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 fluorescen...

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Published in:	Journal of pediatric surgery 2009, Vol.44 (1), p.204-211
Main Authors:	Sims, Thomas L, Hamner, J. Blair, Bush, Rebecca A, Fischer, Peter E, Kim, Seung U, Aboody, Karen S, McCarville, Beth, Danks, Mary K, Davidoff, Andrew M
Format:	Article
Language:	eng
Subjects:	Animals Bone metastasis Bone Neoplasms - pathology Cell Line, Tumor Disease Progression Green Fluorescent Proteins - pharmacology Humans In Vitro Techniques Mice Mice, SCID Neoplasm Metastasis - prevention & control Neural progenitor cells Neuroblastoma Neuroblastoma - pathology Osteoclast Osteoprotegerin Osteoprotegerin - pharmacology Pediatrics Statistics, Nonparametric Stem Cells - metabolism Surgery Transduction, Genetic
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Summary:	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 × 106 NPC-OPG or NPC-GFP (control) every 10 days × 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.
ISSN:	0022-3468 1531-5037