Dickkopf‐1 (DKK‐1) stimulated prostate cancer growth and metastasis and inhibited bone formation in osteoblastic bone metastases

Abstract

Background Osteoblastic bone metastasis is the predominant phenotype observed in prostate cancer patients and is associated with high patient mortality and morbidity. However, the mechanisms determining the development of this phenotype are not well understood. Prostate cancer cells secrete several osteogenic factors including Wnt proteins, which are not only osteoinductive but also oncogenic. Therefore, the purpose of the study was to investigate the contribution of the Wnt signaling pathway in prostate cancer growth, incidence of bone metastases and osteoblastic phenotype of bone metastases. The strategy involved overexpressing the Wnt antagonist, DKK-1, in the mixed osteoblastic and osteolytic Ace-1 prostate cancer cells. Methods Ace-1 prostate cancer cells stably expressing human DKK-1 or empty vector were established and transduced with lentiviral yellow fluorescent protein (YFP)-luciferase (Luc). The Ace-1/vectorYFP-LUC and Ace-1/DKK-1YFP-LUC cells were injected subcutaneously, intratibially, or in the left cardiac ventricle in athymic mice. Results Unexpectedly, DKK-1 significantly increased Ace-1 subcutaneous tumor mass and the incidence of bone metastases after intracardiac injection of Ace-1 cells. DKK-1 increased Ace-1 tumor growth associated with increased phospho46 JNK by the Wnt noncanonical pathway. As expected, DKK-1 decreased the Ace-1 osteoblastic phenotype of bone metastases, as confirmed by radiographic, histopathological, and microcomputer tomographic analysis. DKK-1 decreased osteoblastic activity via the Wnt canonical pathway evidenced by an inhibition of T-cell factor (TCF) activity in murine osteoblast precursor ST2 cells. Conclusion The present study showed that DKK-1 is a potent inhibitor of bone growth in prostate cancer-induced osteoblastic metastases.

Prostate Cancer Progression to Androgen Independent Disease: The Role of the Wnt/β-Catenin Pathway

“…Once CaP cells had invaded the bone, DKK-1 levels subsequently minimized as new bone formation required Wnt activation to propagate osteoblastic activity. This was in line with more recent experimental data showing that intercardiac injection of stably expressing DKK-1 Ace-1 cells (a CaP cell line that produces mixed osteoblastic and osteolytic lesions) into mice, increased the appearance of a subcutaneous tumor mass and decreased Ace-1-induced osteoblast activity (Thudi et al, 2011). Taken together, these results support the association between DKK-1 overexpression in CaP metastases and a decreased overall patient lifespan (Hall et al, 2008).…”

Local treatment of mixed osteolytic/osteoblastic spinal metastases: is photodynamic therapy effective?

“…Osteoblastic metastases tend to induce new woven bone on the surface of pre-existing medullary trabecular bone [15], which was observed in our model, both in untreated and in PDT-treated groups. Similar observations of overwhelming osteolysis in addition to definite areas of new bone formation have also been described in mouse models of mixed osteolytic/osteoblastic metastases [12,[16][17][18]. As such, it remains important to consider host bony repair mechanisms when considering the effect of tumor invasion of vertebrae bone.…”

Wnt Signaling in Bone Development and Disease: Making Stronger Bone with Wnts

“…DKK1 has been proposed to be an important regulator in prostate cancer bone metastasis because alterations in DKK1 expression are linked to several tumor types with a propensity to grow in bone including prostate carcinoma, breast carcinoma, and multiple myeloma (Forget et al 2007). Prostate cancer cells overexpressing DKK1 have a higher potential to metastasize into bone and generate osteolytic lesions (Thudi et al 2010). DKK1 upregulation is a frequent event in mammary cancer, and increased serum levels of DKK1 are associated with the presence of bone metastasis in patients (Voorzanger-Rousselot et al 2007;Bu et al 2008).…”