Molecular profiling of giant cell tumor of bone and the osteoclastic localization of ligand for receptor activator of nuclear factor kappaB.
Giant cell tumor of bone (GCT) is a generally benign, osteolytic neoplasm comprising stromal cells and osteoclast-like giant cells. The osteoclastic cells, which cause bony destruction, are thought to be recruited from normal monocytic pre-osteoclasts by stromal cell expression of the ligand for receptor activator of nuclear factor kappaB (RANKL). This model forms the foundation for clinical trials in GCTs of novel cancer therapeutics targeting RANKL. Using expression profiling, we identified both osteoblast and osteoclast signatures within GCTs, including key regulators of osteoclast differentiation and function such as RANKL, a C-type lectin, osteoprotegerin, and the wnt inhibitor SFRP4. After ex vivo generation of stromal- and osteoclast-enriched cultures, we unexpectedly found that RANKL mRNA and protein were more highly expressed in osteoclasts than in stromal cells, as determined by expression profiling, flow cytometry, immunohistochemistry, and reverse transcriptase-polymerase chain reaction. The expression patterns of molecules implicated in signaling between stromal cells and monocytic osteoclast precursors were analyzed in both primary and fractionated GCTs. Finally, using array-based comparative genomic hybridization, neither GCTs nor the derived stromal cells demonstrated significant genomic gains or losses. These data raise questions regarding the role of RANKL in GCTs that may be relevant to the development of molecularly targeted therapeutics for this disease.
Morgan
Teresa
T
Ian Potter Foundation Center for Cancer Genomics and Predictive Medicine and Research Division, Peter MacCallum Cancer Center, Melbourne, Australia.
Atkins
Gerald J
GJ
Trivett
Melanie K
MK
Johnson
Sandra A
SA
Kansara
Maya
M
Schlicht
Stephen L
SL
Slavin
John L
JL
Simmons
Paul
P
Dickinson
Ian
I
Powell
Gerald
G
Choong
Peter F M
PF
Holloway
Andrew J
AJ
Thomas
David M
DM
D001859:Bone Neoplasms / Q000235:genetics*; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D017931:DNA Primers; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D018212:Giant Cell Tumor of Bone / Q000235:genetics*; D018219:Histiocytoma, Benign Fibrous / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007890:Leiomyosarcoma / Q000235:genetics; D008080:Liposarcoma / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009693:Nucleic Acid Hybridization; D010010:Osteoclasts / Q000378:metabolism*; D011506:Proteins / Q000032:analysis; D053245:RANK Ligand; D012333:RNA, Messenger / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013584:Sarcoma, Synovial / Q000235:genetics
D002352:Carrier Proteins; D017931:DNA Primers; D008562:Membrane Glycoproteins; D011506:Proteins; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human