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Tumor Biology |
B Ligand (RANKL) Is a Key Molecule of Osteoclast Formation for Bone Metastasis in a Newly Developed Model of Human Neuroblastoma1
Department of Environmental Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1101, Japan
Neuroblastoma originates from neural crest cells and is the most common
extracranial solid tumor in childhood. Bone metastasis in neuroblastoma
is an unfavorable prognostic factor even with intensive therapy. In the
present study, we screened four cell lines of human neuroblastoma
(NB-1, NB-16, NB-19, and NH-6) for tumorigenicity and metastatic
capacity in nude mice and found that NB-19 cells caused osteolytic
lesions after s.c. injection into mice. To detect micrometastases in
the host tissue, we performed two kinds of PCR-based metastasis assays:
(a) genomic PCR assay using the primers for human
genome-specific Alu sequence; and (b) reverse
transcription-nested PCR assay that detects the expression of tyrosine
hydroxylase, a marker specific for neuroblastoma. The results of these
PCR assays revealed the colonization of human neuroblastoma cells in
the bone marrow of the mice that had received the s.c. injection of
NB-19 cells. Because osteoclastic bone resorption has been reported to
play important roles in osteolysis in some cancers such as breast
cancer, we next examined the osteoclast (OC)-inducing activity of NB-19
cells using a coculture system in which NB-19 cells were cultured with
murine bone marrow cells containing OC precursors and stromal cells.
NB-19 cells induced tartrate-resistant acid phosphatase-positive
multinucleated OC-like cells without requirement of
1,25-dihydroxyvitamin D3 or other osteoclastogenic
stimulators. To investigate the factors involved in the
osteoclastogenesis in the coculture of mouse marrow cells and NB-19
cells, we performed reverse transcription-PCR analysis and revealed the
increased expression of receptor activator of nuclear factor 
B
ligand (RANKL) in the coculture compared with the culture of bone
marrow cells alone. Interleukin-1
and cyclooxygenase-2 expression in
the murine marrow cells was also increased in the presence of NB-19
cells. To further study the role of RANKL in the OC-like cell formation
in the coculture of NB-19 cells and murine marrow cells, an expression
vector encoding the active portion of the murine osteoprotegerin, which
is the native inhibitor of RANKL action, was constructed and introduced
into COS-7 cells. The conditioned media of the COS-7 cells transfected
with the osteoprotegerin expression vector effectively blocked OC-like
cell formation in the coculture of the bone marrow cells and NB-19
cells. These results suggested that in the bone microenvironment of
NB-19-bearing mice, the stimulated expression of RANKL plays an
important role in OC formation, leading to osteolytic bone metastasis.
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