Stromal Cell-Derived CCL20 Promotes Tumor Progression and Osteolysis in Giant Cell Tumor of Bone
Stromal Cell-Derived CCL20 Promotes Tumor Progression and Osteolysis in Giant Cell Tumor of Bone
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DOI：
10.1159/000495903
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发表时间：
2018-12
影响因子：
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通讯作者：
Chenglong Zhao;Dongsheng Wang;L. Tang;Zhichao Zhang;Song Li;Ming Qian;Zhipeng Wu;Wang Zhou
中科院分区：
文献类型：
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作者：
Chenglong Zhao;Dongsheng Wang;L. Tang;Zhichao Zhang;Song Li;Ming Qian;Zhipeng Wu;Wang Zhou
骨巨细胞瘤（Giant cell tumor of bone，GCTB）是最常见的原发性骨肿瘤之一，可导致广泛的骨破坏。然而，GCTB进展的潜在机制仍然难以捉摸，需要预后因素和治疗靶点。在本研究中，我们探讨了趋化因子家族成员CCL 20在GCTB进展中的功能。方法：采用基因芯片技术检测CCL 20在人骨髓基质细胞（GCTSCs）中的表达。基于我们机构的患者队列，对CCL 20在肿瘤进展中的作用进行了临床分析。MTS法检测CCL 20在肿瘤增殖中的作用，Transwell法检测细胞迁移能力，CCL 20或GCTSC条件培养液诱导破骨细胞生成。采用定量PCR和western blot检测肿瘤进展相关基因和蛋白的表达水平。结果：CCL 20在GCTSCs中表达上调，并与肿瘤的进展和预后相关。CCL 20以自分泌方式诱导GCTSC增殖和迁移。此外，CCL 20通过过度激活AKT和NF-κB信号通路募集单核细胞并诱导破骨细胞生成。CCL 20的抗体阻断消除了破骨细胞生成的加剧。结论：综上所述，我们的数据表明GCTSC分泌CCL 20在GCTB的病理进展中起关键调节作用。它可以以自分泌方式促进GCTSC增殖和迁移，并可以以旁分泌方式将骨髓单核细胞募集到肿瘤微环境中并增强破骨细胞生成。这些发现有力地表明了CCL 20在GCTB中的潜在预后和治疗价值。
Background/Aims: Giant cell tumor of bone (GCTB), one of the most common primary bone tumors, leads to extensive bone destruction. However, the mechanisms underlying GCTB progression remain elusive and prognostic factors and treatment targets are required. In the current study, we explored the function of the chemokine family member CCL20 in GCTB progression. Methods: We explored the expression of CCL20 in stromal cells (GCTSCs) using microarray. Clinical analyses of the role of CCL20 in tumor progression were performed based on the patient cohort of our institution. The role of CCL20 in tumor proliferation was evaluated by MTS assay, migration ability was measured by a Transwell assay, and osteoclastogenesis was induced by CCL20 or GCTSC-conditioned medium. Quantitative PCR and western blot were used to measure the expression levels of mRNAs and proteins related to tumor progression. Results: CCL20 was upregulated in GCTSCs and correlated with tumor progression and prognosis. CCL20 induced GCTSC proliferation and migration in an autocrine manner. In addition, CCL20 recruited mononuclear cells and induced osteoclastogenesis by overactivating the AKT and NF-κB signaling pathways. Antibody blockade of CCL20 abolished the exacerbated osteoclastogenesis. Conclusion: Taken together, our data indicate that GCTSC secretion of CCL20 acts as a key modulator in the pathological progression of GCTB. It can promote GCTSC proliferation and migration in an autocrine manner and can recruit bone marrow monocytes to the tumor microenvironment and enhance osteoclastogenesis in a paracrine manner. These findings strongly indicate the potential prognostic and therapeutic value of CCL20 in GCTB.