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PMID: 22124112 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

The Journal of experimental medicine ·Vol. 208 ·No. 13 ·2011-12-19 ·Pages 2641-55

Kobayashi A, Okuda H, Xing F, Pandey PR, Watabe M, Hirota S, Pai SK, Liu W, Fukuda K, Chambers C, Wilber A, Watabe K

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.

MeSH Terms
Animals Bone Morphogenetic Protein 7/metabolism Bone Morphogenetic Protein Receptors, Type II/biosynthesis Bone Neoplasms/metabolism,pathology,secondary,therapy Cell Cycle Proteins/biosynthesis Cyclin-Dependent Kinase Inhibitor p27/biosynthesis Gene Expression Regulation, Neoplastic Humans Intracellular Signaling Peptides and Proteins Male Mice Neoplasm Metastasis Neoplasm Proteins/metabolism Neoplasm Transplantation Neoplastic Stem Cells/metabolism,pathology Prostatic Neoplasms/metabolism,pathology,therapy Transplantation, Heterologous p38 Mitogen-Activated Protein Kinases/metabolism
Chemicals
BMP7 protein, human Bone Morphogenetic Protein 7 CDKN1B protein, human Cell Cycle Proteins Intracellular Signaling Peptides and Proteins N-myc downstream-regulated gene 1 protein Neoplasm Proteins Cyclin-Dependent Kinase Inhibitor p27 p38 Mitogen-Activated Protein Kinases BMPR2 protein, human Bone Morphogenetic Protein Receptors, Type II
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Kobayashi Aya
Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 19626, USA.
Okuda Hiroshi
Xing Fei
Pandey Puspa R
Watabe Misako
Hirota Shigeru
Pai Sudha K
Liu Wen
Fukuda Koji
Chambers Christopher
Wilber Andrew
Watabe Kounosuke
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20110840
Published
2011-12-19
Epub
2011-00-28
Pages
2641-55
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC3244043
Subset
IM
Grants
NCI NIH HHS · R01 CA124650 · United States
NCI NIH HHS · R01 CA129000 · United States
NCI NIH HHS · R01CA129000 · United States
NCI NIH HHS · R01CA124650 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1084/jem.20110840 PMC Full Text View journal details
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