Osteosarcoma is the most frequent primary bone
tumor that develops mainly during youth, the median age of diagnosis being 18 years. Despite improvement in
osteosarcoma treatment, survival rate is only 30% after 5 years for patients with pulmonary
metastases at diagnosis. This warrants exploration of new therapeutic options. The anti-
bone resorption molecule
receptor activator of NF-kappaB (RANK) is very promising, as it may block the vicious cycle between
bone resorption and
tumor proliferation that takes place during
tumor development in bone site. The
cDNA encoding murine
RANK-Fc (mRANK-Fc) was administered by gene transfer using an amphiphilic
polymer in a mouse model of osteolytic
osteosarcoma. Clinical and bone microarchitecture variables were assessed by radiography and micro-CT analyses. In vitro experiments were designed to determine the mechanism of action of
RANK-Fc on
tumor cell proliferation (XTT assays), apoptosis (
caspase activation), cell cycle distribution (fluorescence-activated cell sorting analysis), or gene expression (reverse transcription-PCR).
RANK-Fc was effective in preventing the formation of osteolytic lesions associated with
osteosarcoma development and in reducing the
tumor incidence, the local
tumor growth, and the lung
metastases dissemination leading to a 3.9-fold augmentation of mice survival 28 days after implantation. On the contrary, mRANK-Fc did not prevent the development of nonosseous
tumor nodules, suggesting that bone environment is necessary for mRANK-Fc therapeutic efficacy. Furthermore, mRANK-Fc has no direct activity on
osteosarcoma cells in vitro. mRANK-Fc exerts an indirect inhibitory effect on
osteosarcoma progression through inhibition of
bone resorption.