title: Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma.
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.
authors.affiliation: Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Chirieac
authors.affiliation: Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bueno
authors.affiliation: Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Pass
authors.affiliation: Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Wu
authors.affiliation: Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Malinowska
authors.affiliation: Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kwiatkowski
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008654:Mesothelioma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D015996:Survival Rate; D046888:Tissue Array Analysis; D000077004:Tuberous Sclerosis Complex 1 Protein; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism* / Q000502:physiology*
chemical_list: C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins