Apo2L/TRAIL inhibits tumor growth and bone destruction in a murine model of multiple myeloma
Agatha Labrinidis1, Peter Diamond, Sally Martin
1Discipline of Orthopaedics and Trauma, The University of Adelaide, Royal Adelaide Hospital, and Hanson Institute, South Australia, Australia.
Purpose:
Multiple myeloma is an incurable disease, for which the development of new therapeutic approaches is required. Here, we report on the efficacy of recombinant soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to inhibit tumor progression and bone destruction in a xenogeneic model of human multiple myeloma.
Experimental Design:
We established a mouse model of myeloma, in which Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells, tagged with a triple reporter gene construct (NES-HSV-TK/GFP/Luc), were transplanted directly into the tibial marrow cavity of nude mice. Tumor burden was monitored progressively by bioluminescence imaging and the development of myeloma-induced osteolysis was measured using high resolution in vivo micro-computed tomography.
Results:
Tumor burden increased progressively in the tibial marrow cavity of mice transplanted with Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells associated with extensive osteolysis directly in the area of cancer cell transplantation. Treatment of mice with recombinant soluble Apo2L/TRAIL reduced myeloma burden in the bone marrow cavity and significantly protected against myeloma-induced osteolysis. The protective effects of Apo2L/TRAIL treatment on bone were mediated by the direct apoptotic actions of Apo2L/TRAIL on myeloma cells within the bone microenvironment.
Conclusions:
This is the first in vivo study that investigates the efficacy of recombinant Apo2L/TRAIL on myeloma burden within the bone microenvironment and associated myeloma-induced bone destruction. Our findings that recombinant soluble Apo2L/TRAIL reduces myeloma burden within the bone microenvironment and protects the bone from myeloma-induced bone destruction argue against an inhibitory role of osteoprotegerin in Apo2L/TRAIL-induced apoptosis in vivo and highlight the need to clinically evaluate Apo2L/TRAIL in patients with multiple myeloma.
Insights
Recombinant soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively reduced multiple myeloma tumor burden and protected against bone destruction in a mouse model. This suggests TRAIL is a promising therapeutic for multiple myeloma patients.
Area of Science:
- Oncology
- Bone Biology
- Apoptosis Signaling
Background:
- Multiple myeloma is an incurable hematologic malignancy.
- Therapeutic strategies are needed to combat tumor progression and bone destruction.
- Recombinant soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anti-cancer agent.
Purpose of the Study:
- To investigate the efficacy of recombinant soluble Apo2L/TRAIL in inhibiting tumor progression and bone destruction in a xenogeneic multiple myeloma model.
- To assess the impact of Apo2L/TRAIL on myeloma burden within the bone microenvironment.
Main Methods:
- A xenogeneic mouse model of multiple myeloma was established using Apo2L/TRAIL-sensitive human myeloma cells (RPMI-8226 or KMS-11) xenografted into the tibial marrow cavity of nude mice.
- Tumor burden was monitored using bioluminescence imaging.
- Myeloma-induced osteolysis was quantified using in vivo micro-computed tomography.
Main Results:
- Transplanted myeloma cells progressively increased tumor burden and caused extensive osteolysis in the bone marrow.
- Treatment with recombinant soluble Apo2L/TRAIL significantly reduced myeloma burden in the bone marrow.
- Apo2L/TRAIL treatment conferred significant protection against myeloma-induced osteolysis, mediated by direct apoptosis of myeloma cells.
Conclusions:
- This study provides the first in vivo evidence of recombinant soluble Apo2L/TRAIL's efficacy against multiple myeloma burden and associated bone destruction within the bone microenvironment.
- The findings support the direct apoptotic action of Apo2L/TRAIL on myeloma cells in vivo.
- Recombinant soluble Apo2L/TRAIL warrants clinical evaluation for patients with multiple myeloma.
Related Concept Videos
mTOR Signaling and Cancer Progression
The mTOR pathway or the...
mTOR Signaling and Cancer Progression
The mTOR pathway or the...

