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

Our plain-English summary of Clinico-pathological features and somatic gene alterations in refractory ceramic fibre-induced murine mesothelioma reveal mineral fibre-induced mesothelioma identities, by P. Andujar, C. Lecomte, A. Renier, et al (Carcinogenesis, 2007).

The study

• Authors: P. Andujar, C. Lecomte, A. Renier, J. Fleury-Feith, L. Kheuang, J. Daubriac, A. Janin, M.C. Jaurand
• Journal: Carcinogenesis
• Published: 2007;28(7):1599-605
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This was an animal experiment in mice bred to carry one disabled copy of the Nf2 gene. The authors injected 55 of these mice in the abdominal cavity with 3 milligrams of a refractory ceramic fibre sample called RCF1, given in two injections 2 months apart. Another 33 mice received saline. Median survival was 478 days in fibre-injected mice and 629 days in saline mice (P value 0.0012). Among mice examined microscopically (47 fibre-injected, 28 saline), peritoneal mesothelioma was found in 26 (55%) fibre-injected and 2 (7.1%) saline mice. The first appeared 223 days after injection in the fibre group. In 12 cell cultures grown from tumour fluid, all but 4 lacked the p15, p16 and p19 genes, 3 of 12 had Trp53 mutations, and 10 of 12 had lost the normal Nf2 copy. The other two made no Nf2 protein. The authors noted that the inherited Nf2 change probably added to tumour numbers. They concluded that the tumours resembled asbestos-induced mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: genetically modified mice injected in the abdominal cavity with ceramic fibres or saline, followed by examination of tumours and genetic analysis of tumour cell cultures
• Who was studied: Mice in the FVB/N background carrying one disabled copy of the Nf2 gene (Nf2+/-): 55 fibre-exposed and 33 saline controls. Of these, 47 exposed and 28 control mice were available for histological examination. Twelve tumour cell cultures were established from the exposed mice.
• Exposure: Refractory ceramic fibre sample RCF1 (supplied by the Thermal Insulation Manufacturer's Association), 3 mg given by intraperitoneal injection in two injections 2 months apart; controls received saline injections
• Main results:
  • Median survival was 478 days in fibre-exposed mice and 629 days in saline controls (P value 0.0012)
  • Peritoneal mesothelioma was found in 26 (55%) fibre-exposed mice, compared with 2 (7.1%) mesotheliomas in the saline control group
  • In fibre-exposed mice, the mesotheliomas were 7 epithelial, 10 fusiform and 9 biphasic
  • In the fibre-exposed group, the first mesothelioma was detected 223 days after injection; in controls, mesotheliomas were found at 450 and 676 days
  • In the fibre-exposed group, 91% of ascites (abdominal fluid build-ups) were associated with mesothelioma, and 80.8% of mesotheliomas were associated with ascites
  • Of the 12 tumour cell cultures from fibre-exposed mice, only 4 (145, 146, 186 and 255) showed normal p15/Cdkn2b, p16/Cdkn2a and p19/Arf genes; the rest showed deletion
  • Trp53 mutations were found in 3 of 12 cell cultures (25%)
  • Loss of the normal Nf2 copy was found in 10 of 12 cultures (printed as 83.5%); the remaining two cultures (178 and 201) showed no Nf2 protein expression
• The authors' conclusion: The authors concluded that the clinical, pathological and molecular features of the tumours induced by RCF1 in these mice were consistent with mesothelioma and similar to those seen in asbestos-induced mesothelioma. They suggested that Nf2 mutation is complementary to Ink4 or Trp53 mutation.
• Limitations the authors state:
  • The authors stated that the inherited Nf2 genetic modification probably contributes to the incidence of mesotheliomas. The percentage was lower (42.5%, 47 mice) in RCF-exposed normal (wild-type) mice, data the authors did not show in detail.
  • The distribution of mesothelioma subtypes in these mice differed from that in human mesothelioma
  • An attempt to confirm the Nf2 results by microdissection of tissue sections did not give sound data, because of normal cells and limited material

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Asbestos Exposure, Carcinogenic, Pleura, Ascites, Mesothelial Cells.

Related studies

• Similar tumor suppressor gene alteration profiles in asbestos-induced murine and human mesothelioma — C. Lecomte, P. Andujar, et al. (2005)
• Exposure to refractory ceramic fibres in the metal industry — M. Linnainmaa, J. Kangas, et al. (2007)
• Mechanism of refractory ceramic fiber- and rock wool-induced cytotoxicity in alveolar macrophages — K.A. Kim, W.K. Lee, et al. (2001)
• Co-exposure to refractory ceramic fibres and asbestos and risk of pleural mesothelioma — A. Lacourt, M. Rinaldo, et al. (2014)
• Health effects of refractory ceramic fibres: scientific issues and policy considerations — L.R. Glass, R.C. Brown, et al. (1995)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)

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