Oncotarget

Interview with Dr. Loeb from Johns Hopkins University

Oncotarget published " A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model " which reported that 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, a Wnt signaling antagonist, possibly playing a pro-tumorigenic role.

In this work the authors investigated the effect of anti-DKK-1 antibodies on the growth and metastasis of patient-derived osteosarcoma xenografts.

Treatment with the anti-DKK-1 antibody, BHQ880, slowed the growth of orthotopically implanted patient-derived osteosarcoma xenografts and inhibited metastasis.

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.

Dr. David M. Loeb from The Johns Hopkins University said, "Osteosarcoma is the most common bone tumor of adolescents and young adults "

"Osteosarcoma is the most common bone tumor of adolescents and young adults "

The extraordinary complexity of the Wnt signaling system is further complicated by the existence of secreted Wnt antagonists such as the secreted frizzled-related proteins and Wnt inhibitory factor 1, which bind Wnt proteins, and sclerostin and the dickkopf family of proteins, which interact with Wnt receptors.

Although Wnt signaling has been implicated as a driver of osteoblast differentiation, other work has suggested that Wnt signaling may also drive proliferation of osteosarcoma cells.

In vitro, WIF1 suppresses β-catenin expression in osteosarcoma cell lines and induces differentiation of primary human osteoblasts, and in primary human osteosarcoma samples, silencing of WIF1 is associated with increased proliferation, increased β-catenin expression, and loss of differentiation, implying that de-repression of Wnt signaling plays a positive role in osteosarcoma pathogenesis.

The best studied of this group is DKK-1. The hallmark of DKK-1, -2, and -4 is their inhibition of Wnt signaling, though DKK-2 may activate Wnt signaling in select circumstances.

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.

The Loeb Research Team concluded in their Oncotarget Research Paper, "in this work we report 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 we 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. "

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

Full text - https://www.oncotarget.com/article/8522/text/

Correspondence to - David M. Loeb - loebda@jhmi.edu

Keywords - sarcoma, metastasis, Wnt signaling, DKK-1, mouse model

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