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RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes.
Prostate. 2008 Jan 01; 68(1):92-104.P

Abstract

BACKGROUND

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.

Authors+Show Affiliations

Department of Hematology, Amgen Inc., Seattle, Washington 98119, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18008334

Citation

Armstrong, Allison P., et al. "RANKL Acts Directly On RANK-expressing Prostate Tumor Cells and Mediates Migration and Expression of Tumor Metastasis Genes." The Prostate, vol. 68, no. 1, 2008, pp. 92-104.
Armstrong AP, Miller RE, Jones JC, et al. RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate. 2008;68(1):92-104.
Armstrong, A. P., Miller, R. E., Jones, J. C., Zhang, J., Keller, E. T., & Dougall, W. C. (2008). RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. The Prostate, 68(1), 92-104.
Armstrong AP, et al. RANKL Acts Directly On RANK-expressing Prostate Tumor Cells and Mediates Migration and Expression of Tumor Metastasis Genes. Prostate. 2008 Jan 1;68(1):92-104. PubMed PMID: 18008334.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. AU - Armstrong,Allison P, AU - Miller,Robert E, AU - Jones,Jon C, AU - Zhang,Jian, AU - Keller,Evan T, AU - Dougall,William C, PY - 2007/11/17/pubmed PY - 2008/2/22/medline PY - 2007/11/17/entrez SP - 92 EP - 104 JF - The Prostate JO - Prostate VL - 68 IS - 1 N2 - BACKGROUND: 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. SN - 0270-4137 UR - https://www.unboundmedicine.com/medline/citation/18008334/RANKL_acts_directly_on_RANK_expressing_prostate_tumor_cells_and_mediates_migration_and_expression_of_tumor_metastasis_genes_ L2 - https://doi.org/10.1002/pros.20678 DB - PRIME DP - Unbound Medicine ER -