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Submitted on September 13, 2004
Accepted on December 23, 2004
Department of Periodontics/Prevention/Geriatrics, School of Dentistry, University of Michigan; Department of Urology, Medical School, University of Michigan; Department of Pathology, Medical School, University of Michigan; Department of Internal Medicine, Division of Hematology/Oncology, Medical School, University of Michigan, Ann Arbor, MI 48109; Department of Orthopedic Surgery, SUNY Upstate Medical University, Syracuse, NY 13210
* To whom correspondence should be addressed. E-mail: mccauley{at}umich.edu.
Bone metastasis is a common untreatable complication associated with prostate cancer. Metastatic cells seed in skeletal sites under active turnover containing dense marrow cellularity. We hypothesized that differences in these skeletal-specific processes are among the critical factors that facilitate the preferential localization of metastatic prostate cancer in bone. To test this, athymic mice were administered parathyroid hormone (PTH) to induce bone turnover and increase marrow cellularity daily one week before and after intracardiac inoculation of luciferase-tagged PC-3 cells. Tumor localization was monitored by bioluminescence imaging weekly for 5 weeks. At the time of tumor inoculation, PTH-treated mice demonstrated significant increases in serum levels of bone turnover markers such as osteocalcin and TRAP 5b and in the number of TRAP+ osteoclasts/mm bone when compared with the other groups. Likewise, PTH treatment stimulated a qualitative increase in marrow cellular proliferation as determined by BrdU immunostaining. Skeletal metastases formed in the hind limb and craniofacial regions of young mice with no difference between groups. In adult mice, however, bioluminescent signals in the hind limb and craniofacial regions were 3-fold higher in PTH-treated mice vs. controls. Fluorochrome labeling revealed increased bone formation activity in trabecular bone adjacent to tumors. When zoledronic acid, a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption, was administered concurrently with PTH, a significant reduction in the incidence of bone tumors was observed. Overall, these studies provide new evidence that skeletal sites rich in marrow cellularity under active turnover offer a more congenial microenvironment to facilitate cancer localization in the skeleton.
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