Therapeutic Relevance of Osteoprotegerin Gene Therapy in Osteosarcoma: Blockade of the Vicious Cycle between Tumor Cell Proliferation and Bone Resorption

Abstract

Osteosarcoma is the most frequent primary bone tumor that develops mainly in the young, the median age of diagnosis being 18 years. Despite improvement in osteosarcoma treatment, survival rate is only 30% at 5 years for patients with pulmonary metastases at diagnosis. This warrants exploration of new therapeutic options, and among them, osteoprotegerin (OPG), a naturally occurring protein that inhibits bone resorption, is very promising in blocking the vicious cycle between bone resorption and tumor proliferation that takes place during tumor development in bone site. As OPG binds and inhibits the activity of tumor necrosis factorrelated apoptosis-inducing ligand, the truncated form of murine OPG 1-194 was used. The cDNA encoding OPG was administered by gene transfer using replication-defective adenoviral vector or was associated with an amphiphilic polymer in two models of rodent osteosarcoma. In both models, OPG gene transfer was effective in preventing the formation of osteolytic lesions associated with osteosarcoma development, in reducing the tumor incidence and the local tumor growth, leading to a 4-fold augmentation of mice survival 28 days postimplantation. On the contrary, OPG did not prevent the development of pulmonary metastasis alone, suggesting that bone environment is necessary for OPG therapeutic efficacy. Because OPG has no direct activity on osteosarcoma cells in vitro (cell binding, cell proliferation, apoptosis, or cell cycle distribution), we show that OPG exerts indirect inhibitory effect on tumor progression through the inhibition of RANKL whose production is enhanced in bone tumor environment, leading to osteolysis inhibition as reflected by osteoclast number decrease. [Cancer Res 2007; 67(15):7308-18]

Osteosarcoma of Maxilla with Unusual Image Findings in Child

“…Osteosarcoma lesions are also characterized by bone destruction and high biological virulence apparently caused by active osteoclasts 5) . In this case, pressure-type bone destruction adjacent to the lesion was shown on CT images (Figs.…”

“…Osteosarcoma, the most frequent malignant tumor of bone, is characterized by production of variable amounts of osteoid tissue by neoplastic cells 4,5) . It develops mainly in the young, and the median age at diagnosis is the teens 5) .…”

“…It develops mainly in the young, and the median age at diagnosis is the teens 5) . Osteosarcoma of the head and neck is relatively rare and accounts for less than 10 percent of all osteosarcomas in general 10) , with the jaw being the most frequently encountered site.…”

<b>Unusual Case of Maxillary Osteosarcoma in a 12-year-old Child: A Case Report </b>

“…Osteosarcoma, the most frequent malignant tumor of bone, is characterized by the production of variable amounts of osteoid tissue by neoplastic cells (1,2). Osteosarcoma of the head and neck is relatively rare, and accounts for less than 10% of all osteosarcomas in general, with the jaw being the most frequently encountered site.…”

Radioisotope therapy of bone metastases

“…They produce type I collagen and proteoglycans that form the organic intracellular structure of the bone which is further calcified. Osteoblasts are also responsible for synthesis of osteonectin, osteopontin, osteocalcin, and various types of proteinase [3,4]. …”