Lack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastases.
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.
Schwaninger
Ruth
R
Urology Research Laboratory, Department of Urology, University of Bern, Murtenstrasse 35, CH-3010, Bern, Switzerland.
Rentsch
Cyrill A
CA
Wetterwald
Antoinette
A
van der Horst
Geertje
G
van Bezooijen
Rutger L
RL
van der Pluijm
Gabri
G
Löwik
Clemens W G M
CW
Ackermann
Karin
K
Pyerin
Walter
W
Hamdy
Freddie C
FC
Thalmann
George N
GN
Cecchini
Marco G
MG
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
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D000099176:Noggin Protein; C501126:DKK1 protein, human