A mouse model recapitulating molecular features of human mesothelioma

Our plain-English summary of A mouse model recapitulating molecular features of human mesothelioma, by D.A. Altomare, C.A. Vaslet, K.L. Skele, et al (Cancer Research, 2005).

The study

• Authors: D.A. Altomare, C.A. Vaslet, K.L. Skele, A. De Rienzo, K. Devarajan, S.C. Jhanwar, A.I. McClatchey, A.B. Kane, J.R. Testa
• Journal: Cancer Research
• Published: 2005;65(18):8090-5
• Cited by: 114 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma has been linked to asbestos exposure and generally has a poor prognosis because it is often diagnosed in advanced stages and is refractory to conventional therapy. Human malignant mesotheliomas accumulate multiple somatic genetic alterations, including inactivation of the NF2 and CDKN2A/ARF tumor suppressor genes. To better understand the significance of NF2 inactivation in malignant mesothelioma and identify tumor suppressor gene alterations that cooperate with NF2 loss of function in malignant mesothelioma pathogenesis, we treated Nf2 (+/-) knockout mice with asbestos to induce malignant mesotheliomas. Asbestos-exposed Nf2 (+/-) mice exhibited markedly accelerated malignant mesothelioma tumor formation compared with asbestos-treated wild-type (WT) littermates. Loss of the WT Nf2 allele, leading to biallelic inactivation, was observed in all nine asbestos-induced malignant mesotheliomas from Nf2 (+/-) mice and in 50% of malignant mesotheliomas from asbestos-exposed WT mice. For a detailed comparison with the murine model, DNA analyses were also done on a series of human malignant mesothelioma samples. Remarkably, similar to human malignant mesotheliomas, tumors from Nf2 (+/-) mice showed frequent homologous deletions of the Cdkn2a/Arf locus and adjacent Cdkn2b tumor suppressor gene, as well as reciprocal inactivation of Tp53 in a subset of tumors that retained the Arf locus. As in the human disease counterpart, malignant mesotheliomas from the Nf2 (+/-) mice also showed frequent activation of Akt kinase, which plays a central role in tumorigenesis and therapeutic resistance. Thus, this murine model of environmental carcinogenesis faithfully recapitulates many of the molecular features of human malignant mesothelioma and has significant implications for the further characterization of malignant mesothelioma pathogenesis and preclinical testing of novel therapeutic modalities.

In plain English

In this experiment, the authors injected male mice carrying one disabled copy of the Nf2 tumor suppressor gene, and normal littermates, with crocidolite asbestos into the abdominal cavity eight times (3.2 mg per mouse in total). Control mice received titanium dioxide particles. None of the titanium dioxide-treated mice developed malignant mesothelioma. Asbestos-treated Nf2-deficient mice developed mesothelioma faster and had significantly shorter survival than asbestos-treated normal mice, with four times the odds of getting mesothelioma. All nine tumors tested from Nf2-deficient mice had lost their remaining normal Nf2 copy. In 4 of 8 tumors from normal mice, both Nf2 copies were inactivated. Among tumors from Nf2-deficient mice, 6 of 9 had lost the p16(Ink4a) and p19(Arf) genes, 4 of 9 had lost Tp53 expression, and all nine showed strong Akt activation. The authors also tested human mesothelioma cell lines: 36 of 40 had both copies of part or all of p14(ARF) deleted, and 19 of 20 cases had an alteration in the p14(ARF)/p53 pathway. The authors concluded that the mouse model recapitulates many molecular features of human malignant 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 (asbestos injection in genetically modified and normal mice), with additional genetic analysis of human mesothelioma cell lines and tumor samples
• Who was studied: Male Nf2 (+/-) mice and normal (wild-type, WT) littermates on an inbred 129Sv/Jae background. 35 Nf2 (+/-) and 32 WT mice were given asbestos, and 14 Nf2 (+/-) and 15 WT mice were given titanium dioxide. 1 Nf2 (+/-) and 5 WT asbestos-treated mice could not be analyzed for cause of death. Human mesothelioma cell lines were also studied: 40 for deletion mapping, and 20 with matched tumor specimens for TP53.
• Exposure: UICC-grade crocidolite asbestos, 400 micrograms injected into the abdominal (peritoneal) cavity every 21 days for eight injections (3.2 mg per mouse in total). Controls received 320 micrograms of titanium dioxide particles on the same schedule.
• Main results:
  • None of the titanium dioxide-treated control mice developed malignant mesothelioma.
  • Mesothelioma formed markedly faster in asbestos-treated Nf2 (+/-) mice than in asbestos-treated WT littermates.
  • Nf2 (+/-) mice had significantly shorter survival times than WT mice (log-rank test).
  • Genotype was statistically significantly associated with mesothelioma incidence (two-sided P = 0.039). The odds of mesothelioma were four times as high in Nf2 (+/-) mice as in WT mice.
  • In Nf2 (+/-) mice, all nine mesothelioma cultures analyzed had lost the remaining WT Nf2 allele.
  • In WT mice, which began with two normal Nf2 copies, biallelic (both-copy) Nf2 inactivation was found in 4 of 8 (50%) mesotheliomas, shown by absence of the Nf2 protein, merlin.
  • p16(Ink4a) and p19(Arf) were deleted together in 6 of 9 (67%) mesotheliomas from Nf2 (+/-) mice.
  • Loss of Tp53 expression and p53 protein was found in 4 of 9 (44%) mesotheliomas from Nf2 (+/-) mice. Tp53 expression was lost in cultures that kept p19(Arf), and vice versa.
  • All nine tumors tested from asbestos-treated Nf2 (+/-) mice showed strong staining for activated (phospho-) Akt.
  • In human mesothelioma cell lines, homozygous (both-copy) deletions of part or all of p14(ARF) were found in 36 of 40 (90%).
  • In human mesothelioma, TP53 mutations were found in 3 of 20 (15%) cell lines, and 19 of 20 cases had an alteration affecting the p14(ARF)/p53 pathway.
• The authors' conclusion: The authors concluded that this mouse model faithfully recapitulates many molecular features of human malignant mesothelioma and could be useful for designing new treatments.
• Limitations the authors state:
  • The authors did not do a detailed analysis of mesothelioma cell lines from asbestos-treated WT mice.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Asbestos Exposure, Prognosis, CDKN2A, Tumor Suppressor Gene, Tumorigenesis, Carcinogenesis.

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