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Published on: September 13, 2017
Apo2l/Tumor necrosis factor-related apoptosis-inducing ligand prevents breast cancer-induced bone destruction in a
Le Minh Thai1, Agatha Labrinidis, Shelley Hay
1Department of Orthopaedics, Royal Adelaide Hospital, Adelaide University, Adelaide, Australia.
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.
Insights
Recombinant soluble Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) significantly reduced breast cancer bone destruction and tumor burden in mice. Resistance developed but was reversed with chemotherapy combinations.
Area of Science:
- Oncology
- Molecular Biology
- Bone Metastasis Research
Background:
- Breast cancer commonly metastasizes to bone, causing significant osteolytic lesions.
- Effective treatments for bone metastases remain a critical unmet need in oncology.
Purpose of the Study:
- To evaluate the efficacy of recombinant soluble Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against breast cancer bone metastasis.
- To investigate the development of resistance to Apo2L/TRAIL and strategies to overcome it.
Main Methods:
- A mouse model was established by transplanting MDA-MB-231 breast cancer cells into the tibiae of athymic nude mice.
- Treatment efficacy was assessed using radiography, micro-computed tomography, and histology.
- Tumor cells were explanted to assess resistance and test combination therapies.
Main Results:
- Apo2L/TRAIL treatment resulted in an 85% reduction in osteolysis and a 90% reduction in tumor burden.
- No soft tissue invasion was observed in treated animals.
- Acquired resistance to Apo2L/TRAIL was observed but reversed by combining with chemotherapeutic drugs and a histone deacetylase inhibitor.
Conclusions:
- Recombinant soluble Apo2L/TRAIL effectively prevents breast cancer-induced bone destruction.
- Apo2L/TRAIL holds potential for treating metastatic breast cancer in bone, especially when combined with other agents to overcome resistance.
