HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes.

AbstractBACKGROUND:
Metastases to bone are a frequent complication of human prostate cancer and result in the development of osteoblastic lesions that include an underlying osteoclastic component. Previous studies in rodent models of breast and prostate cancer have established that receptor activator of NF-kappaB ligand (RANKL) inhibition decreases bone lesion development and tumor growth in bone. RANK is essential for osteoclast differentiation, activation, and survival via its expression on osteoclasts and their precursors. RANK expression has also been observed in some tumor cell types such as breast and colon, suggesting that RANKL may play a direct role on tumor cells.
METHODS:
Male CB17 severe combined immunodeficient (SCID) mice were injected with PC3 cells intratibially and treated with either PBS or human osteprotegerin (OPG)-Fc, a RANKL antagonist. The formation of osteolytic lesions was analyzed by X-ray, and local and systemic levels of RANKL and OPG were analyzed. RANK mRNA and protein expression were assessed on multiple prostate cancer cell lines, and events downstream of RANK activation were studied in PC3 cells in vitro.
RESULTS:
OPG-Fc treatment of PC3 tumor-bearing mice decreased lesion formation and tumor burden. Systemic and local levels of RANKL expression were increased in PC3 tumor bearing mice. PC3 cells responded to RANKL by activating multiple signaling pathways which resulted in significant changes in expression of genes involved in osteolysis and migration. RANK activation via RANKL resulted in increased invasion of PC3 cells through a collagen matrix.
CONCLUSION:
These data demonstrate that host stromal RANKL is induced systemically and locally as a result of PC3 prostate tumor growth within the skeleton. RANK is expressed on prostate cancer cells and promotes invasion in a RANKL-dependent manner.
AuthorsAllison P Armstrong, Robert E Miller, Jon C Jones, Jian Zhang, Evan T Keller, William C Dougall
JournalThe Prostate (Prostate) Vol. 68 Issue 1 Pg. 92-104 (Jan 01 2008) ISSN: 0270-4137 [Print] United States
PMID18008334 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright(c) 2007 Wiley-Liss, Inc.
Chemical References
  • Osteoprotegerin
  • RANK Ligand
  • RNA, Messenger
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFRSF11A protein, human
  • Tnfsf11 protein, mouse
Topics
  • Animals
  • Bone Neoplasms (genetics, physiopathology, secondary)
  • Cell Line, Tumor
  • Cell Movement (drug effects, physiology)
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic (drug effects, physiology)
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Osteolysis (pathology, physiopathology)
  • Osteoprotegerin (pharmacology)
  • Prostatic Neoplasms (genetics, pathology, physiopathology)
  • RANK Ligand (antagonists & inhibitors, genetics, metabolism)
  • RNA, Messenger (metabolism)
  • Receptor Activator of Nuclear Factor-kappa B (genetics, metabolism)
  • Signal Transduction (drug effects, physiology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: