MexTAg mice exposed to asbestos develop cancer that faithfully replicates key features of the pathogenesis of human mesothelioma

Our plain-English summary of MexTAg mice exposed to asbestos develop cancer that faithfully replicates key features of the pathogenesis of human mesothelioma, by C. Robinson, A. Walsh, I. Larma, et al (European Journal of Cancer, 2011).

The study

• Authors: C. Robinson, A. Walsh, I. Larma, S. O'Halloran, A.K. Nowak, R.A. Lake
• Journal: European Journal of Cancer
• Published: 2011;47(1):151-61
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Animal models provide an important tool for investigating the biology of cancer and for testing the efficacy of novel treatments. Here we describe several aspects of the transgenic MexTAg mouse that develops asbestos-induced mesothelioma. Targeted expression of the TAg transgene causes mesothelioma to develop more rapidly after asbestos exposure in wild-type mice with 100% incidence compared to 30% incidence in wild-type mice. MexTAg mice do not develop spontaneous mesothelioma and exhibit a very low incidence of other tumours. Here we show that TAg does not affect the aggressiveness or rate of progression of the mesotheliomas, suggesting that the oncogene alters only the rate at which disease is initiated. The instillation of an alternative inflammatory agent, thioglycollate, did not induce mesotheliomas, demonstrating acute inflammation is not sufficient for tumour development in MexTAg mice. We found that neither the age of a mouse at the time of exposure nor its gender were prognostic factors. MexTAg mice with mesotheliomas respond to treatment with a cytotoxic drug in a similar way to that of patients with mesothelioma, demonstrating the validity of the model. We also show that long-term treatment with a COX-2 inhibitor prior to the development of disease does not have a survival benefit, suggesting that this is not a useful cancer prevention therapy for asbestos-exposed individuals. The model is robust and suitable for testing a wide variety of protocols and a range of translational studies.

Copyright © 2010 Elsevier Ltd. All rights reserved.

In plain English

This was a laboratory study in mice. It used MexTAg mice, genetically modified to carry a cancer-promoting gene in the cells lining the body cavities, and ordinary (wild-type) mice. Mice received two 3 mg injections of crocidolite asbestos into the abdominal cavity, one month apart. Mesothelioma developed in 100%, 93%, 78% and 69% of the four MexTAg lines, from most to fewest gene copies, compared with 27% of wild-type mice. No mouse injected with thioglycollate, a non-asbestos irritant, or salt solution had mesothelioma at 45 weeks. Age at exposure and sex did not significantly affect overall survival. In pooled data, older mice lived a shorter time after signs of disease appeared. Gemcitabine, a chemotherapy drug, increased median survival from 33 to 48 weeks. Celecoxib, an anti-inflammatory drug given in food, made no significant difference to overall survival (median 31 versus 28 weeks), but mice receiving it lived a shorter time after signs of disease appeared (2 versus 13 days). The authors concluded that the model is robust and relevant to human 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 in transgenic and wild-type mice
• Who was studied: Four lines of MexTAg transgenic mice (299h, 304i, 270i, 266s, carrying 100, 32, 15 and 1 copies of the transgene) and C57/Bl 6J wild-type mice, studied at the University of Western Australia. Group sizes varied by experiment: 10 to 15 mice per asbestos group, 5 to 7 per thioglycollate or PBS group, 10 per gemcitabine group and 30 per celecoxib group.
• Exposure: Crocidolite asbestos (IUCC reference sample of Wittenoom Gorge crocidolite), two intraperitoneal doses of 3 mg given one month apart. The comparison groups received thioglycollate (a non-carcinogenic irritant) or PBS. Treatments tested were gemcitabine and dietary celecoxib (a COX-2 inhibitor) at 1.5 g/kg of diet.
• Main results:
  • Mesothelioma incidence after asbestos was 100%, 93%, 78% and 69% in the MexTAg 299h, 304i, 270i and 266s lines respectively, compared with 27% in wild-type mice.
  • At 45 weeks, no thioglycollate-treated or PBS-treated mouse in any line had mesothelioma. Among asbestos-exposed mice at that point, 11/11 MexTAg 299h mice and 0/11 wild-type mice had mesothelioma.
  • TAg protein was not detected in MexTAg mouse tissues that had not been exposed to asbestos. It was highly expressed in exposed mesothelial and mesothelioma cells.
  • Both asbestos and thioglycollate caused an acute inflammatory cell response in the peritoneum. Only asbestos caused lasting changes, with more neutrophils still present at 4 weeks (p = 0.02).
  • Across all cases, time from first signs of disease to euthanasia was not significantly different among the four MexTAg lines and wild-type mice.
  • Among mesothelioma cases only, the three wild-type mice survived a mean of 134 days after first signs of disease. This was significantly longer than the mean of 73 days for MexTAg 299h mice (n = 11, p = 0.03).
  • In MexTAg 299h mice, age at asbestos exposure (6 weeks, 5 to 6 months, 8 to 11 months) did not significantly affect mesothelioma development or overall survival.
  • In pooled data from MexTAg 299h mice, older age at exposure was associated with a shorter time from diagnosis to euthanasia (r = minus 0.27, p = 0.014).
  • In MexTAg 299h mice (27 male, 45 female), overall survival (p = 0.67) and time from first signs to euthanasia (p = 0.65) did not differ between males and females.
  • In MexTAg 299h mice, gemcitabine started 16 weeks after exposure increased median survival from 33 weeks in control mice to 48 weeks in treated mice (p = 0.001).
  • With gemcitabine, the increase in survival from first signs of disease to euthanasia (median 7 days in controls versus 38 days in treated mice) approached but did not reach statistical significance (p = 0.052).
  • Dietary celecoxib did not significantly change overall survival in MexTAg 299h mice: median survival was 31 weeks with celecoxib and 28 weeks in controls (p = 0.95).
  • Time from first signs of disease to euthanasia was shorter in celecoxib-fed mice than in controls (2 versus 13 days, p = 0.007).
• The authors' conclusion: The authors concluded that the MexTAg model is robust and suitable for a range of translational experimental work relevant to human mesothelioma.
• Limitations the authors state:
  • The longer survival after diagnosis in wild-type mice was based on only three mesothelioma cases. The authors did not know whether it would hold in larger groups, noting high variability in survival after diagnosis.

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Wittenoom, Western Australia

All asbestos mines

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: Mesothelioma, Asbestos Exposure, Inflammation.

Related studies

• Statins do not alter the incidence of mesothelioma in asbestos exposed mice or humans — C. Robinson, H. Alfonso, et al. (2014)
• The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop — S.A. Fisher, K. Patrick, et al. (2024)
• 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)
• A mouse model recapitulating molecular features of human mesothelioma — D.A. Altomare, C.A. Vaslet, et al. (2005)
• Reduced tumor necrosis factor-alpha and transforming growth factor-beta1 expression in the lungs of inbred mice that fail to develop fibroproliferative lesions consequent to asbestos exposure — D.M. Brass, G.W. Hoyle, et al. (1999)
• Novel orthotopic implantation model of human malignant pleural mesothelioma (EHMES-10 cells) highly expressing vascular endothelial growth factor and its receptor — E. Nakataki, S. Yano, et al. (2006)

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