Neural progenitor cell-mediated delivery of osteoprotegerin limits disease progression in a preclinical model of neuroblastoma bone metastasis.

Abstract

PURPOSE:

Osteoprotegerin (OPG) inhibits osteoclast activation and reduces osteolysis in bone tumors. We hypothesized that tumor-tropic neural progenitor cells (NPCs) engineered to express OPG would reduce neuroblastoma disease burden in the bone.

METHODS:

Stable expression of green fluorescent protein (NPC-GFP) and OPG (NPC-OPG) was established in human NPCs by lentivirus-mediated transduction. Bone disease was established by intrafemoral injection of luciferase-expressing human neuroblastoma (CHLA-255) cells into 20 SCID mice. Three weeks later, mice began receiving intravenous injection of 2 x 10(6) NPC-OPG or NPC-GFP (control) every 10 days x 3 doses. Disease was monitored with quantitative bioluminescence imaging and x-ray images, which were evaluated on a scale of 0 to 4. These studies were approved by the Institutional Animal Care and Use Committee.

RESULTS:

Osteoprotegerin treatment in vitro produced no direct toxicity to tumor cells. Coculture of tumor cells with bone marrow significantly increased activation of bone marrow-derived osteoclasts as assessed by tartrate-resistant acid phosphatase staining (156 +/- 10.8 osteoclasts per well) compared to bone marrow culture alone (91.67 +/- 4.7, P = .005). This increase was abrogated by adding OPG-containing media (68.3 +/- 2.8, P = .001). NPC-OPG slowed tumor progression (108-fold increase from pretreatment) compared to mice treated with NPC-GFP (538-fold), as judged by bioluminescence imaging. X-rays subjectively demonstrated less bone disease in NPC-OPG-treated mice (2.27 +/- 0.25) compared to NPC-GFP-treated mice (3.25 +/- 0.22, P = .04).

CONCLUSIONS:

Neural progenitor cell-mediated delivery of OPG slowed disease progression in a preclinical model of neuroblastoma bone metastasis. The decrease in bone disease was not from direct tumor cell toxicity but likely occurred indirectly through inhibition of osteoclast-directed bone resorption. Thus, targeted delivery of OPG by NPCs may be effective in the treatment of neuroblastoma bone metastasis.

• Authors: Thomas L Sims Jr, J Blair Hamner, Rebecca A Bush, Peter E Fischer, Seung U Kim, Karen S Aboody, Beth McCarville, Mary K Danks, Andrew M Davidoff
• Journal: Journal of pediatric surgery (J Pediatr Surg) Vol. 44 Issue 1 Pg. 204-10; discussion 210-1 (Jan 2009) ISSN: 1531-5037 [Electronic] United States
• PMID: 19159744 (Publication Type: Journal Article)

Chemical References

• Osteoprotegerin
• Green Fluorescent Proteins

Topics

• Animals
• Bone Neoplasms (pathology)
• Cell Line, Tumor
• Disease Progression
• Green Fluorescent Proteins (pharmacology)
• Humans
• In Vitro Techniques
• Mice
• Mice, SCID
• Neoplasm Metastasis (prevention & control)
• Neuroblastoma (pathology)
• Osteoprotegerin (pharmacology)
• Statistics, Nonparametric
• Stem Cells (metabolism)
• Transduction, Genetic