title: Osteoprotegerin inhibits bone resorption and prevents tumor development in a xenogenic model of Ewing's sarcoma by inhibiting RANKL.
abstract: Ewing's sarcoma (ES) associated with high osyeolytic lesions typically arises in the bones of children and adolescents. The development of multi-disciplinary therapy has increased current long-term survival rates to greater than 50% but only 20% for high risk group patients (relapse, metastases, etc.). Among new therapeutic approaches, osteoprotegerin (OPG), an anti-bone resorption molecule may represent a promising candidate to inhibit RANKL-mediated osteolytic component of ES and consequently to limit the tumor development. Xenogenic orthotopic models of Ewing's sarcoma were induced by intra-osseous injection of human TC-71 ES cells. OPG was administered in vivo by non-viral gene transfer using an amphiphilic non ionic block copolymer. ES bearing mice were assigned to controls (no treatment, synthetic vector alone or F68/empty pcDNA3.1 plasmid) and hOPG treated groups. A substantial but not significant inhibition of tumor development was observed in the hOPG group as compared to control groups. Marked bone lesions were revealed by micro-computed tomography analyses in control groups whereas a normal bone micro-architecture was preserved in the hOPG treated group. RANKL over-expressed in ES animal model was expressed by tumor cells rather than by host cells. However, TRAIL present in the tumor microenvironment may interfere with OPG effect on tumor development and bone remodeling via RANKL inhibition. In conclusion, the use of a xenogenic model of Ewing's sarcoma allowed discriminating between the tumor and host cells responsible for the elevation of RANKL production observed in this tumor and demonstrated the relevance of blocking RANKL by OPG as a promising therapy in ES.
authors.affiliation: INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France; Université de Nantes, EA3822, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Picarda
authors.affiliation: INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France; Université de Nantes, EA3822, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Matous
authors.affiliation: INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France; Université de Nantes, EA3822, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Amiaud
authors.affiliation: INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France; Université de Nantes, EA3822, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Charrier
authors.affiliation: INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France; Université de Nantes, EA3822, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: François
authors.initials: F
authors.lastname: Lamoureux
authors.affiliation: INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France; Université de Nantes, EA3822, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France; Service d'anatomo-pathologie, CHU Hôtel Dieu, Nantes F-44035, France.
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Heymann
authors.affiliation: INSERM UMR830, Institut Curie, 26 rue d'Ulm, Paris F-75006, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Tirode
authors.affiliation: INSERM UMR1087, IRT-UN, Quai Moncousu, Nantes F-44035, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Pitard
authors.affiliation: INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France; Université de Nantes, EA3822, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Trichet
authors.affiliation: INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France; Université de Nantes, EA3822, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Heymann
authors.affiliation: INSERM, Equipe Ligue Contre le Cancer 2012, UMR-957, Nantes F-44035, France; Université de Nantes, EA3822, Faculté de Médecine, Laboratoire de physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Nantes F-44035, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Redini
keywords: Bone resorption; Ewing's sarcoma; Osteoprotegerin; RANKL; TRAIL