Neural progenitor cell-mediated delivery of osteoprotegerin limits disease progression in a preclinical model of neuroblastoma bone metastasis.
OBJECTIVE
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.
Sims
Thomas L
TL
Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Hamner
J Blair
JB
Bush
Rebecca A
RA
Fischer
Peter E
PE
Kim
Seung U
SU
Aboody
Karen S
KS
McCarville
Beth
B
Danks
Mary K
MK
Davidoff
Andrew M
AM
D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D049452:Green Fluorescent Proteins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009447:Neuroblastoma / Q000473:pathology*; D053244:Osteoprotegerin / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D013234:Stem Cells / Q000378:metabolism*; D014161:Transduction, Genetic
D053244:Osteoprotegerin; D049452:Green Fluorescent Proteins