Osteoprotegerin in Prostate Cancer Bone Metastasis

Abstract

Osteoprotegerin (OPG), a critical regulator of osteoclastogenesis, is expressed by prostate cancer cells, and OPG levels are increased in patients with prostate cancer bone metastases. The objective of this study was to investigate the effects of OPG overexpression on prostate cancer cells and prostate cancer/bone cell interactions in vitro and in vivo. OPGtransfected C4-2 cells expressed 8.0 ng OPG per mL per 10 6 cells, whereas no OPG was detected in the media of C4-2 cells transfected with a control plasmid. OPG overexpressed by C4-2 cells protected these cells from tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis and decreased osteoclast formation. Subcutaneous OPG-C4-2 and pcDNA-C4-2 tumors exhibited similar growth and take-rate characteristics. However, when grown in bone, tumor volume was decreased in OPG-C4-2 versus pcDNA-C4-2 (P = 0.0017). OPG expressed by C4-2 cells caused increases in bone mineral density (P = 0.0074) and percentage of trabecular bone volume (P = 0.007), and decreases in numbers of osteoblasts and osteoclasts when compared with intratibial pcDNA-C4-2 tumors (P = 0.003 and P = 0.019, respectively). In summary, our data show that increased expression of OPG in C4-2 cells does not directly affect proliferation of prostate cancer cells but indirectly decreases growth of C4-2 tumors in the bone environment. Our data also show that OPG expressed by C4-2 cells inhibits bone lysis associated with C4-2 bone metastasis, which results in net increases in bone volume. We therefore hypothesize that OPG expressed in prostate cancer patient bone metastases may be at least partially responsible for the osteoblastic character of most prostate cancer bone lesions. (Cancer Res 2005; 65(5): 1710-8)

DU145 human prostate cancer cells express functional receptor activator of NFκB: New insights in the prostate cancer bone metastasis process

“…Thus, RANK expressed on both osteoclasts and prostate cancer cells in tumoral bone microenvironment has a propensity for prostate cancer bone metastasis development by synergic effect. Indeed, despite its overall osteoblastic profile, recent evidences suggested the significant involvement of osteolytic lesion preceding osteoblastic prostate cancer bone metastasis development [4][5][6][7][8][9].…”

“…Previous studies reported that OPG expression by prostate cancer cells [8] and more recently RANK expression by cancer cells [21,22], these all findings therefore led us to elucidate the molecular mechanisms underlying prostate cancer bone metastases and the therapeutic relevance of RANKL/RANK/OPG triad in these processes, using DU145 and PC3 human prostate cancer cell lines.…”

“…Unlike other solid tumors that are associated with osteolytic bone metastases, prostate cancer bone metastases stimulate an overall increase in both bone remodelling and bone volume [3]. In contrast, recent findings strongly suggest the importance of osteoclast function [4][5][6][7][8][9]; however the mechanisms underlining these processes are not fully determined.…”

“…Recent data strongly revealed the significant involvement of the RANKL/RANK/OPG system in metastatic bone cancer diseases, including prostate cancer bone metastases [16]. Indeed, current studies have disclosed that blocking RANKL-RANK interaction prevents the progression of prostate cancer in bone [6][7][8][9].…”

RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

“…Four-to 6-week-old male SCID mice (Fox Chase SCID mice, Charles River, Wilmington, MA) were injected with approximately 2 × 10 5 cells into the proximal end of the right tibia as we have described previously [33][34][35]. Tumor growth was monitored by serum levels of prostate specific antigen (PSA).…”