Apoptotic genes as potential markers of metastatic phenotype in human osteosarcoma cell lines. Metastasis is the most frequent cause of death among patients with osteosarcoma. We have previously demonstrated in independent experiments that the forced expression of L/B/K ALP and CD99 in U-2 OS osteosarcoma cell lines markedly reduces the metastatic ability of these cancer cells. This behavior makes these cell lines a useful model to assess the intersection of multiple and independent gene expression signatures concerning the biological problem of dissemination. With the aim to characterize a common transcriptional profile reflecting the essential features of metastatic behavior, we employed cDNA microarrays to compare the gene expression profiles of L/B/K ALP- and CD99-transfected osteosarcoma clones showing low metastatic ability with those of osteosarcoma cell lines showing contrasting behavior. Changes in gene expression were validated by real-time PCR and immunohistochemistry in independent samples. In our study we identified several differentially expressed genes (GADD45alpha, VCP, DHX9, survivin, alpha-catulin, ARPC1B) related to growth arrest and apoptosis. Most of these genes are functionally related with the nuclear factor (NF)-kappaB cell survival pathway that appeared to be inhibited in the less malignant osteosarcoma cells. Hence, we propose the inhibition of the NF-kappaB pathway as a rational strategy for effective management of human osteosarcoma.