Abstract
BackgroundProstate cancers frequently metastasize to bone, where the best microenvironment for distant colonization is provided. Since osteotropic metastasis of prostate cancer is a critical determinant of patients’ survival, searches for preventive measures are ongoing in the field. Therefore, it is important to dissect the mechanisms of each step of bone metastasis, including the epithelial-mesenchymal transition (EMT) and cross-talk between metastatic niches and cancer cells.MethodsIn this study, we established a highly bone-metastatic subline of human prostate cancer cells by selecting bone-homing population of PC3 cells after cardiac injection of eight-week-old male BALB/c-nude mice. Then we assessed the proliferation, EMT characteristics, and migration properties of the subline (mtPC3) cells in comparison with the parental PC3 cells. To investigate the role of S100A4, we performed gene knock-down by lentiviral transduction, or treated cells with recombinant S100A4 protein or a S100A4-neutralizing antibody. The effect of cancer cells on osteoclastogenesis was evaluated after treatment of pre-osteoclasts with conditioned medium (CM) from cancer cells.ResultsThe mtPC3 cells secreted a markedly high level of S100A4 protein and showed elevated cell proliferation and mesenchymal properties. The increased proliferation and EMT traits of mtPC3 cells was inhibited by S100A4 knock-down, but was not affected by exogenous S100A4. Furthermore, S100A4 released from mtPC3 cells stimulated osteoclast development via the cell surface receptor RAGE. Down-regulation or neutralization of S100A4 in the CM of mtPC3 cells attenuated cancer-induced osteoclastogenesis.ConclusionAltogether, our results suggest that intracellular S100A4 promotes cell proliferation and EMT characteristics in tumor cells, and that secreted S100A4 activates osteoclastogenesis, contributing to osteolytic bone metastasis. Thus, S100A4 upregulation in cancer cells highly metastatic to bone might be a key element in regulating bone metastasis.
Highlights
Prostate cancers frequently metastasize to bone, where the best microenvironment for distant colonization is provided
S100 calcium-binding protein A4 (S100A4) is up-regulated in bone-metastatic prostate cancer cells To obtain bone-metastasized prostate cancer cells, we performed an in vivo selection experiment previously described for collecting highly bone-metastatic breast cancer cells [28]
We tested whether the S100A4 protein was secreted from the cells by performing a human S100A4 Enzyme-linked immunosorbent assay (ELISA) with conditioned medium (CM) of cancer cells
Summary
Prostate cancers frequently metastasize to bone, where the best microenvironment for distant colonization is provided. Metastatic cells in the bone microenvironment support osteoclast activation directly or indirectly by inducing factors such as RANKL, the most potent osteoclastogenic factor, in osteoblasts [4] In support of this notion, tumor-secreted molecules such as parathyroid hormone-related peptide (PTHrP) and interleukin 8 (IL-8) enhance osteoclast-mediated bone resorption, thereby increasing the local availability of bone matrix storage proteins such as transforming growth factor-β (TGF-β) [5]. The increasing concentration of TGF-β perpetuates tumor growth in the bone, leading to a vicious cycle between tumor and bone [4] This emphasizes the role of osteoclasts in releasing tumor growth factors from the bone matrix; in addition, recent studies have shown that dormant tumor cells in the bone microenvironment are re-activated by osteoclasts [6, 7]. Based on these findings, unveiling cross-talk between tumor cells and osteoclasts is a valid approach to find a cure for bone metastasis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
