Apo2L/TRAIL inhibits tumor growth and bone destruction in a murine model of multiple myeloma.
OBJECTIVE
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.


METHODS
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.
Labrinidis
Agatha
A
Discipline of Orthopaedics and Trauma, The University of Adelaide, Royal Adelaide Hospital, and Hanson Institute, South Australia, Australia.
Diamond
Peter
P
Martin
Sally
S
Hay
Shelley
S
Liapis
Vasilios
V
Zinonos
Irene
I
Sims
Natalie A
NA
Atkins
Gerald J
GJ
Vincent
Cristina
C
Ponomarev
Vladimir
V
Findlay
David M
DM
Zannettino
Andrew C W
AC
Evdokiou
Andreas
A
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010014:Osteolysis / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand