A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model.
A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model.
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DOI：
10.18632/oncotarget.8522
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发表时间：
2016-04-19
期刊：
影响因子：
--
通讯作者：
Loeb DM
中科院分区：
文献类型：
--
作者：
Goldstein SD;Trucco M;Bautista Guzman W;Hayashi M;Loeb DM
自20世纪70年代引入化疗以来，转移性骨肉瘤患者的结局并未改善。靶向转移级联的疗法的开发是巨大的未满足的医疗需求。Wnt信号通路在骨肉瘤的发生发展中起重要作用，因此成为骨肉瘤研究的热点。尽管Wnt信号在骨肉瘤发病机制中的作用存在争议，但有几份报告表明Wnt信号拮抗剂dickkopf-1（DKK-1）可能发挥促肿瘤发生作用。在这项工作中，我们研究了抗DKK-1抗体对患者来源的骨肉瘤异种移植物的生长和转移的影响。我们能够在荷瘤小鼠的血液中检测到人DKK-1，并发现DKK-1水平与肿瘤增殖之间的相关性。用抗DKK-1抗体BHQ 880治疗，减缓原位植入的患者来源的骨肉瘤异种移植物的生长并抑制转移。这种效应与细胞核β-连环蛋白染色增加和骨分化标志物骨桥蛋白表达增加相关。这些发现表明Wnt信号在骨肉瘤中具有抗肿瘤作用，并支持靶向DKK-1作为骨肉瘤患者的抗转移策略。
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.
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