Whereas, in the study of Strube et al., PTHrP was highly expressed in metastatic cell lines suggesting that PTHrP might play a role in tumor-induced osteolysis similar to breast cancer bone metastasis. Additionally, it has also shown that RANKL did not substantially contribute to RANK-induced bone resorption. In the current study, we found that gene expression of PTHrP and IL-6 was significantly lower in bone-derived RCC 786-O cells than that in parental 786-O cells, and that RANKL gene expression in the 786-O RCC cells was too low to be detected. Our results agree with previous Erlotinib reports indicating that no RANKL mRNA expression was detected in human clear cell RCC cell lines, such as ACHN and Caki-1 cells. From these observations, we conclude that these tumor-produced factors may not play a critical role in affecting the metastasis of 786-O cells to bone. However, the possibility that these factors may be secreted as a result of interactions between 786-O RCC cells and bone marrow mesenchymal cells, and therefore may play a role in supporting the growth of RCC 786-O cells in bone, cannot be excluded. Strube et al. has also reported the selection of bone-derived metastatic 786-O cell lines through multiple cycles of in vivo selection. The highly selected cells showed strong osteolytic property with high levels of PTHrP. As tumor cells are heterogeneous with ability to metastasize to various organ sites, we chose to use first generation of metastatic tumor 786-O RCC cell lines to determine the very initial factors that may involve in homing, retention and proliferation at bone site. Whether repeated in vivo selection enriched for the cells that express high levels of PTHrP is not clear. In conclusion, among the several candidate factors examined, including angiogenic and osteolytic factors, we found that only one membrane protein, Cad11, was involved in organ-specific metastasis in bone using the 786-O cell line. Additional membrane proteins that are important for organ-specific targeting of metastatic RCC cells may be identified by using other RCC cell lines, and by other methods such as proteomics. We recently report that living in an enriched housing environment that provides physical, social, and cognitive stimuli reduces tumor growth and increases remission in mouse models of melanoma and colon cancer. Our mechanistic studies have elucidated one key mechanism underlying the anti-cancer effect of environmental enrichment : the activation of a previously poorly understood neuroendocrine hypothalamic-sympathoneural-adipocyte axis. The complex environmental stimuli induce the expression of brain-derived neurotrophic factor in the hypothalamus and the ensuing increase in sympathetic tone to white adipose tissue. The preferential sympathetic activation of white adipose tissue suppresses leptin expression and release via action on b-adrenergic receptors leading to a robust drop of leptin level in circulation.