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

Thomas L. Sims, J. Blair Hamner, Rebecca A. Bush, Peter Fischer, Seung U. Kim, Karen S. Aboody, Beth McCarville, Mary K. Danks, Andrew M. Davidoff

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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.

Original languageEnglish (US)
Pages (from-to)204-211
Number of pages8
JournalJournal of pediatric surgery
Volume44
Issue number1
DOIs
StatePublished - Jan 1 2009

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Osteoprotegerin
Neuroblastoma
Disease Progression
Stem Cells
Neoplasm Metastasis
Bone and Bones
Osteoclasts
Bone Diseases
Neoplasms
Bone Marrow
Animal Care Committees
X-Rays
Lentivirus
Osteolysis
SCID Mice
Bone Resorption
Coculture Techniques
Green Fluorescent Proteins
Luciferases
Intravenous Injections

All Science Journal Classification (ASJC) codes

  • Surgery
  • Pediatrics, Perinatology, and Child Health

Cite this

Neural progenitor cell-mediated delivery of osteoprotegerin limits disease progression in a preclinical model of neuroblastoma bone metastasis. / Sims, Thomas L.; Hamner, J. Blair; Bush, Rebecca A.; Fischer, Peter; Kim, Seung U.; Aboody, Karen S.; McCarville, Beth; Danks, Mary K.; Davidoff, Andrew M.

In: Journal of pediatric surgery, Vol. 44, No. 1, 01.01.2009, p. 204-211.

Research output: Contribution to journalArticle

Sims, Thomas L. ; Hamner, J. Blair ; Bush, Rebecca A. ; Fischer, Peter ; Kim, Seung U. ; Aboody, Karen S. ; McCarville, Beth ; Danks, Mary K. ; Davidoff, Andrew M. / Neural progenitor cell-mediated delivery of osteoprotegerin limits disease progression in a preclinical model of neuroblastoma bone metastasis. In: Journal of pediatric surgery. 2009 ; Vol. 44, No. 1. pp. 204-211.
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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.",
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AU - Sims, Thomas L.

AU - Hamner, J. Blair

AU - Bush, Rebecca A.

AU - Fischer, Peter

AU - Kim, Seung U.

AU - Aboody, Karen S.

AU - McCarville, Beth

AU - Danks, Mary K.

AU - Davidoff, Andrew M.

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N2 - 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.

AB - 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.

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