Human
breast cancer frequently metastasizes to bone, and effective
therapies for patients with bone
metastasis are required. However, the molecular mechanism for the bone
metastasis of human
breast cancer has not yet been fully elucidated. The present study aimed to evaluate the importance of active osteoclasts and bone-derived
insulin-like growth factors (IGFs) for the survival and growth of
breast cancer cells in bone. Human
breast cancer cell line MCF-7 cells were injected into human adult bone (HAB) implanted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. The mice were then treated with recombinant human
osteoclastogenesis inhibitory factor/
osteoprotegerin (rhOCIF/OPG), a decoy receptor for
receptor activator of NF-kappaB ligand (RANKL), or an anti-human IGF
monoclonal antibody. Histomorphometric analyses revealed that both treatments significantly decreased the
tumor area of MCF-7 cells in cross-sections of the implanted HAB to about 30% of the
tumor area in control mice, but had no effect on the growth of subcutaneously injected MCF-7 cells. Consistent with the results for the
tumor area in HAB, there were fewer osteoclasts in the implanted HAB in rhOCIF/OPG-treated mice than in vehicle-treated mice. However, treatment with the anti-human IGF
monoclonal antibody had no effect on the number of osteoclasts in HAB. The results indicate that the active osteoclasts induced by RANKL and the IGFs released as a result of
bone resorption by these osteoclasts play crucial roles in the survival and growth of human
breast cancer cells in bone and suggest that neutralization of bone-derived IGFs will be effective in preventing the development of bone
tumors in
breast cancer patients.