Abstract
Malignant mesothelioma is a devastating disease that has been associated with loss of Neurofibromatosis type 2 (NF2) and genetic lesions affecting RB and P53 pathways. We introduced similar lesions in the mesothelial lining of the thoracic cavity of mice. Mesothelioma developed at high incidence in Nf2;Ink4a/Arf and Nf2;p53 conditional knockout mice with median survival times of approximately 30 and 20 weeks, respectively. Murine mesothelioma closely mimicked human malignant mesothelioma. Conditional Nf2;Ink4a/Arf mice showed increased pleural invasion compared to conditional Nf2;p53 mice. Interestingly, upon Ink4a loss in the latter mice median survival was significantly reduced and all tumors were highly invasive, suggesting that Ink4a loss substantially contributes to the poor clinical outcome of malignant mesothelioma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / genetics
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Animals
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology*
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Epithelioid Cells / metabolism
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Epithelioid Cells / pathology
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Genetic Vectors
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Genotype
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Immunohistochemistry
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Integrases / genetics
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Integrases / metabolism
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Loss of Heterozygosity
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Luminescent Measurements
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Mesothelioma / genetics
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Mesothelioma / metabolism
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Mesothelioma / pathology*
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Mice
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Mice, Knockout
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Mixed Tumor, Malignant / metabolism
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Mixed Tumor, Malignant / pathology
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Neoplasm Invasiveness
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Neoplasms, Experimental / genetics
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Neurofibromatosis 2 / genetics
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Neurofibromatosis 2 / metabolism*
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Phenotype
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Recombination, Genetic
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Sarcoma / metabolism
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Sarcoma / pathology
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Thoracic Cavity / metabolism*
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Thoracic Cavity / pathology
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Thoracic Neoplasms / genetics
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Thoracic Neoplasms / metabolism
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Thoracic Neoplasms / pathology*
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Time Factors
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Cyclin-Dependent Kinase Inhibitor p16
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Tumor Suppressor Protein p53
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Cre recombinase
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Integrases