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Although human malignant mesothelioma (HMM) is mainly caused by asbestos exposure, refractory ceramic fibres (RCFs) have been classified as possibly carcinogenic to humans 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 intra-peritoneal 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 p15 Ink4b , p16 Ink4a  and p19 Arf  or p53 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.

carcinogenesis

Clinico-pathological features and somatic gene alterations in refractory ceramic fibre-induced murine mesothelioma reveal mineral fibre-induced mesothelioma identities