Prostate Cancer Induces Bone Metastasis through Wnt-Induced Bone Morphogenetic Protein-Dependent and Independent Mechanisms
- 15 July 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (14), 5785-5794
- https://doi.org/10.1158/0008-5472.can-07-6541
Abstract
Prostate cancer (PCa) is frequently accompanied by osteosclerotic (i.e., excessive bone production) bone metastases. Although bone morphogenetic proteins (BMP) and Wnts are mediators of PCa-induced osteoblastic activity, the relation between them in PCa bone metastases is unknown. The goal of this study was to define this relationship. Wnt3a and Wnt5a administration or knockdown of DKK-1, a Wnt inhibitor, induced BMP-4 and 6 expression and promoter activation in PCa cells. DKK-1 blocked Wnt activation of the BMP promoters. Transfection of C4-2B cells with axin, an inhibitor of canonical Wnt signaling, blocked Wnt3a but not Wnt5a induction of the BMP promoters. In contrast, Jnk inhibitor I blocked Wnt5a but not Wnt3a induction of the BMP promoters. Wnt3a, Wnt5a, and conditioned medium (CM) from C4-2B or LuCaP23.1 cells induced osteoblast differentiation in vitro. The addition of DKK-1 and Noggin, a BMP inhibitor, to CM diminished PCa CM–induced osteoblast differentiation in a synergistic fashion. However, pretreatment of PCa cells with DKK-1 before collecting CM blocked osteoblast differentiation, whereas pretreatment with Noggin only partially reduced osteoblast differentiation, and pretreatment with both DKK-1 and Noggin had no greater effect than pretreatment with DKK-1 alone. Additionally, knockdown of BMP expression in C4-2B cells inhibited Wnt-induced osteoblastic activity. These results show that PCa promotes osteoblast differentiation through canonical and noncanonical Wnt signaling pathways that stimulate both BMP-dependent and BMP-independent osteoblast differentiation. These results show a clear link between Wnts and BMPs in PCa-induced osteoblast differentiation and provide novel targets, including the noncanonical Wnt pathway, for therapy of PCa. [Cancer Res 2008;68(14):5785–94]Other Versions
This publication has 59 references indexed in Scilit:
- BMP7, a Putative Regulator of Epithelial Homeostasis in the Human Prostate, Is a Potent Inhibitor of Prostate Cancer Bone Metastasis in VivoThe American Journal of Pathology, 2007
- Wnt-4 signaling is involved in the control of smooth muscle cell fate via Bmp-4 in the medullary stroma of the developing kidneyDevelopmental Biology, 2006
- Purified Wnt5a Protein Activates or Inhibits β-Catenin–TCF Signaling Depending on Receptor ContextPLoS Biology, 2006
- Mechanisms of Osteoblastic Metastases: Role of Endothelin-1Clinical Orthopaedics and Related Research, 2003
- Regulation of BMP‐7 expression by retinoic acid and prostaglandin E2Journal of Cellular Physiology, 2002
- Transcriptional Mechanisms of Bone Morphogenetic Protein-induced Osteoprotegrin Gene ExpressionOnline Journal of Public Health Informatics, 2001
- Differentiation of Human Marrow Stromal Precursor Cells: Bone Morphogenetic Protein-2 Increases OSF2/CBFA1, Enhances Osteoblast Commitment, and Inhibits Late Adipocyte MaturationJournal of Bone and Mineral Research, 1999
- Bone morphogenetic protein‐7 in growth‐plate chondrocytes: Regulation by retinoic acid is dependent on the stage of chondrocyte maturationJournal of Orthopaedic Research, 1998
- Evidence for the upregulation of osteogenic protein-1 mRNA expression in musculoskeletal neoplasmsJournal of Orthopaedic Research, 1998
- Osteogenic Protein-1 mRNA in the Uterine EndometriumBiochemical and Biophysical Research Communications, 1997