title: Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone.
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.
authors: Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 19626, USA.
authors: Aya
authors: A
authors: Kobayashi
authors: Hiroshi
authors: H
authors: Okuda
authors: Fei
authors: F
authors: Xing
authors: Puspa R
authors: PR
authors: Pandey
authors: Misako
authors: M
authors: Watabe
authors: Shigeru
authors: S
authors: Hirota
authors: Sudha K
authors: SK
authors: Pai
authors: Wen
authors: W
authors: Liu
authors: Koji
authors: K
authors: Fukuda
authors: Christopher
authors: C
authors: Chambers
authors: Andrew
authors: A
authors: Wilber
authors: Kounosuke
authors: K
authors: Watabe
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000096:biosynthesis; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary / Q000628:therapy; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D014183:Transplantation, Heterologous; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D055419:Bone Morphogenetic Protein 7; D052006:Bone Morphogenetic Protein Receptors, Type II; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C525819:BMP7 protein, human; C436291:CDKN1B protein, human; C498218:BMPR2 protein, human