Prostate Cancer Skeletal Metastases: Pathobiology and Interventions
Abstract
Prostate cancer skeletal metastases are considered osteoblastic; however, histopathological examination usually reveals underlying osteoclastic activity (reviewed in 1). A key molecule required for induction of osteoclastic activity is receptor activator of NFkB ligand (KANKL). RANKL activity is opposed by osteoprotegerin (OPG). Thus, the balance of RANKL and OPG in the prostate cancer tissue may regulate the overall phenotype of the metastatic lesion. We have determined that prostate cancer cells express increasing levels of RANKL and decreasing levels of OPG. Additionally, we have determined that androgen promotes OPG expression at the transcriptional level. Thus, loss of androgen may reduce OPG expression and favor a shift towards RANKL activity. Additionally, in a murine model, we have demonstrated the ability to inhibit establishment of prostate cancer in bone by blocking RANKL-induced osteoclastic activity using OPG. However, OPO can bind pro-apoptotic molecules and block apoptosis of cancer cells indicating that it may not be useful for clinical use (2). Instead, alternative methods to block RANKL activity may be more clinically relevant. Based on our previous findings and those of others our hypothesis is that an increase in the PANKL:OPO ratio contributes to the development of CaP skeletal metastases. Accordingly, a corollary hypothesis is that restoring the RANKL:OPG axis through inhibition of RANKL activity will diminish progression of skeletal metastases. Accordingly, the specific aims of this project are to (1) identify the mechanisms through which OPG expression is regulated in CaP cells and (2) determine if inhibition of RANKL activity by methods other than OPG can block the establishment and progression of CaP skeletal metastases in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2005
- Accession Number
- ADA442830
Entities
People
- Evan T Keller
Organizations
- University of Michigan