Carcinogenesis Advance Access published online on February 1, 2007
Carcinogenesis, doi:10.1093/carcin/bgm023
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Clinico-pathological features and somatic gene alterations in refractory ceramic fibre-induced murine mesothelioma reveal mineral fibre-induced mesothelioma identities
1 INSERM, E0337, IMRB, Créteil, F-94000, France
2 Université Paris 12, Faculté de Médecine, IFR10, Créteil, F-94000, France
3 INSERM, U674, Fondation Jean Dausset – CEPH, IFR105, Paris, F-75010, France
4 Present address: Université du Havre, UFR de Sciences et Techniques, UPRES-EA3222, Laboratoire d'Ecotoxicologie, Le Havre, F-76000, France
5 Université Paris 7, Paris, F-75005, France
6 AP-HP, GHU Est, Hôpital Tenon, Laboratoire d'Histologie et de Biologie Tumorale, Paris, F-75020, France
7 Université Paris 6, UFR Pierre et Marie Curie, Paris, F-75012, France
8 INSERM, U728, Paris, F-75010, France
9 AP-HP, GHU Nord, Hôpital Saint-Louis, Laboratoire de Pathologie, Paris, F-75010, France
Corresponding author: M.C. JAURAND, INSERM U674, IFR105 – CEPH – IUH, 27 Rue Juliette Dodu, 75010 Paris – France, Tel: + 33 1 53 72 51 88 – Fax: + 33 1 53 72 51 92, e-mail: jaurand{at}cephb.fr
While human malignant mesothelioma (HMM) is mainly caused by asbestos exposure, refractory ceramic fibers (RCFs) have been classified as possibly carcinogenic to human on the basis of their biological effects in rodents' lung and pleura, and in cultured cells. Hence, further investigations are needed to clarify the mechanism of fibre-induced carcinogenicity and to prevent use of harmful particles. In a previous study mesotheliomas were found in hemizygous Nf2 (Nf2+/-) mice exposed to asbestos fibres, and showed similar alterations in genes at the Ink4 locus and in Trp53 as described in HMM. Here we found that Nf2+/- mice developed mesotheliomas after intraperitoneal inoculation of a RCF sample (RCF1). Clinical features in exposed mice were similar to those observed in HMM, showing association between ascite and mesothelioma. Early passages of 12 mesothelioma cell cultures from ascites developed in RCF1-exposed Nf2+/- mice demonstrated frequent inactivation by deletion of genes at the Ink4 locus, and low rate of Trp53 point and insertion mutations. Nf2 gene was inactivated in all cultures. In most cases, co-inactivation of genes at the Ink4 locus and Nf2 was found and, at a lower rate, of Trp53 and Nf2. These results are the first to identify mutations in RCF-induced mesothelioma. They suggest that Nf2 mutation is complementary of Ink4 or Trp53 mutations and show similar profile of gene alterations resulting from exposure to ceramic or asbestos fibres in Nf2+/- mice, also consistent with the one found in HMM. These somatic genetic changes define different pathways of mesothelial cell transformation.
Key Words: Ceramic fibres • Cell Cycle • INK4 • Knockout-mice • NF2 • Mesothelioma • p16 • p15 • p19 • p53 • Trp53 • Tumour suppressor genes