Therapeutic efficacy of soluble receptor activator of nuclear factor-kappa B-Fc delivered by nonviral gene transfer in a mouse model of osteolytic osteosarcoma.
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.
INSERM, ERI 7, Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, EA3822, 1 rue Gaston Veil, 44035 Nantes cedex 1, France.
François
F
Lamoureux
Gaëlle
G
Picarda
Julie
J
Rousseau
Clothilde
C
Gourden
Séverine
S
Battaglia
Céline
C
Charrier
Bruno
B
Pitard
Dominique
D
Heymann
Françoise
F
Rédini
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics*; D008168:Lung / Q000473:pathology; D051379:Mice; D010014:Osteolysis / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D012516:Osteosarcoma / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics* / Q000627:therapeutic use*; D015203:Reproducibility of Results; D012995:Solubility; D016019:Survival Analysis; D019076:Transgenes; D016896:Treatment Outcome
D007141:Immunoglobulin Fc Fragments; D053246:Receptor Activator of Nuclear Factor-kappa B