Walkley Carl R, Qudsi Rameez, Sankaran Vijay G, Perry Jennifer A, Gostissa Monica, Roth Sanford I, Rodda Stephen J, Snay Erin, Dunning Patricia, Fahey Frederic H, Alt Frederick W, McMahon Andrew P, Orkin Stuart H
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston, MA 02115, USA.
Genes Dev. 2008 Jun 15;22(12):1662-76. doi: 10.1101/gad.1656808.
Osteosarcoma is the most common primary malignant tumor of bone. Analysis of familial cancer syndromes and sporadic cases has strongly implicated both p53 and pRb in its pathogenesis; however, the relative contribution of these mutations to the initiation of osteosarcoma is unclear. We describe here the generation and characterization of a genetically engineered mouse model in which all animals develop short latency malignant osteosarcoma. The genetically engineered mouse model is based on osteoblast-restricted deletion of p53 and pRb. Osteosarcoma development is dependent on loss of p53 and potentiated by loss of pRb, revealing a dominance of p53 mutation in the development of osteosarcoma. The model reproduces many of the defining features of human osteosarcoma including cytogenetic complexity and comparable gene expression signatures, histology, and metastatic behavior. Using a novel in silico methodology termed cytogenetic region enrichment analysis, we demonstrate high conservation of gene expression changes between murine osteosarcoma and known cytogentically rearranged loci from human osteosarcoma. Due to the strong similarity between murine osteosarcoma and human osteosarcoma in this model, this should provide a valuable platform for addressing the molecular genetics of osteosarcoma and for developing novel therapeutic strategies.
骨肉瘤是最常见的原发性骨恶性肿瘤。对家族性癌症综合征和散发病例的分析强烈表明，p53和视网膜母细胞瘤蛋白（pRb）均涉及其发病机制；然而，这些突变对骨肉瘤起始的相对贡献尚不清楚。我们在此描述了一种基因工程小鼠模型的构建及特征，该模型中的所有动物均会在短潜伏期内发生恶性骨肉瘤。该基因工程小鼠模型基于成骨细胞特异性缺失p53和pRb。骨肉瘤的发生依赖于p53的缺失，并因pRb的缺失而增强，这揭示了p53突变在骨肉瘤发生过程中的主导作用。该模型重现了人类骨肉瘤的许多典型特征，包括细胞遗传学复杂性、可比的基因表达特征、组织学和转移行为。使用一种称为细胞遗传学区域富集分析的新型计算机方法，我们证明了小鼠骨肉瘤与人类骨肉瘤已知细胞遗传学重排位点之间基因表达变化的高度保守性。由于该模型中小鼠骨肉瘤与人类骨肉瘤之间具有很强的相似性，这应为研究骨肉瘤的分子遗传学和开发新的治疗策略提供一个有价值的平台。
