Gene expression analyses of primary tumors and metastases, using p53 mouse models. Mus musculus

Osteosarcoma (OS) is the most frequent malignant bone tumor with a high propensity for metastases. Through the tissue-specific alteration of p53 status, we have developed a genetically engineered mouse model of localized and metastatic OS. Gene expression analysis revealed naked cuticle homolog 2 (NKD2), a negative regulator of the Wnt signaling pathway, to be significantly downregulated in metastatic OS. An assessment of human OS tumors revealed downregulation of NKD2 in metastatic and recurrent OS. We determined that downregulation was secondary to methylation of the NKD2 promoter region for both mouse and human tumors. Furthermore, in vivo investigations indicate that NKD2 overexpression significantly diminishes OS tumor growth and metastasis and small molecule Wnt inhibitors can decrease OS growth and metastatic potential. Overall design: Development of novel osteoblast-specific alteration of a p53 mouse model that forms de novo localized and gross, macroscopic osteosarcoma that mimics the human disease allowing determination of novel genetic alterations involved in OS progression. Gene expression profiling of primary osteosarcomas (OS) and OS metastases to lung and liver. In order to identify genes and pathways that regulate OS metastasis, we performed an initial screen comparing the gene expression profiles of six localized, non-metastatic OS with those of 12 primary OS that produced metastatic lesions. In addition, seven lung metastatic lesion gene expression profiles were compared to those of the primary tumor from which they originated. multiple group comparison