title: Apo2l/Tumor necrosis factor-related apoptosis-inducing ligand prevents breast cancer-induced bone destruction in a mouse model.
abstract: Breast cancer is the most common carcinoma that metastasizes to bone. To examine the efficacy of recombinant soluble Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against breast cancer growth in bone, we established a mouse model in which MDA-MB-231 human breast cancer cells were transplanted directly into the marrow cavity of the tibiae of athymic nude mice producing osteolytic lesions in the area of injection. All vehicle-treated control animals developed large lesions that established in the marrow cavity, eroded the cortical bone, and invaded the surrounding soft tissue, as assessed by radiography, micro-computed tomography, and histology. In contrast, animals treated with recombinant soluble Apo2L/TRAIL showed significant conservation of the tibiae, with 85% reduction in osteolysis, 90% reduction in tumor burden, and no detectable soft tissue invasion. Tumor cells explanted from Apo2L/TRAIL-treated animals were significantly more resistant to the effects of Apo2L/TRAIL when compared with the cells explanted from the vehicle-treated control animals, suggesting that prolonged treatment with Apo2/TRAIL in vivo selects for a resistant phenotype. However, such resistance was readily reversed when Apo2L/TRAIL was used in combination with clinically relevant chemotherapeutic drugs, including taxol, etoposide, doxorubicin, cisplatin, or the histone deacetylase inhibitor suberoylanilide hydroxamic acid. These studies show for the first time that Apo2L/TRAIL can prevent breast cancer-induced bone destruction and highlight the potential of this ligand for the treatment of metastatic breast cancer in bone.
authors.affiliation: Department of Orthopaedics, Royal Adelaide Hospital, Adelaide University, Adelaide, Australia.
authors.forename: Le Minh
authors.initials: le M
authors.lastname: Thai
authors.forename: Agatha
authors.initials: A
authors.lastname: Labrinidis
authors.forename: Shelley
authors.initials: S
authors.lastname: Hay
authors.forename: Vasilios
authors.initials: V
authors.lastname: Liapis
authors.forename: Steve
authors.initials: S
authors.lastname: Bouralexis
authors.forename: Katie
authors.initials: K
authors.lastname: Welldon
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Coventry
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006801:Humans; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010014:Osteolysis / Q000517:prevention & control*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins