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Osteosclerotic prostate cancer metastasis to murine bone are enhanced with increased bone formation

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Abstract

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.

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Abbreviations

PCa:

Prostate cancer

PSA:

Prostate specific antigen

hPTH:

Human parathyroid hormone fragment 1–34

BMD:

Bone mineral density

BV:

Bone volume

TV:

Total volume

BV/TV:

Bone volume fraction

Tb.N:

Trabecular number

Tb.Th:

Trabecular thickness

Tb.Sp:

Trabecular separation

SMI:

Structural model index

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Acknowledgments

We thank high school student Dyanna González for her assistance with the immunohistochemistry, and Dr. Arivalanagan Muthusamy, Sarah Sheehan, and members of the Division of Musculoskeletal Sciences for helpful discussions and critical reading of the manuscript, and Ananya Das for secretarial assistance.

Grant support

Dean’s Feasibility Grant from the Penn State College of Medicine, and the Pennsylvania Department of Health using Tobacco Settlement Funds (to R.R.G.). The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. Support was also provided from NIH INBRE P20RR016472, DoD PCRP PC073886 (R.A.S. and K.L.V.G)

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Authors and Affiliations

  1. Department of Orthopaedics and Rehabilitation, Division of Musculoskeletal Sciences, Penn State College of Medicine, Hershey, PA, 17033, USA

    Ronald R. Gomes Jr., Patricia Buttke & Emmanuel M. Paul

  2. Center for Translational Cancer Research, Laboratory for Cancer Ontogeny and Therapeutics, Department of Biological Sciences, University of Delaware, Newark, DE, 19716, USA

    Robert A. Sikes

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  1. Ronald R. Gomes Jr.
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  2. Patricia Buttke
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  3. Emmanuel M. Paul
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Correspondence to Ronald R. Gomes Jr..

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Gomes, R.R., Buttke, P., Paul, E.M. et al. Osteosclerotic prostate cancer metastasis to murine bone are enhanced with increased bone formation. Clin Exp Metastasis 26, 641–651 (2009). https://doi.org/10.1007/s10585-009-9263-x

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  • DOI: https://doi.org/10.1007/s10585-009-9263-x

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