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Prostate cancer metastasis to bone is the major cause of prostate cancer associated morbidity and occurs in greater than 80% of patients with advanced disease. Animal models of prostate cancer metastasis are largely limited to the use of xenografted human cells in immune compromised murine hosts. By taking advantage of murine prostate cancer cells established using the mouse prostate reconstitution model (MPR), we are investigating the role of a matricellular protein, secreted protein acidic and rich in cysteine (SPARC or osteonectin), in the development and progression of experimental prostate cancer bone metastases.

Our results indicate that direct intramedullar implantation of RM1 cells, androgen independent prostate cancer cells derived from the MPR model, into immune competent, transgenic mice may prove to be a valuable model for investigating the role of specific bone matrix proteins in prostate cancer progression in bone. By longitudinally monitoring bone remodeling of prostate cancer cell injected tibiae using microcomputed tomography, we found that RM1 cells promote the development of mixed osteolytic and osteoblastic bone lesions. Within a 2-3 week period, RM1 cells grow to fill the medullary cavity of the tibia, promote extensive osteolysis and invade local soft tissue. Tumor growth adjacent to bone then promotes periosteal bone deposition. Bone resorption is more extensive in mice deficient in SPARC expression compared to wild-type mice while the degree of bone deposition appears the same. SPARC deficiency was previously shown to lead to compromised osteoblast formation and maturation. However, our data indicates that osteoblasts from SPARC deficient mice readily deposit woven bone in the presence of prostate cancer cells in vivo. We are currently carrying out in vitro studies to investigate this phenomenon.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA