of preneoplastic and neoplastic rat mesothelial cell lines: the involvement of TETs, DNMTs, and 5-hydroxymethylcytosine
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David Roulois1,2,3, Sophie Deshayes1,2,3, Marie-Noëlle Guilly4, Joëlle S. Nader1,2,3, Charly Liddell1,2,3, Myriam Robard2,5, Philippe Hulin2,5, Amal Ouacher1,2,3, Vanessa Le Martelot1,2,3, Jean-François Fonteneau1,2,3, Marc Grégoire1,2,3, Christophe Blanquart1,2,3,*, Daniel L. Pouliquen1,2,3,*
1CRCNA, Université d’Angers, Université de Nantes, Nantes, France
2INSERM, Université d’Angers, Université de Nantes, Nantes, France
3CNRS, Université d’Angers, Université de Nantes, Nantes, France
4CEA, DSV, iRCM, LCE, BP6, Fontenay aux Roses cedex, France
5Cellular and Tissular Imaging Core Facility (MicroPICell), Nantes, France
*These authors contributed equally to this work
Daniel L. Pouliquen, e-mail: [email protected]
Keywords: mesothelioma, preneoplastic mesothelial cells, rat, TETs, DNMTs
Received: September 04, 2015 Accepted: April 10, 2016 Published: April 25, 2016
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.
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