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Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone

Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 19626, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 11/2011; 208(13):2641-55. DOI: 10.1084/jem.20110840
Source: PubMed

ABSTRACT Metastatic disease is the major cause of cancer deaths, and recurrent tumors at distant organs are a critical issue. However, how metastatic tumor cells become dormant and how and why tumors recur in target organs are not well understood. In this study, we demonstrate that BMP7 (bone morphogenetic protein 7) secreted from bone stromal cells induces senescence in prostate cancer stem-like cells (CSCs) by activating p38 mitogen-activated protein kinase and increasing expression of the cell cycle inhibitor, p21, and the metastasis suppressor gene, NDRG1 (N-myc downstream-regulated gene 1). This effect of BMP7 depended on BMPR2 (BMP receptor 2), and BMPR2 expression inversely correlated with recurrence and bone metastasis in prostate cancer patients. Importantly, this BMP7-induced senescence in CSCs was reversible upon withdrawal of BMP7. Furthermore, treatment of mice with BMP7 significantly suppressed the growth of CSCs in bone, whereas the withdrawal of BMP7 restarted growth of these cells. These results suggest that the BMP7-BMPR2-p38-NDRG1 axis plays a critical role in dormancy and recurrence of prostate CSCs in bone and suggest a potential therapeutic utility of BMP7 for recurrent metastatic disease.

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Available from: Andrew Wilber, Aug 16, 2015
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    • "Bone morphogenic protein 7 (BMP7) secreted from endothelial cells effects a reversible cell cycle block in prostate cancer stem cells through p38 induction. Constant exposure of BMP7 leads to senescence and death (Kobayashi et al., 2011). Alternatively, upon induction of angiogenesis, TGFβ1 from sprouting vascular tips is linked to an exit from dormancy and proliferation (Ghajar et al., 2013). "
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    • "For example, previous studies suggested that zinc is important for bone formation and mineralization [38], while bone morphogenetic protein 7 (BMP7) induces cartilage and bone formation [43]. Recently, the TGF-beta family member protein secreted from bone stromal cells BMP7 was found to be critical in tumor dormancy and the recurrence of prostate cancer [44], and was proposed to be a potential drug target. The prediction by GRE4Zn suggested there is a 4-res zinc-binding site of Cys38-Cys71-Cys104-Cys138 in BMP7 (PDB ID: 1BMP) (Fig. 4A). "
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