Therapeutic relevance of osteoprotegerin gene therapy in osteosarcoma: blockade of the vicious cycle between tumor cell proliferation and bone resorption.
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 factor-related 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.
Institut National de la Sante et de la Recherche Medicale (INSERM), ERI 7, Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.
Francois
F
Lamoureux
Peggy
P
Richard
Yohann
Y
Wittrant
Séverine
S
Battaglia
Paul
P
Pilet
Valérie
V
Trichet
Frédéric
F
Blanchard
Francois
F
Gouin
Bruno
B
Pitard
Dominique
D
Heymann
Francoise
F
Redini
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015519:Bone Density; D001859:Bone Neoplasms / Q000150:complications; D001862:Bone Resorption; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D010014:Osteolysis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D053244:Osteoprotegerin / Q000235:genetics* / Q000627:therapeutic use; D012516:Osteosarcoma / Q000150:complications*; D053245:RANK Ligand / Q000378:metabolism; D051381:Rats; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
D053244:Osteoprotegerin; D053245:RANK Ligand; D020169:Caspases