Animal models of malignant mesothelioma

Our plain-English summary of Animal models of malignant mesothelioma, by A.B. Kane (Inhalation Toxicology, 2006).

The study

• Author: A.B. Kane
• Journal: Inhalation Toxicology
• Published: 2006;18(12):1001-4
• Type of article: Review
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Animal models of diffuse malignant mesothelioma have historically been used to assess carcinogenicity of various fiber types and to study the pathogenesis of this unusual neoplasm. Pleural and peritoneal mesotheliomas have been induced in rodents following exposure to erionite or asbestos fibers, radionuclides, particulate nickel compounds, and chemicals such as 3-methylcholanthrene. The role of SV40 virus as a cofactor with asbestos fibers in the development of diffuse malignant mesotheliomas in humans has been explored in animal models. SV40 virus alone induces mesotheliomas in hamsters. Generation of new transgenic mouse strains with targeted expression of SV40 large T and small t antigens in the mesothelium would be very useful for mechanistic studies. Human malignant mesotheliomas frequently show hypermethylation or deletions at the Cdkn2a/Arf and Cdkn2b gene loci and deletions or mutations at the NF2 gene locus. Heterozygous Nf2 (+/-) mice exposed to crocidolite asbestos fibers exhibited accelerated development of malignant mesotheliomas compared to wild-type littermates. Loss of the wild-type Nf2 allele, leading to biallelic inactivation, was observed in nine mesothelioma cell lines derived from Nf2 (+/-) mice. Similar to human malignant mesotheliomas, tumors from Nf2 (+/-) mice showed frequent homozygous deletions of the Cdkn2a/Arf locus and adjacent Cdkn2b tumor suppressor gene. As in the human disease, murine mesotheliomas also showed constitutive activation of Akt. This murine model of asbestos carcinogenesis recapitulates the molecular and histopathological features of the human disease and has significant implications for preclinical testing of novel preventive or therapeutic modalities.

In plain English

This article was a short review by the author of rodent models of malignant mesothelioma, focusing on genetically engineered mice. It reported no new experiment of its own. The review noted that rare spontaneous mesotheliomas occur in older male Fischer 344 rats, but none have been described in hamsters or mice. It listed fibers (including asbestos and erionite), chemicals, metals and SV40 virus that induce mesotheliomas in rodents. It described an earlier SV40 transgenic mouse strain in which 21–25% of mice developed adrenal, prostate and peritoneal tumors; these mice could not reproduce. Citing earlier studies, it reported that mice missing one copy of the Nf2 gene and exposed to crocidolite asbestos developed peritoneal mesotheliomas that grew and invaded faster. In these mice, 67% of the tumors also showed codeletion of p16(Ink4a) and p19(arf), and the tumors showed constant activation of the Akt pathway, as in human disease. The author concluded that this mouse model reproduces features of human diffuse malignant mesothelioma and is a valuable tool for developing prevention and treatment strategies. The author also noted that mice are not perfect models for humans.

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: narrative review of rodent (mainly genetically engineered mouse) models of malignant mesothelioma; no new data
• Who was studied: rodent models described in earlier studies: rats, hamsters and mice, including genetically engineered mice (Nf2-heterozygous, p53-heterozygous, SV40 T-antigen transgenic)
• Exposure: mainly crocidolite asbestos in Nf2-heterozygous mice; the review also lists other agents that induce mesothelioma in rodents, including asbestos, erionite, synthetic vitreous fibers, silicon carbide, chemicals, radionuclides, particulate nickel and SV40 virus
• Main results:
  • Rare spontaneous mesotheliomas develop in older male Fischer 344 rats and some other rat strains; none have been described in hamsters or mice
  • Mesotheliomas have been produced in hamsters by inoculation with SV40 virus (cited earlier work); the role of SV40 as a cofactor with asbestos in humans was described as controversial
  • In an earlier transgenic mouse strain expressing SV40 T-antigen (Grippo and Sandgren, 2000), 100% developed bladder tumors at 11–14 weeks and 21–25% developed tumors of the adrenal gland, prostate and peritoneum; these mice could not reproduce
  • Heterozygous p53-deficient mice showed accelerated development and progression of asbestos-induced peritoneal malignant mesothelioma (cited study, Vaslet et al., 2002)
  • In heterozygous Nf2-deficient mice exposed to asbestos, tumor growth and invasion were accelerated, and a majority of cell lines from these mice showed loss of the wild-type Nf2 allele (cited earlier studies)
  • Asbestos-induced peritoneal mesotheliomas in these mice showed lymphatic metastases and extensive invasion, resembling the clinical presentation of human diffuse malignant mesothelioma
  • In heterozygous Nf2-deficient mice, 67% of the mesotheliomas showed codeletion of p16(Ink4a) and p19(arf)
  • The mouse mesotheliomas showed constitutive activation of the Akt pathway, as in human mesotheliomas
• The authors' conclusion: The author concluded that the asbestos-exposed Nf2-heterozygous mouse model reproduces the molecular and histopathological features of human diffuse malignant mesothelioma and is a valuable tool for developing new chemopreventive and chemotherapeutic strategies
• Limitations the authors state:
  • Mice are not perfect models for humans: they have a higher basal metabolic rate and use different pathways to activate or detoxify carcinogens
  • Mice deficient in common tumor suppressor genes often develop a different range of tumors than humans; Nf2-deficient mice do not fully reproduce the human syndrome

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Neoplasm, Peritoneal Mesothelioma, erionite, SV40, Mesothelioma, Mesothelium, CDKN2A.

Related studies

• The role of SV40 in malignant mesothelioma and other human malignancies — M.A. Pershouse, S. Heivly, et al. (2006)
• The use of animal models for studies on asbestos bioeffects — J.M. Davis (1979)
• Early animal research on asbestos cancer — P.E. Enterline (1993)
• Effect of NSAIDS and COX-2 inhibitors on the incidence and severity of asbestos-induced malignant mesothelioma: evidence from an animal model and a human cohort — C. Robinson, H. Alfonso, et al. (2014)
• Histogenesis and fine structure of peritoneal tumors produced in animals by injections of asbestos — J.M. Davis (1974)
• Carcinoma induction by 3-methylcholanthrene in hamster tracheal tissue implanted in syngeneic animals — J.E. Craighead, B.T. Mossman (1979)

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