Preclinical evidence that use of TRAIL in Ewing's sarcoma and osteosarcoma therapy inhibits tumor growth, prevents osteolysis, and increases animal survival.
OBJECTIVE
Osteosarcoma and Ewing's sarcoma are high-grade neoplasms typically arising in the bones of children and adolescents. Despite improvement in therapy, the five-year survival rate is only 20% for patients not responding to treatment or presenting with metastases. Among new therapeutic strategies, the efficacy of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily with strong antitumoral activity and minimal toxicity to most normal cells and tissues, was investigated by complementary approaches both in vitro and in preclinical models.


METHODS
The sensitivity of osteosarcoma and Ewing's sarcoma cell lines to TRAIL was investigated in vitro by determining TRAIL receptor expression together with TRAIL effects on cell viability and apoptosis. Complementary preclinical studies were carried out in respective tumor models by inoculation of osteosarcoma or Ewing's sarcoma tumor cells in paraosseous location. In addition, a model of lung nodule dissemination was developed by i.v. injection of osteosarcoma cells.


RESULTS
In vitro, both osteosarcoma and Ewing's sarcoma cells that express the TRAIL death receptors were highly sensitive to TRAIL-induced caspase-8-mediated apoptosis. TRAIL administered in vivo by nonviral gene therapy inhibited primary bone tumor incidence and growth by 87% and prevented tumor-induced osteolysis, leading to a significant 2-fold increase in animal survival 40 days after tumor induction. Furthermore, TRAIL inhibited tumor nodule dissemination in lungs and increased survival in an osteosarcoma model.


CONCLUSIONS
These findings suggest that TRAIL is a promising candidate for the development of new therapeutic strategies in the most frequent malignant primary bone tumors.
Picarda
Gaëlle
G
Institut National de la Sante et de la Recherche Medicale UMR_S 957, Université de Nantes EA 3822, Nantes Atlantique Universités, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes, France.
Lamoureux
François
F
Geffroy
Loïc
L
Delepine
Pascal
P
Montier
Tristan
T
Laud
Karine
K
Tirode
Franck
F
Delattre
Olivier
O
Heymann
Dominique
D
Rédini
Françoise
F
D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation; D002648:Child; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D010014:Osteolysis / Q000517:prevention & control*; D012516:Osteosarcoma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D015996:Survival Rate; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000494:pharmacology*; D019076:Transgenes / Q000502:physiology
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand