Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/51733
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Type: Journal article
Title: Apo2L/TRAIL inhibits tumor growth and bone destruction in a murine model of multiple myeloma
Author: Labrinidis, A.
Diamond, P.
Martin, S.
Hay, S.
Liapis, V.
Zinonos, I.
Sims, N.
Atkins, G.
Vincent, C.
Ponomarev, V.
Findlay, D.
Zannettino, A.
Evdokiou, A.
Citation: Clinical Cancer Research, 2009; 15(6):1998-2009
Publisher: Amer Assoc Cancer Research
Issue Date: 2009
ISSN: 1078-0432
1557-3265
Statement of
Responsibility: 
Agatha Labrinidis, Peter Diamond, Sally Martin, Shelley Hay, Vasilios Liapis, Irene Zinonos, Natalie A. Sims, Gerald J. Atkins, Cristina Vincent, Vladimir Ponomarev, David M. Findlay, Andrew C.W. Zannettino and Andreas Evdokiou
Abstract: 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.
Keywords: Bone and Bones; Cell Line, Tumor; Osteoclasts; Animals; Humans; Mice; Multiple Myeloma; Osteolysis; Disease Models, Animal; Recombinant Proteins; Transplantation, Heterologous; Neoplasm Transplantation; Cell Differentiation; Female; TNF-Related Apoptosis-Inducing Ligand
Description: Grant support: National Health and Medical Research Council of Australia, The Cancer Council of South Australia, and National Breast Cancer Foundation.
RMID: 0020090393
DOI: 10.1158/1078-0432.CCR-08-2444
Appears in Collections:Orthopaedics and Trauma publications

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