Wnt and Wnt inhibitors in bone metastasis

Abstract

Bone metastasis is a clinically devastating development of progressive cancers including prostate carcinoma, breast carcinoma and multiple myeloma. Bone metastases are typically painful, lead to adverse skeletal-related events, such as fracture, and are highly resistant to therapy. A major contribution to the ability of cancers to successfully establish bone metastases is their ability to exploit mechanisms of normal bone remodeling. Wnts are a large family of morphogenic proteins that are critical for bone development and contribute to maintaining bone mass in the mature organism. Wnt function is balanced by the presence of a variety of endogenous inhibitors, such as the dickkopf family members, secreted frizzled related proteins and sclerostin. Together, these factors contribute to normal bone homeostasis, allowing for dynamic changes in bone to withstand alterations in physical forces and physiological needs. In this review, we describe the role that Wnts and their inhibitors have in normal bone biology and cancer-related bone pathology. An overview of Wnt signaling pathways is discussed and key bone microenvironment cellular players, as they pertain to Wnt biology, are examined. Finally, we describe clinical trials of several Wnt inhibitor antagonists for patients with tumor-related bone disease. As few options currently exist for the treatment of bone-metastatic disease, Wnt proteins and their inhibitors offer promise for the development of novel therapeutics.

Figure 1. Overview of canonical Wnt signaling.

Wnt binding to membrane-bound frizzled (FRZ) receptors and association of low-density LRP5/6 leads to sequestration of the β-catenin phosphorylation complex composed of disheveled (DSH), adenomatous polyposis coli (APC), axin and GSK-3β. Complex formation allows for β-catenin accumulation and translocation to the nucleus, where it binds to the TCF/LEF and initiates transcription. However, Dicckopf-1 (DKK1) can bind to LRP5/6 leading to association of Kremen 1/2 (Krm1/2) leading to complex degradation and inhibition of Wnt binding and signaling initiation. sFRP can also bind Wnt's extracellularly to prevent binding to Frz. Frz-LRP5/6 degradation allows for the axin, DSH, APC and GSK-3β to phosphorylate β-catenin. Phosphorylated β-catenin is subsequently proteosomally degraded.

Figure 2. Bone microenvironment interactions of metastatic tumor cells.

Wnt signaling between tumor cells and resident bone cells is coerced during metastases, with tumor cells disrupting normal signals to promote tumor growth and invasion. MM, BCa and PCa, have a high incidence of bone metastases. Expression of Dickkopf-1 (DKK1) and sclerostin (Sost) activate osteoclasts (OC) leading to bone resorption (heavier arrows denote changes seen more prominently in more aggressive forms of those diseases). Increased expression of Wnt from tumor cells activates osteoblasts and promotes bone mineralization. Differential expression of Wnt and DKK1 has been associated with aggressiveness of disease in BCa and PCa. Expression of DKK1 is thought to be a primary driving factor of MM progression.

Figure 3. Novel therapeutics to inhibit metastatic induced bone lysis.

Tumor cells produce numerous factors, such as Dickkopf-1 (DKK1) and sclerostin (Sost), to inhibit osteoblast function and enhance osteoclastic bone resorption in the tumor microenvironment, facilitating tumor growth and invasion. Novel therapeutics to target DKK1 and Sost are currently undergoing clinical trials. Specifically, fully humanized antibodies against DKK1 (α-DKK1 Ab) and Sost (α-SostAb) are being investigated. These therapeutics inhibit mediators associated with osteoclast (OC) activation established by tumor cells. Inhibition of osteoclasts may further indirectly decrease tumor growth by decreasing the effectiveness of the vicious cycle associated with bone lysis and tumor growth. Further, inhibition of DKK1 may also increase osteoblast differentiation and maturation, thereby restoring bone growth and possibly inhibiting tumor growth.