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

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.

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Zhao S, Kurenbekova L, Gao Y, Roos A, Creighton CJ, Rao P, Hicks J, Man TK, Lau C, Brown AM, Jones SN, Lazar AJ, Ingram D, Lev D, Donehower LA, Yustein JT