Development of Organ-specific Treatment for Bone Metastasis in Neuroblastoma

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Bone metastasis in neuroblastoma is an unfavorable prognostic factor even with intensive therapy. We have previously reported that nuclear factor κB ligand (RANKL) expression is stimulated in the coculture of human neuroblastoma cell line and murine bone marrow cells containing osteoclast precursors and stromal cells, compared with the culture of bone marrow cells alone. As the result, osteoclastogenesis was increased in the coculture. In other cancers such as prostate cancer and multiple myeloma as well, RANKL signaling is suggested to play a role. In an attempt to develop an organ-specific treatment for bone metastasis in neuroblastoma, we examined the effect of gene therapy using osteoprotegerin (OPG) expression vector in some animal models of osteolytic bone diseases. As the expression vector, we utilized pCAGGS containing CAG promoter. We constructed pCAGGS-OPG-FLAG, and confirmed the biological activity of OPG-FLAG in an in vitro osteoclastogenesis assay. To introduce pCAGGS-OPG-FLAG into the muscle of animals, we utilized naked DNA injection method combined with electroporation. In animal models of humoral hypercalcemia of malignancy, introduction of pCAGGS-OPG-FLAG restored hypercalcemia. In OPG knockout mice, the treatment using pCAGGS-OPG-FLAG increased bone mineral density. These data suggested the usefulness of treatment targeting RANKL signaling in osteolytic bone diseases, containing bone metasatsis in neuroblastoma.