Fischer 344-Tp53 knockout rats exhibit a high rate of bone and brain neoplasia with frequent metastasis
Autor: | Taybor W. Parker, James M. Amos-Landgraf, Marcia L. Hart, Elizabeth C. Bryda, Susheel Bhanu Busi, Angela Goerndt, Kevin B. Jones, Sarah A. Hansen |
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Rok vydání: | 2016 |
Předmět: |
p53
0301 basic medicine Lung Neoplasms Time Factors Carcinogenesis lcsh:Medicine Medicine (miscellaneous) Germline Metastasis Gene Knockout Techniques 0302 clinical medicine Immunology and Microbiology (miscellaneous) Meningeal Neoplasms Neoplasm Metastasis Cancer Osteosarcoma Brain Neoplasms Sarcoma Primary tumor 3. Good health Phenotype 030220 oncology & carcinogenesis Research Article lcsh:RB1-214 Tumor suppressor gene Neuroscience (miscellaneous) Bone Neoplasms Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Germline mutation lcsh:Pathology medicine Animals Allele neoplasms lcsh:R medicine.disease Rats Inbred F344 Disease Models Animal 030104 developmental biology Mutation Immunology Cancer research Rat Tumor Suppressor Protein p53 |
Zdroj: | Disease Models & Mechanisms, Vol 9, Iss 10, Pp 1139-1146 (2016) Disease Models & Mechanisms |
ISSN: | 1754-8411 1754-8403 |
Popis: | Somatic mutations in the Tp53 tumor suppressor gene are the most commonly seen genetic alterations in cancer, and germline mutations in Tp53 predispose individuals to a variety of early-onset cancers. Development of appropriate translational animal models that carry mutations in Tp53 and recapitulate human disease are important for drug discovery, biomarker development and disease modeling. Current Tp53 mouse and rat models have significant phenotypic and genetic limitations, and often do not recapitulate certain aspects of human disease. We used a marker-assisted speed congenic approach to transfer a well-characterized Tp53-mutant allele from an outbred rat to the genetically inbred Fischer-344 (F344) rat to create the F344-Tp53tm1(EGFP-Pac)Qly/Rrrc (F344-Tp53) strain. On the F344 genetic background, the tumor spectrum shifted, with the primary tumor types being osteosarcomas and meningeal sarcomas, compared to the hepatic hemangiosarcoma and lymphoma identified in the original outbred stock model. The Fischer model is more consistent with the early onset of bone and central nervous system sarcomas found in humans with germline Tp53 mutations. The frequency of osteosarcomas in F344-Tp53 homozygous and heterozygous animals was 57% and 36%, respectively. Tumors were highly representative of human disease radiographically and histologically, with tumors found primarily on long bones with frequent pulmonary metastases. Importantly, the rapid onset of osteosarcomas in this promising new model fills a current void in animal models that recapitulate human pediatric osteosarcomas and could facilitate studies to identify therapeutic targets. Editors' choice: Transferring a Tp53-knockout allele from an outbred rat stock to the F344 inbred rat genetic background alters the spectrum of tumors, providing a model of early-onset brain and bone sarcomas. |
Databáze: | OpenAIRE |
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