Role of wnts in prostate cancer bone metastases

Abstract

Prostate cancer (CaP) is unique among all cancers in that when it metastasizes to bone, it typically forms osteoblastic lesions (characterized by increased bone production). CaP cells produce many factors, including Wnts that are implicated in tumor-induced osteoblastic activity. In this prospectus, we describe our research on Wnt and the CaP bone phenotype. Wnts are cysteine-rich glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Wnts have been shown to have autocrine tumor effects, such as enhancing proliferation and protecting against apoptosis. In addition, we have recently identified that CaP-produced Wnts act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. In addition to Wnts, CaP cells express the soluble Wnt inhibitor dickkopf-1 (DKK-1). It appears that DKK-1 production occurs early in the development of skeletal metastases, which results in masking of osteogenic Wnts, thus favoring osteolysis at the metastatic site. As metastases progress, DKK-1 expression decreases allowing for unmasking of Wnt's osteoblastic activity and ultimately resulting in osteosclerosis at the metastatic site. We believe that DKK-1 is one of the switches that transitions the CaP bone metastasis activity from osteolytic to osteoblastic. Wnt/DKK-1 activity fits a model of CaP-induced bone remodeling occurring in a continuum composed of an osteolytic phase, mediated by receptor activator of NFkB ligand (RANKL), parathyroid hormone-related protein (PTHRP) and DKK-1; a transitional phase, where environmental alterations promote expression of osteoblastic factors (Wnts) and decreases osteolytic factors (i.e., DKK-1); and an osteoblastic phase, in which tumor growth-associated hypoxia results in production of vascular endothelial growth factor and endothelin-1, which have osteoblastic activity. This model suggests that targeting both osteolytic activity and osteoblastic activity will provide efficacy for therapy of CaP bone metastases.

Prostate cancer cells modulate osteoblast mineralisation and osteoclast differentiation through Id-1

“…The reason for effective treatment targeting bone resorption may be mainly because of the osteolytic initial stage during the establishment of the bone metastasis. Recent studies on Wnt signalling have shown important evidence that prostate cancer to bone metastasis might transit from an early osteolytic stage to late osteoblastic stage (Hall et al, 2005(Hall et al, , 2006(Hall et al, , 2008. We found that overexpression of Id-1 in LNCaP cells reduced their ability to stimulate osteoblast mineralisation and enhanced their ability to promote osteoclast differentiation, whereas Id-1 knockdown in PC3 cells reduced their ability to stimulate osteoclast differentiation.…”

A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies

“…The osteoinductive properties of GSK3b inhibitors have been demonstrated both in vivo and in vitro by numerous investigators (Gregory et al, 2006), proteasomal inhibitors have been shown to reduce Dkk-1 and RANKL levels (Terpos et al, 2006), and the benefits of administration of an anti-Dkk-1 antibody have recently been demonstrated in a murine model of multiple myeloma (Yaccoby et al, 2007). However, it remains to be seen whether the induction of Wnt signalling either by GSK3b inhibition, or by antibody administration may affect the metastatic potential of OS cells since Wnt signalling and/or b-catenin upregulation has been shown to be a key regulator of migration in prostate tumours, multiple myeloma cells and also in OS cells (Iwaya et al, 2003;Qiang et al, 2005;Hall et al, 2006). Although we did not detect signs of pulmonary metastasis in this study, further investigation employing highly metastatic OS cell lines should be performed in future work.…”

The role of Dickkopf-1 in bone development, homeostasis, and disease

“…Prostate cancer cells induce osteoblastic metastases through activation of Wnt signaling. 52,59 DKK1 was found to block prostate cancer-associated osteoblastic metastases without affecting tumor growth, while inhibition of DKK1 in osteolytic prostate cancer cells altered the nature of bone metastases from osteolytic to osteoblastic. 59 Consistent with this notion, DKK1 was found to increase early in prostate cancer and decrease as tumors progress from primary tumor to metastasis.…”