The role of Wnts in bone metastases

Abstract

Wnts are a large family of secreted glycoproteins that mediate bone development in the embryo and promote bone production in the adult. Autocrine Wnt signaling within tumor cells has been shown to promote tumorigenesis by enhancing tumor cell proliferation and survival. We recently demonstrated that prostate cancer cells (CaP) produce Wnts which act in a paracrine fashion to induce osteoblastic activity in CaP bone metastases. The ability of tumor-derived Wnts to influence bone development is regulated by multiple families of secreted antagonists including soluble frizzled related receptors (sFrp) and dickkopfs (DKK). CaP cells appear to produce DKK-1 early in the development of skeletal metastases, which masks osteogenic Wnts and thus favors an osteolytic environment at the metastatic site. As the metastases progresses, DKK-1 expression is lost allowing for a Wnt mediated osteoblastic response which predominates CaP boney lesions. Interestingly, blocking DKK-1 expression early in CaP metastasis prevents tumor establishment within the bone suggesting that osteolysis is a required first step in the development of CaP bone metastases. In this review, we discuss our data on the Wnt inhibitor DKK-1 in CaP bone metastasis in the context of current literature evidence that demonstrate that Wnt inhibitors can function as both tumor suppressors and tumor promoters. We provide a model that the affect of Wnt inhibitors on tumor development is dependent on the tumor micro-environment and suggest that DKK-1 is a switch which transitions CaP bone metastases from osteolytic to osteoblastic.

shRNA against CD44 inhibits cell proliferation, invasion and migration, and promotes apoptosis of colon carcinoma cells

“…Proliferation and invasion of tumor cells is under the control of several different signaling pathways, including Wnt signaling (15). Aberrant Wnt signaling initiates malignant transformation of intestinal epithelium in both humans and mice (38), perturbing the proliferation, migration, differentiation, and apoptosis of progenitor cells in colon cancer (39). In the present study, CD44 is an important regulator of cell adhesion, tumor initiation, migration, and proliferation targeting Wnt signaling.…”

Osteoblast expression of an engineered G s -coupled receptor dramatically increases bone mass

“…Stem cell and osteoblast models could be developed to determine the cellular basis of the ColI(2.3)ϩ/Rs1ϩ phenotype and to further investigate the roles of specific signaling pathways as downstream mediators of Rs1 activity. Direct, controlled regulation of the yet-to-be-identified anabolic target may also be useful for improving fracture healing or surgical repair, as well as for developing potential treatments for skeletal diseases such as fibrous dysplasia (9), osteoblastomas, osteoid sarcomas (48,49), and osteoblastic bone metastases (50). Our RASSL system will also permit examination of the contributions of both basal G s signaling activity and ligand-mediated receptor activation.…”

Wnt/β-catenin signaling mediates oval cell response in rodents

“…Such paracrine signaling has been described in events such as hair follicle development and bone metastasis of pros- tate tumor cells. 35,36 There is no change in ␤-catenin gene expression during oval cell response. This lack of change in ␤-catenin gene expression during oval cell activation was probably why it was not identified as a key player in a recent gene array study identifying some markers and ongoing signaling events critical for oval cells.…”