title: Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases.
abstract: Prostate and mammary cancer bone metastases can be osteoblastic or osteolytic, but the mechanisms determining these features are unclear. Bone morphogenetic and Wnt proteins are osteoinductive molecules. Their activity is modulated by antagonists such as noggin and dickkopf-1. Differential expression analysis of bone morphogenetic and Wnt protein antagonists in human prostate and mammary cancer cell lines showed that osteolytic cell lines constitutively express in vitro noggin and dickkopf-1 and at least one of the osteolytic cytokines parathyroid hormone-related protein, colony-stimulating factor-1, and interleukin-8. In contrast, osteoinductive cell lines express neither noggin nor dickkopf-1 nor osteolytic cytokines in vitro. The noggin differential expression profile observed in vitro was confirmed in vivo in prostate cancer cell lines xenografted into bone and in clinical samples of bone metastasis. Forced noggin expression in an osteoinductive prostate cancer cell line abolished the osteoblast response induced in vivo by its intraosseous xenografts. Basal bone resorption and tumor growth kinetics were marginally affected. Lack of noggin and possibly dickkopf-1 expression by cancer cells may be a relevant mechanism contributing to the osteoblast response in bone metastases. Concomitant lack of osteolytic cytokines may be permissive of this effect. Noggin is a candidate drug for the adjuvant therapy of bone metastasis.
authors.affiliation: Urology Research Laboratory, Department of Urology, University of Bern, Murtenstrasse 35, CH-3010, Bern, Switzerland.
authors.forename: Ruth
authors.initials: R
authors.lastname: Schwaninger
authors.forename: Cyrill A
authors.initials: CA
authors.lastname: Rentsch
authors.forename: Antoinette
authors.initials: A
authors.lastname: Wetterwald
authors.forename: Geertje
authors.initials: G
authors.lastname: van der Horst
authors.forename: Rutger L
authors.initials: RL
authors.lastname: van Bezooijen
authors.forename: Gabri
authors.initials: G
authors.lastname: van der Pluijm
authors.forename: Clemens W G M
authors.initials: CW
authors.lastname: Löwik
authors.forename: Karin
authors.initials: K
authors.lastname: Ackermann
authors.forename: Walter
authors.initials: W
authors.lastname: Pyerin
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.forename: George N
authors.initials: GN
authors.lastname: Thalmann
authors.forename: Marco G
authors.initials: MG
authors.lastname: Cecchini
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D000099176:Noggin Protein; C501126:DKK1 protein, human