Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation

BACKGROUND. Late-stage prostate cancer patients are refractory to hormone therapy and exhibit a high propensity to develop skeletal metastasis. In this regard, the role of a novel cytokine system belonging to the tumor necrosis factor (TNF) family that is critical for osteoclastic osteolysis and that consists of receptor activator of NF-kappa B ligand (RANKL), its receptor (RANK), and decoy receptor osteoprotegerin (OPG) is of potential interest. METHODS. Reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemical analysis was used to examine the expression of RANKL, RANK, and OPG in human prostate cancer cell lines and in 89 archival samples of primary and metastatic (lymph nodes, skeleton) prostate cancer patients. Expression of these proteins was correlated with clinicopathogic parameters of the prostate cancer. RESULTS. Expression of RANKL/RANK/OPG was low in normal but markedly higher in prostate cancer cell lines. Analysis of surgical biopsy specimens showed the expression of RANKL (31%), RANK (38%), and OPG (19%) in primary carcinoma. The expression frequency was significantly higher (RANKL [44%], RANK [49%], and OPG [73%]) in metastatic prostate cancer. OPG (83%) production was more common in skeletal as compared with lymph node metastases (46%), whereas the expression of RANKL expression was less discordant in bone (47%) and lymph node metastases (36%). The increased expression of RANKL/RANK/ OPG observed correlated with Gleason score, TNM stage, androgen status, and serum prostate-specific antigen (PSA) levels in the prostate cancer patients. CONCLUSIONS. Expression of RANKL/RANK/OPG correlates with more aggressive, advanced, metastatic prostate carcinoma to suggest their role as diagnostic, prognostic, and therapeutic targets for prostate cancer.