A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model.

Seth D Goldstein,Wendy Bautista Guzman,Matteo Trucco,Masanori Hayashi,David M Loeb

doi:10.18632/oncotarget.8522

Seth D Goldstein, Wendy Bautista Guzman + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.8522

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Abstract

The outcome of patients with metastatic osteosarcoma has not improved since the introduction of chemotherapy in the 1970s. Development of therapies targeting the metastatic cascade is a tremendous unmet medical need. The Wnt signaling pathway has been the focus of intense investigation in osteosarcoma because of its role in normal bone development. Although the role of Wnt signaling in the pathogenesis of osteosarcoma is controversial, there are several reports of dickkopf-1 (DKK-1), a Wnt signaling antagonist, possibly playing a pro-tumorigenic role. In this work we investigated the effect of anti-DKK-1 antibodies on the growth and metastasis of patient-derived osteosarcoma xenografts. We were able to detect human DKK-1 in the blood of tumor-bearing mice and found a correlation between DKK-1 level and tumor proliferation. Treatment with the anti-DKK-1 antibody, BHQ880, slowed the growth of orthotopically implanted patient-derived osteosarcoma xenografts and inhibited metastasis. This effect was correlated with increased nuclear beta-catenin staining and increased expression of the bone differentiation marker osteopontin. These findings suggest that Wnt signaling is anti-tumorigenic in osteosarcoma, and support the targeting of DKK-1 as an anti-metastatic strategy for patients with osteosarcoma.

Highlights

Osteosarcoma is the most common bone tumor of adolescents and young adults [1, 2]
In light of the reports that DKK-1 can be measured in the serum of osteosarcoma patients, that DKK-1 can inhibit osteoblastic differentiation, and that overexpression of DKK-1 appears to induce a more aggressive phenotype in osteosarcoma cells implanted in an orthotopic location, we investigated DKK-1 expression in an orthotopic patient-derived xenograft model of osteosarcoma as well as the effect of anti-DKK-1 antibodies on growth and metastasis of patient-derived osteosarcoma xenografts
(18) We measured levels of human DKK-1 in the serum of mice implanted with human osteosarcoma patient-derived xenografts

Summary

Introduction

Osteosarcoma is the most common bone tumor of adolescents and young adults [1, 2]. Surgery alone cures only a small minority of patients who present with localized disease [3, 4]. The introduction of systemic chemotherapy resulted in rates of long term survival approaching 75% in patients with localized osteosarcoma, but has had a minimal impact on the survival of patients who present with metastatic disease [5, 6]. The Wnt signaling pathway has been the focus of intense investigation in osteosarcoma because of its role in normal bone development. Wnt ligands bind to transmembrane receptors, including the 10 members of the Frizzled family of G protein coupled receptors (which mediate β-catenin-dependent, or canonical signaling) and the receptor tyrosine kinases ROR1 and ROR2 and the receptor tyrosine kinase-like receptor RYK (which mediate so-called noncanonical signaling) [8]. Www.impactjournals.com/oncotarget activation of noncanonical signaling by Wnt5a binding to ROR2 enhances osteoclastogenesis and bone resorption [9], while Wnt5a signaling through the G-protein-linked activation of Protein Kinase Cδ induces osteoblastogenic differentiation of murine mesenchymal stem cells [10]

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