Abstract
Pentraxin 3 (PTX3), a modulator of tumor-associated inflammation, is known to be positively correlated with tumor grade and severity of malignancies, but its exact role remains unclear. This study found that PTX3 expression was up-regulated in distant bone metastases of breast cancer compared to lung, liver, and brain metastases in 64 human breast cancer patients. Elevated expression of PTX3 was correlated with poor survival in patients with breast cancer. PTX3 expression was also up-regulated in a bone metastatic breast cancer cell line and further enhanced by pro-inflammatory cytokine TNFα. Administration of PTX3 promoted the migratory potential of breast cancer cells and the mobilization of macrophages, a precursor of osteoclasts (OCs), toward breast cancer cells. In addition, elevated expression of PTX3 by TNFα led to enhanced OC formation, implying the distinct role of PTX3 in osteolytic bone metastasis of breast cancer cells. Furthermore, PTX3 silencing using PTX3-specific siRNA prevented breast cancer cell migration, macrophage chemotaxis, and subsequent OC formation. These findings provide an important insight into the key role of PTX3 in inflammation-associated osteolytic complications of breast cancer.
Highlights
Bone is a unique environment storing a variety of growth factors, and is one of the most common target sites for distant metastasis of breast cancer [1]
The expression level of Pentraxin 3 (PTX3) in bone metastasis sample was significantly higher than that of lung, liver, or brain metastases in breast cancer patients. These results suggested that PTX3 mRNA was over-expressed (p
The present study provides the first evidence of the clinical importance of PTX3 as a prognostic factor in bone metastatic breast cancer
Summary
Bone is a unique environment storing a variety of growth factors, and is one of the most common target sites for distant metastasis of breast cancer [1]. OCs degrade bone and release a variety of bone-storing growth factors, such as insulin-like growth factors (IGF), transforming growth factor-beta (TGF-beta), fibroblast growth factor (FGF), platelet-derived growth factor, and bone morphogenic proteins (BMPs) from bone [58]. These growth factors facilitate tumor growth, establishing a “vicious cycle” [7, 8]. Metastases to bone worsen quality of life in these patients by causing pathological manifestations of osteolytic lesions, including devastating bone pain, pathological fractures, spinal compression, and hypercalcemia, which indirectly lead to earlier death [9]. Early detection of bone metastases and an increased understanding of the cellular and molecular mechanisms contributing to osteolysis will www.impactjournals.com/oncotarget improve patients’ quality of life and decrease morbidity and mortality [10]
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