title: Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP-6 induction.
abstract: BACKGROUND
  Androgen ablation is the first-line therapy for patients with metastatic prostate cancer (CaP). However, castration resistance will eventually emerge. In the present study, we have investigated the role of bone morphogenetic protein-6 (BMP-6) in the development of castration-resistant prostate cancer (CRPC) in the context of bone metastases.
  
  
  METHODS
  We initially investigated the clinical course of 158 men with advanced CaP who were treated with primary androgen deprivation therapy. To elucidate the underlying mechanism of CRPC in the context of bone metastases, we examined the impact of bone stromal cells on CaP in the absence of androgens using a co-culture model.
  
  
  RESULTS
  In the 158 patients, we found that the median time to prostate-specific antigen progression was significantly shorter when bone metastases were present (14 months (95% CI, 10.2-17.8 months) vs 57 months (95% CI, 19.4-94.6 months)). These results suggest that bone-tumour interactions may accelerate castration resistance. Consistent with this hypothesis, in vitro co-cultures demonstrated that CaP cells proliferated under an androgen-depleted condition when incubated with bone stromal cells. Mechanistically, gene expression analysis using quantitative polymerase chain reaction arrays showed a dramatic induction of BMP-6 by CaP cell lines in the presence of bone stromal cells. Further studies revealed that WNT5A derived from bone stromal cells induced the expression of BMP-6 by CaP cells; BMP-6 in turn stimulated cellular proliferation of CaP cells in an androgen-deprived media via a physical interaction between Smad5 and β-catenin. Intracellularly, WNT5A increased BMP-6 expression via protein kinase C/NF-κB pathway in CaP cell lines.
  
  
  CONCLUSIONS
  These observations suggest that bone-CaP interaction leads to castration resistance via WNT5A/BMP-6 loop.
authors: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Rutgers, The State University of New Jersey, 195 Little Albany Street no. 4560, New Brunswick, NJ 08901, USA.
authors: G T
authors: GT
authors: Lee
authors: 1] Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Rutgers, The State University of New Jersey, 195 Little Albany Street no. 4560, New Brunswick, NJ 08901, USA [2] Department of Urology, Inje University College of Medicine, Busan, Korea.
authors: D I
authors: DI
authors: Kang
authors: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Rutgers, The State University of New Jersey, 195 Little Albany Street no. 4560, New Brunswick, NJ 08901, USA.
authors: Y-S
authors: YS
authors: Ha
authors: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Rutgers, The State University of New Jersey, 195 Little Albany Street no. 4560, New Brunswick, NJ 08901, USA.
authors: Y S
authors: YS
authors: Jung
authors: Department of Urology, Inje University College of Medicine, Busan, Korea.
authors: J
authors: J
authors: Chung
authors: Department of Urology, Inje University College of Medicine, Busan, Korea.
authors: K
authors: K
authors: Min
authors: Department of Urology, Dong-A University, College of Medicine, Busan, Korea.
authors: T H
authors: TH
authors: Kim
authors: Department of Urology, Ulsan University, College of Medicine, Ulsan, Korea.
authors: K H
authors: KH
authors: Moon
authors: Department of Urology, Kosin University, College of Medicine, Busan, Korea.
authors: J M
authors: JM
authors: Chung
authors: Department of Urology, Ehwa Womans University, College of Medicine, Seoul, Korea.
authors: D H
authors: DH
authors: Lee
authors: Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.
authors: W-J
authors: WJ
authors: Kim
authors: Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey and Rutgers, The State University of New Jersey, 195 Little Albany Street no. 4560, New Brunswick, NJ 08901, USA.
authors: I Y
authors: IY
authors: Kim
mesh_terms: D000328:Adult; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000813:Anilides / Q000627:therapeutic use; D055418:Bone Morphogenetic Protein 6 / Q000096:biosynthesis* / Q000378:metabolism; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary* / Q000628:therapy*; D002450:Cell Communication / Q000502:physiology; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009570:Nitriles / Q000627:therapeutic use; D009919:Orchiectomy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D012189:Retrospective Studies; D017154:Stromal Cells / Q000473:pathology; D014105:Tosyl Compounds / Q000627:therapeutic use; D051153:Wnt Proteins / Q000096:biosynthesis* / Q000378:metabolism; D000071818:Wnt-5a Protein
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C053541:bicalutamide