Drugs which inhibit osteoclast function suppress tumor growth through calcium reduction in bone

Xin Li, Jinhui Liao, Serk In Park, Amy J. Koh, William D. Sadler, Kenneth J. Pienta, Thomas J. Rosol, Laurie K. McCauley

Research output: Contribution to journalArticle

Abstract

Prostate carcinoma frequently metastasizes to bone where the microenvironment facilitates its growth. Inhibition of bone resorption is effective in reducing tumor burden and bone destruction in prostate cancer. However, whether drugs that inhibit osteoclast function inhibit tumor growth independent of inhibition of bone resorption is unclear. Calcium is released during bone resorption and the calcium sensing receptor is an important regulator of cancer cell proliferation. The goal of this investigation was to elucidate the role of calcium released during bone resorption and to determine the impact of drugs which suppress bone resorption on tumor growth in bone. To compare tumor growth in a skeletal versus non-skeletal site, equal numbers of canine prostate cancer cells expressing luciferase (ACE-1luc) were inoculated into a simple collagen matrix, neonatal mouse vertebrae (vossicles), human de-proteinized bone, or a mineralized collagen matrix. Implants were placed subcutaneously into athymic mice. Luciferase activity was used to track tumor growth weekly, and at one month tumors were dissected for histologic analysis. Luciferase activity and tumor size were greater in vossicles, de-proteinized bone and mineralized collagen matrix versus non-mineralized collagen implants. The human osteoblastic prostate carcinoma cell line C4-2b also grew better in a mineral rich environment with a greater proliferation of C4-2b cells reflected by Ki-67 staining. Zoledronic acid (ZA), a bisphosphonate, and recombinant OPG-Fc, a RANKL inhibitor, were administered to mice bearing vertebral implants (vossicles) containing ACE-1 osteoblastic prostate cancer cells. Vossicles or collagen matrices were seeded with ACE-1luc cells subcutaneously in athymic mice (2 vossicles, 2 collagen implants/mouse). Mice received ZA (5μg/mouse, twice/week), (OPG-Fc at 10mg/kg, 3 times/week) or vehicle, and luciferase activity was measured weekly. Histologic analysis of the tumors, vossicles and endogenous bones and serum biochemistry were performed. Antiresorptive administration was associated with decreased serum TRAP5b, reduced osteoclast numbers, and increased tibia and vossicle bone areas. ZA significantly decreased bone marrow calcium concentrations without affecting serum calcium. ZA and OPG-Fc significantly inhibited tumor growth in bone but not in collagen implants. In conclusion, the inhibitory effects of ZA or OPG-Fc on prostate tumor growth in bone are mediated via blocking bone resorption and calcium release from bone.

Original languageEnglish (US)
Pages (from-to)1354-1361
Number of pages8
JournalBone
Volume48
Issue number6
DOIs
StatePublished - Jun 1 2011

Fingerprint

zoledronic acid
Osteoclasts
Calcium
Bone and Bones
Bone Resorption
Collagen
Growth
Pharmaceutical Preparations
Neoplasms
Luciferases
Bone Development
Prostate
Prostatic Neoplasms
Nude Mice
Serum
Carcinoma
Calcium-Sensing Receptors
Diphosphonates
Tumor Burden
Tibia

Keywords

  • Anti-resorptive
  • Bone resorption
  • Calcium
  • Osteoprotegrin (OPG)
  • Prostate tumor
  • Zoledronic acid (ZA)

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

Li, X., Liao, J., Park, S. I., Koh, A. J., Sadler, W. D., Pienta, K. J., ... McCauley, L. K. (2011). Drugs which inhibit osteoclast function suppress tumor growth through calcium reduction in bone. Bone, 48(6), 1354-1361. https://doi.org/10.1016/j.bone.2011.03.687

Drugs which inhibit osteoclast function suppress tumor growth through calcium reduction in bone. / Li, Xin; Liao, Jinhui; Park, Serk In; Koh, Amy J.; Sadler, William D.; Pienta, Kenneth J.; Rosol, Thomas J.; McCauley, Laurie K.

In: Bone, Vol. 48, No. 6, 01.06.2011, p. 1354-1361.

Research output: Contribution to journalArticle

Li, X, Liao, J, Park, SI, Koh, AJ, Sadler, WD, Pienta, KJ, Rosol, TJ & McCauley, LK 2011, 'Drugs which inhibit osteoclast function suppress tumor growth through calcium reduction in bone', Bone, vol. 48, no. 6, pp. 1354-1361. https://doi.org/10.1016/j.bone.2011.03.687
Li, Xin ; Liao, Jinhui ; Park, Serk In ; Koh, Amy J. ; Sadler, William D. ; Pienta, Kenneth J. ; Rosol, Thomas J. ; McCauley, Laurie K. / Drugs which inhibit osteoclast function suppress tumor growth through calcium reduction in bone. In: Bone. 2011 ; Vol. 48, No. 6. pp. 1354-1361.
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