Abstract
Bone is one of the common sites of metastases from renal cell carcinoma (RCC), however the mechanism by which RCC preferentially metastasize to bone is poorly understood. Homing/retention of RCC cells to bone and subsequent proliferation are necessary steps for RCC cells to colonize bone. To explore possible mechanisms by which these processes occur, we used an in vivo metastasis model in which 786-O RCC cells were injected into SCID mice intracardially, and organotropic cell lines from bone, liver, and lymph node were selected. The expression of molecules affecting cell adhesion, angiogenesis, and osteolysis were then examined in these selected cells. Cadherin-11, a mesenchymal cadherin mainly expressed in osteoblasts, was significantly increased on the cell surface in bone metastasis-derived 786-O cells (Bo-786-O) compared to parental, liver, or lymph node-derived cells. In contrast, the homing receptor CXCR4 was equivalently expressed in cells derived from all organs. No significant difference was observed in the expression of angiogenic factors, including HIF-1α, VEGF, angiopoeitin-1, Tie2, c-MET, and osteolytic factors, including PTHrP, IL-6 and RANKL. While the parental and Bo-786-O cells have similar proliferation rates, Bo-786-O cells showed an increase in migration compared to the parental 786-O cells. Knockdown of Cadherin-11 using shRNA reduced the rate of migration in Bo-786-O cells, suggesting that Cadherin-11 contributes to the increased migration observed in bone-derived cells. Immunohistochemical analysis of cadherin-11 expression in a human renal carcinoma tissue array showed that the number of human specimens with positive cadherin-11 activity was significantly higher in tumors that metastasized to bone than that in primary tumors. Together, these results suggest that Cadherin-11 may play a role in RCC bone metastasis.
Highlights
Renal cell carcinoma (RCC) often metastasizes to bone, lymph nodes, liver, lung, and brain [1]
Strong bioluminescence signals were observed in the hind legs as well as a few other organs (Fig. 1B), indicating that a fraction of parental 786-O cells disseminated to multiple tissues and grew at these sites
Tumor cells were isolated from affected organ sites, including liver, lymph nodes, and femur, and cultured in vitro to generate liverderived (Liv-), lymph node-derived (LN-) and bone-derived (Bo-) 786-O RCC cells, respectively
Summary
Renal cell carcinoma (RCC) often metastasizes to bone, lymph nodes, liver, lung, and brain [1]. RCC bone metastases are relatively resistant to radio- and chemotherapy [4,5]. The management of bone metastases has been significantly improved by the addition of anti-angiogenic agents, most patients eventually develop resistance to these therapies. Surgical resection of RCC bone metastasis remains challenging due to induced vascularity, and a propensity to recur if complete resection is not possible [6,7]. The prognosis for RCC patients who develop bone metastases is dismal, with a mean survival of 12 months [3,5]. A better understanding of the factors that play a role in RCC bone metastasis could result in preventive/therapeutic strategies that might be effective in prolonging patients’ survival
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