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

被引:177
作者
Chen, Gaoping
Sircar, Kanishka
Aprikian, Armen
Potti, Anil
Goltzman, David
Rabbani, Shafaat A.
机构
[1] McGill Univ, Ctr Hlth, Dept Med, Montreal, PQ H3A 1A1, Canada
[2] McGill Univ, Ctr Hlth, Dept Pathol, Montreal, PQ H3A 1A1, Canada
[3] McGill Univ, Ctr Hlth, Dept Urol, Montreal, PQ H3A 1A1, Canada
[4] Duke Univ, Med Ctr, Div Hematol, Durham, NC USA
[5] Duke Univ, Med Ctr, Div Oncol & Transplantat, Durham, NC USA
关键词
prostate cancer; bone metastasis; RANK; RANKL; OPG;
D O I
10.1002/cncr.21978
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:289 / 298
页数:10
相关论文
共 40 条
[21]   Cancer statistics, 2005 [J].
Jemal, A ;
Murray, T ;
Ward, E ;
Samuels, A ;
Tiwari, RC ;
Ghafoor, A ;
Feuer, EJ ;
Thun, MJ .
CA-A CANCER JOURNAL FOR CLINICIANS, 2005, 55 (01) :10-30
[22]   Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread:: Diagnostic and prognostic implications [J].
Jung, K ;
Lein, M ;
Stephan, C ;
Von-Hösslin, K ;
Semjonow, A ;
Sinha, P ;
Loening, SA ;
Schnorr, D .
INTERNATIONAL JOURNAL OF CANCER, 2004, 111 (05) :783-791
[23]   Prostate cancer bone metastases promote both osteolytic and osteoblastic activity [J].
Keller, ET ;
Brown, J .
JOURNAL OF CELLULAR BIOCHEMISTRY, 2004, 91 (04) :718-729
[24]   The effect of osteoprotegerin administration on the intra-tibial cyrowth of the osteoblastic LuCaP 23.1 prostate cancer xenograft [J].
Kiefer, JA ;
Vessella, RL ;
Quinn, JE ;
Odman, AM ;
Zhang, J ;
Keller, ET ;
Kostenuik, P ;
Dunstan, CR ;
Corey, E .
CLINICAL & EXPERIMENTAL METASTASIS, 2004, 21 (05) :381-387
[25]   Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand [J].
Kong, YY ;
Feïge, U ;
Sarosi, I ;
Bolon, B ;
Tafuri, A ;
Morony, S ;
Capparelli, C ;
Li, J ;
Elliott, R ;
McCabe, S ;
Wong, T ;
Campagnuolo, G ;
Moran, E ;
Bogoch, ER ;
Van, G ;
Nguyen, LT ;
Ohashi, PS ;
Lacey, DL ;
Fish, E ;
Boyle, WJ ;
Penninger, JM .
NATURE, 1999, 402 (6759) :304-309
[26]   Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation [J].
Lacey, DL ;
Timms, E ;
Tan, HL ;
Kelley, MJ ;
Dunstan, CR ;
Burgess, T ;
Elliott, R ;
Colombero, A ;
Elliott, G ;
Scully, S ;
Hsu, H ;
Sullivan, J ;
Hawkins, N ;
Davy, E ;
Capparelli, C ;
Eli, A ;
Qian, YX ;
Kaufman, S ;
Sarosi, I ;
Shalhoub, V ;
Senaldi, G ;
Guo, J ;
Delaney, J ;
Boyle, WJ .
CELL, 1998, 93 (02) :165-176
[27]   MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL [J].
Lynch, CC ;
Hikosaka, A ;
Acuff, HB ;
Martin, MD ;
Kawai, N ;
Singh, RK ;
Vargo-Gogola, TC ;
Begtrup, JL ;
Peterson, TE ;
Fingleton, B ;
Shirai, T ;
Matrisian, LM ;
Futakuchi, M .
CANCER CELL, 2005, 7 (05) :485-496
[28]   Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor osteoprotegerin [J].
Mizuno, A ;
Amizuka, N ;
Irie, K ;
Murakami, A ;
Fujise, N ;
Kanno, T ;
Sato, Y ;
Nakagawa, N ;
Yasuda, H ;
Mochizuki, S ;
Gomibuchi, T ;
Yano, K ;
Shima, N ;
Washida, N ;
Tsuda, E ;
Morinaga, T ;
Higashio, K ;
Ozawa, H .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 247 (03) :610-615
[29]   Prognostic significance of serum osteoprotegerin levels in patients with bladder carcinoma [J].
Mizutani, Y ;
Matsubara, H ;
Yamamoto, K ;
Li, YN ;
Mikami, K ;
Okihara, K ;
Kawauchi, A ;
Bonavida, B ;
Miki, T .
CANCER, 2004, 101 (08) :1794-1802
[30]   The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy [J].
Morony, S ;
Warmington, K ;
Adamu, S ;
Asuncion, F ;
Geng, ZP ;
Grisanti, M ;
Tan, HL ;
Capparelli, C ;
Starnes, C ;
Weimann, B ;
Dunstan, CR ;
Kostenuik, PJ .
ENDOCRINOLOGY, 2005, 146 (08) :3235-3243