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(American Journal of Pathology. 2007;170:160-175.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.051276

Lack of Noggin Expression by Cancer Cells Is a Determinant of the Osteoblast Response in Bone Metastases

Ruth Schwaninger^*, Cyrill A. Rentsch^*, Antoinette Wetterwald^*, Geertje van der Horst, Rutger L. van Bezooijen, Gabri van der Pluijm, Clemens W.G.M. Löwik, Karin Ackermann^¶, Walter Pyerin^¶, Freddie C. Hamdy^||, George N. Thalmann^* and Marco G. Cecchini^*

From the Urology Research Laboratory, Department of Urology and Department of Clinical Research,^* University of Bern, Bern, Switzerland; Department of Endocrinology, Department of Urology, and Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands; Biochemical Cell Physiology,^¶ German Cancer Research Center, Heidelberg, Germany; and the Academic Urology Unit,|| University of Sheffield, Royal Hallamshire Hospital, Sheffield, United Kingdom

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.

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