Abstract
Bone destruction induced by breast cancer metastasis causes severe complications, including death, in breast cancer patients. Communication between cancer cells and skeletal cells in metastatic bone microenvironments is a principal element that drives tumor progression and osteolysis. Tumor-derived factors play fundamental roles in this form of communication. To identify soluble factors released from cancer cells in bone metastasis, we established a highly bone-metastatic subline of MDA-MB-231 breast cancer cells. This subline (mtMDA) showed a markedly elevated ability to secrete S100A4 protein, which directly stimulated osteoclast formation via surface receptor RAGE. Recombinant S100A4 stimulated osteoclastogenesis in vitro and bone loss in vivo. Conditioned medium from mtMDA cells in which S100A4 was knocked down had a reduced ability to stimulate osteoclasts. Furthermore, the S100A4 knockdown cells elicited less bone destruction in mice than the control knockdown cells. In addition, administration of an anti-S100A4 monoclonal antibody (mAb) that we developed attenuated the stimulation of osteoclastogenesis and bone loss by mtMDA in mice. Taken together, our results suggest that S100A4 released from breast cancer cells is an important player in the osteolysis caused by breast cancer bone metastasis.
Highlights
Bone metastasis affects >80% of patients with breast cancer at advanced stages of the disease and causes severe pain, fracture, hypercalcemia, and nerve compression, leading to increased morbidity and mortality.[1,2] Most bone metastases of breast cancer are catabolic to the skeleton
To gain further insights into the mechanism involved in the stimulation of osteoclastogenesis by S100A4 from mtMDA, we examined the intracellular signaling pathways reported to be activated during osteoclast differentiation
S100A4 blockade ameliorates bone destruction by breast cancer metastasis We investigated whether systemic administration of a S100A4-blocking antibody would have beneficial effects on bone metastasis of mtMDA cells
Summary
Bone metastasis affects >80% of patients with breast cancer at advanced stages of the disease and causes severe pain, fracture, hypercalcemia, and nerve compression, leading to increased morbidity and mortality.[1,2] Most bone metastases of breast cancer are catabolic to the skeleton. MDA CM and mtMDA CM increased osteoclast formation by 2.9- and 6.2-fold, respectively, compared with MCF7 CM (Fig. 2f) These results indicated that bone-metastasized breast cancer cells have high levels of S100A4 gene expression and protein secretion and that S100A4 secretion may be associated with cancer-induced osteoclastogenesis. A higher number of osteoclasts was detected in mtMDACsh-injected tibia than in mtMDA-S100A4sh-injected tibia (Fig. 8e, f) Taken together, these data suggest that S100A4 released by bone metastatic MDA cells plays critical roles in stimulating osteolysis and increasing tumor burden in the bone marrow. Serum CTX-I levels were lower in 4A-treated mice than in control mice (Fig. 9f) These results indicate that blocking S100A4 was effective in suppressing skeletal destruction by bone metastasis of breast cancer cells. Iamin B α-tubulin β-actin c p65 / Iamin B p65 activation (OD at 450 nm) (Green + nuclei/total nuclei)/% p65 activation (OD at 450 nm) p50 activation (OD at 450 nm)
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