Osteosclerotic prostate cancer metastasis to murine bone are enhanced with increased bone formation.
Spontaneous development of osteoblastic lesions of prostate cancer (PCa) in mice is modeled by orthotopic (intraprostatic) deposition of neoplastic cells followed by an extremely long latency associated with low incidence of spontaneous bone metastasis. Intracardial injection results in overt bone metastases only with osteoclastic PCa cells (i.e., PC-3). Herein, we report that androgen independent osteoblastic PCa cells readily colonize bone when in a high remodeling state. SCID/Beige mice were subjected to periods of intermittent human parathyroid hormone 1-34 (hPTH) exposure, followed by an intracardiac infusion of osteoblastic C4-2 PCa cells. At the time of PCa infusion, analysis of bone turnover markers from mice treated with hPTH revealed significant increases in osteocalcin (55.06 +/- 7.5 vs. 74.01 +/- 18.5 ng/ml) and TRAcP-5b (3.3 +/- 0.6 vs. 4.81 +/- 0.8 U/l), but no change in type I collagen C-terminal teleopeptide levels relative to control mice. Analysis of femoral cancellous bone architecture revealed significant increases in bone mineral density, trabecular thickness (0.056 +/- 0.002 vs. 0.062 +/- 0.001 mm) and porosity, but significant decreases in connectivity density and trabecular number in hPTH treated mice relative to controls. By 8 weeks post-infusion, 70% of mice pre-treated with hPTH demonstrated detectable serum prostate specific antigen (PSAs) ranging between 2 and 18.8 ng/ml. Immuno-histochemical labeling of femurs for PSA and pan-Cytokeratin revealed the presence of significant tumor cell nests in marrow and trabecular spaces. These results suggest that: (1) local bone physiology is an important factor for developing osteoblastic/sclerotic PCa bone metastases in murine hosts; (2) the establishment of osteosclerotic PCa bone metastases in mice is enhanced by alterations that drive bone formation.
Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, Hershey, PA 17033, USA. rgomes@psu.edu
Ronald R
RR
Gomes
Patricia
P
Buttke
Emmanuel M
EM
Paul
Robert A
RA
Sikes
D000818:Animals; D015153:Blotting, Western; D001846:Bone Development; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010026:Osteosclerosis / Q000473:pathology*; D010281:Parathyroid Hormone / Q000008:administration & dosage; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000473:pathology*; D014057:Tomography, X-Ray Computed
D010281:Parathyroid Hormone; D017430:Prostate-Specific Antigen