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Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma

Oncogene volume 33, pages 3151–3160 (2014)Cite this article

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Abstract

Mesothelioma is diagnosed in ∼2500 patients in the United States every year, most often arising in the pleural space, but also occurring as primary peritoneal mesothelioma. The vast majority of patients with mesothelioma die of their disease within 3 years. We developed a new mouse model of mesothelioma by bladder or intraperitoneal injection of adenovirus Cre into mice with conditional alleles of each of Tp53 and Tsc1. Such mice began to develop malignant ascites about 6 months after injection, which was due to peritoneal mesothelioma, on the basis of tumor morphology and immunohistochemical staining. Mesothelioma cell lines were established, which showed loss of both Tsc1 and Tp53, with mammalian target of rapamycin complex (mTORC)1 activation. Treatment of mice with malignant ascites due to mesothelioma with rapamycin led to a marked reduction in ascites, extended survival and a 95–99% reduction in the mesothelioma tumor volume, in comparison with vehicle-treated mice. To see whether TSC1/TSC2 loss was a common genetic event in human mesothelioma, we examined nine human mesothelioma cell lines, and found that four of nine showed persistent activation of mTORC1, although none had loss of TSC1 or TSC2. A tissue microarray analysis of 198 human mesothelioma specimens showed that 33% of cases had reduced TSC2 expression and 60% showed activation of mTOR, indicating that mTOR activation is common in human mesothelioma, suggesting that it is a potential therapeutic target.

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Acknowledgements

We thank Dr Nathanael Gray (Dana Farber Cancer Institute, Boston, MA, USA) for kindly providing mTOR inhibitor Torin1 used in this study. This work was supported by Grants 1P01CA120964 and 2P50CA090578 from the National Institutes of Health, and the Chip Thayer Fund.

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Authors and Affiliations

  1. Division of Translational Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Y Guo, W Wu, I A Malinowska & D J Kwiatkowski

  2. Department of Pathology, Harvard Medical School, Boston, MA, USA

    L R Chirieac

  3. Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    R Bueno

  4. Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, NY, USA

    H Pass

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  1. Y Guo
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Correspondence to D J Kwiatkowski.

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Guo, Y., Chirieac, L., Bueno, R. et al. Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma. Oncogene 33, 3151–3160 (2014). https://doi.org/10.1038/onc.2013.280

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