title: BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo.
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.
authors.affiliation: Department of Urology, Leiden University Medical Center, J3-100, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Jeroen T
authors.initials: JT
authors.lastname: Buijs
authors.forename: Cyrill A
authors.initials: CA
authors.lastname: Rentsch
authors.forename: Geertje
authors.initials: G
authors.lastname: van der Horst
authors.forename: Petra G M
authors.initials: PG
authors.lastname: van Overveld
authors.forename: Antoinette
authors.initials: A
authors.lastname: Wetterwald
authors.forename: Ruth
authors.initials: R
authors.lastname: Schwaninger
authors.forename: Niek V
authors.initials: NV
authors.lastname: Henriquez
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
authors.forename: Fran
authors.initials: F
authors.lastname: Borovecki
authors.forename: Regula
authors.initials: R
authors.lastname: Markwalder
authors.forename: George N
authors.initials: GN
authors.lastname: Thalmann
authors.forename: Socrates E
authors.initials: SE
authors.lastname: Papapoulos
authors.forename: Rob C M
authors.initials: RC
authors.lastname: Pelger
authors.forename: Slobodan
authors.initials: S
authors.lastname: Vukicevic
authors.forename: Marco G
authors.initials: MG
authors.lastname: Cecchini
authors.forename: Clemens W G M
authors.initials: CW
authors.lastname: Löwik
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D001859:Bone Neoplasms / Q000556:secondary*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D012333:RNA, Messenger