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PMID: 17724140 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo.

The American journal of pathology ·Vol. 171 ·No. 3 ·2007-09-00 ·Pages 1047-57

Buijs JT, Rentsch CA, van der Horst G, van Overveld PG, Wetterwald A, Schwaninger R, Henriquez NV, Ten Dijke P, Borovecki F, Markwalder R, Thalmann GN, Papapoulos SE, Pelger RC, Vukicevic S, Cecchini MG, Löwik CW, van der Pluijm G

Abstract

Bone morphogenic protein 7 (BMP7) counteracts physiological epithelial-to-mesenchymal transition, a process that is indicative of epithelial plasticity. Because epithelial-to-mesenchymal transition is involved in cancer, we investigated whether BMP7 plays a role in prostate cancer growth and metastasis. BMP7 expression in laser-microdissected primary human prostate cancer tissue was strongly down-regulated compared with normal prostate luminal epithelium. Furthermore, BMP7 expression in prostate cancer cell lines was inversely related to tumorigenic and metastatic potential in vivo and significantly correlated to E-cadherin/vimentin ratios. Exogenous addition of BMP7 to human prostate cancer cells dose-dependently inhibited transforming growth factor beta-induced activation of nuclear Smad3/4 complexes via ALK5 and induced E-cadherin expression. Moreover, BMP7-induced activation of nuclear Smad1/4/5 signaling transduced via BMP type I receptors was synergistically stimulated in the presence of transforming growth factor beta, a growth factor that is enriched in the bone microenvironment. Daily BMP7 administration to nude mice inhibited the growth of cancer cells in bone. In contrast, no significant growth inhibitory effect of BMP7 was observed in intraprostatic xenografts. Collectively, our observations suggest that BMP7 controls and preserves the epithelial phenotype in the human prostate and underscore a decisive role of the tumor microenvironment in mediating the therapeutic response of BMP7. Thus, BMP7 can still counteract the epithelial-to-mesenchymal transition process in the metastatic tumor, positioning BMP7 as a novel therapeutic molecule for treatment of metastatic bone disease.

MeSH Terms
Animals Bone Morphogenetic Protein 7 Bone Morphogenetic Proteins/genetics,metabolism Bone Neoplasms/secondary Cell Line, Tumor Epithelial Cells/cytology,physiology Homeostasis Humans Male Mesoderm/cytology,physiology Mice Mice, Inbred BALB C Mice, Nude Neoplasm Transplantation Prostate/cytology,metabolism Prostatic Neoplasms/metabolism,pathology RNA, Messenger/metabolism
Chemicals
BMP7 protein, human Bone Morphogenetic Protein 7 Bone Morphogenetic Proteins RNA, Messenger
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Buijs Jeroen T
Department of Urology, Leiden University Medical Center, J3-100, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Rentsch Cyrill A
van der Horst Geertje
van Overveld Petra G M
Wetterwald Antoinette
Schwaninger Ruth
Henriquez Niek V
Ten Dijke Peter
Borovecki Fran
Markwalder Regula
Thalmann George N
Papapoulos Socrates E
Pelger Rob C M
Vukicevic Slobodan
Cecchini Marco G
Löwik Clemens W G M
van der Pluijm Gabri
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.2353/ajpath.2007.070168
Published
2007-09-00
Pages
1047-57
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1959502
Subset
IM
Corrections
CommentIn
PMID: 17690188
External Links
PubMed source DOI: 10.2353/ajpath.2007.070168 PMC Full Text View journal details
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