Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

Our plain-English summary of Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours, by J. Fleury-Feith, C. Lecomte, A. Renier, et al (Oncogene, 2003).

The study

• Authors: J. Fleury-Feith, C. Lecomte, A. Renier, M. Matrat, L. Kheuang, V. Abramowski, F. Levy, A. Janin, M. Giovannini, M.C. Jaurand
• Journal: Oncogene
• Published: 2003;22(24):3799-805
• Cited by: 73 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Biallelic NF2 gene inactivation is frequently found in human malignant mesothelioma. In order to assess whether NF2 hemizygosity may enhance susceptibility to asbestos fibres, we investigated the Nf2 status in mesothelioma developed in mice presenting a heterozygous mutation of the Nf2 gene (Nf2(KO3/+)), after intraperitoneal inoculation of crocidolite fibres. Asbestos-exposed Nf2(KO3/+) mice developed tumoural ascites and mesothelioma at a higher frequency than their wild-type (WT) counterparts (P&<0.05). Six out of seven mesothelioma cell lines established from neoplastic ascitic fluids of Nf2(KO3/+) mice exhibited loss of the WT Nf2 allele and no neurofibromatosis type 2 protein expression was found in these cells. The results show the importance of the NF2 gene in mesothelial oncogenesis, the potential association of asbestos exposure and tumour suppressor gene inactivation, and suggest that NF2 gene mutation may be a susceptibility factor to asbestos.

In plain English

In this animal experiment, the authors injected crocidolite asbestos fibres into the abdominal cavity of normal (wild-type) mice and of mice carrying one faulty copy of the Nf2 gene (Nf2KO3/+). 44 wild-type and 55 Nf2 mutant mice received 5 mg of crocidolite; 16 wild-type and 25 Nf2 mutant mice received salt water as controls. Asbestos shortened survival in both types of mice; no statistically significant survival difference was found between the two types. Tumours of the peritoneal wall appeared only in asbestos-exposed mice and were more frequent in Nf2 mutant than wild-type mice (p less than or equal to 0.05). Of 23 malignant mesotheliomas, three were in wild-type and 20 in Nf2 mutant mice. Among exposed mice examined microscopically (18 wild-type, 43 Nf2 mutant), about 90% of each type had diffuse fibrosis. Abdominal fluid (ascites) was more frequent in exposed Nf2 mutant mice (p less than 0.006). In six of seven tumour cell lines grown from this fluid in Nf2 mutant mice, the normal Nf2 copy was lost. The authors concluded this confirms a role for Nf2 in mesothelial tumours. They cautioned that cell lines may not represent the tumour.

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: intraperitoneal injection of crocidolite in heterozygous Nf2 mutant and wild-type mice, with saline controls, followed by pathology and genetic analysis of tumour cell lines
• Who was studied: Wild-type FVB/N mice and Nf2KO3/+ mice on the FVB/N background, aged 2 to 3 months at exposure. 44 wild-type and 55 Nf2 mutant mice were exposed to asbestos; 16 wild-type and 25 Nf2 mutant mice were saline controls. Histology was done on 18 wild-type and 43 Nf2 mutant crocidolite-treated mice.
• Exposure: 5 mg of crocidolite fibres suspended in saline, injected into the abdominal cavity (intraperitoneal), with a first and second injection over a lag time of 2 months; controls received saline
• Main results:
  • In both wild-type and Nf2 mutant mice, survival was significantly reduced in asbestos-exposed mice compared with saline-treated mice. Within each treatment group, no statistically significant difference in survival was found between the two types of mice.
  • Tumours of the peritoneal wall occurred only in crocidolite-treated mice. Nf2 mutant mice were more susceptible to these tumours than wild-type mice (p less than or equal to 0.05).
  • There were 23 malignant mesotheliomas: three in wild-type mice and 20 in Nf2 mutant mice. Seven were epithelial, one biphasic and 15 had a fusiform pattern.
  • Among crocidolite-treated mice studied by histology (18 wild-type, 43 Nf2 mutant), diffuse fibrosis was found in about 90% of either type.
  • Ascites occurred in crocidolite-exposed mice (eight wild-type, 35 Nf2 mutant), with a greater incidence in Nf2 mutant mice (p less than 0.006).
  • In cell lines grown from ascites of Nf2 mutant mice, the normal (wild-type) Nf2 copy was lost in six of seven cell lines (85.7%). Nf2 protein was still produced only in one of these cell lines (905).
  • Non-peritoneal tumours occurred at the same frequency in wild-type and Nf2 mutant mice, in both controls and crocidolite-treated mice.
• The authors' conclusion: The authors concluded that loss of the normal Nf2 copy in tumour cells from the ascites confirms a role for Nf2 in mesothelial cell tumours. They also concluded that it supports the relevance of this mouse model to human mesothelioma. They suggested that asbestos fibres might play a role in inactivating both copies of the gene.
• Limitations the authors state:
  • Gene changes in cell lines should be interpreted with caution, because the cells may have an unknown selection advantage in culture and may not represent the tumour.
  • Intraperitoneal injection was used instead of inhalation, which is more physiological, because inhalation produces a very low yield of pleural tumours in rodents.
  • Unlike human mesothelioma, the fusiform tumour pattern was more frequent in these mice.
  • Bone tumour development was not scored.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Mesothelioma, Crocidolite, Ascites, Oncogenesis, Asbestos Exposure.

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