LIGHT/TNFSF14 Promotes Osteolytic Bone Metastases in Non-small Cell Lung Cancer Patients
LIGHT/TNFSF14 Promotes Osteolytic Bone Metastases in Non-small Cell Lung Cancer Patients
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DOI：
10.1002/jbmr.3942
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发表时间：
2020-01-07
影响因子：
6.2
通讯作者：
Roato, Ilaria
中科院分区：
文献类型：
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作者：
Brunetti, Giacomina;Belisario, Dimas C.;Roato, Ilaria
肿瘤坏死因子超家族成员14（TNFSF 14），LIGHT，是调节先天性和适应性免疫应答的细胞因子网络的组分，其促进淋巴器官、肝和骨的稳态。转移性肿瘤通常会破坏组织微环境，从而改变受侵器官的稳态;然而，其潜在机制需要进一步研究。我们研究了LIGHT在转移性非小细胞肺癌（NSCLC）诱导的溶骨性骨病中的作用。与非骨转移性肿瘤和健康对照相比，诊断为NSCLC骨转移的患者显示单核细胞中表达的LIGHT水平显著更高。骨转移患者的血清LIGHT水平也高于对照组，表明LIGHT在刺激破骨细胞前体中的作用。在骨转移患者中，我们还检测到RNA表达和血清RANKL水平增加，因此通过在PBMC培养物中添加抗LIGHT或RANK片段可结晶区（RANK-Fc），观察到破骨细胞生成的显著抑制。为了在小鼠中模拟这种观察，我们使用小鼠肺癌细胞系LLC-1。胫骨内植入后，野生型小鼠破骨细胞数量增加，但成骨细胞数量减少，类骨质形成减少。相比之下，Tnfsf 14（-/-）小鼠未显示与该模型相关的显著骨丢失或骨稳态的其他变化。这些数据表明LIGHT是转移性侵袭期间调节骨稳态的关键控制机制。因此，LIGHT可能是溶骨性骨转移瘤的一个新的治疗靶点。(c)2019年美国骨与矿物质研究学会。
Tumor necrosis factor superfamily member 14 (TNFSF14), LIGHT, is a component of the cytokine network that regulates innate and adaptive immune responses, which promote homeostasis of lymphoid organs, liver, and bone. Metastatic tumors often disrupt the tissue microenvironment, thus altering the homeostasis of the invaded organ; however, the underlying mechanisms required further studies. We investigated the role of LIGHT in osteolytic bone disease induced by metastatic non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC bone metastasis show significantly higher levels of LIGHT expressed in monocytes compared with non-bone metastatic tumors and healthy controls. Serum LIGHT levels were also higher in patients with bone metastases than in controls, suggesting a role for LIGHT in stimulating osteoclast precursors. In bone metastatic patients, we also detected increased RNA expression and serum RANKL levels, thus by adding anti-LIGHT or RANK-fragment crystallizable region (RANK-Fc) in PBMC cultures, a significant inhibition of osteoclastogenesis was observed. To model this observation in mice, we used the mouse lung cancer cell line LLC-1. After intratibial implantation, wild-type mice showed an increased number of osteoclasts but reduced numbers of osteoblasts and decreased osteoid formation. In contrast, Tnfsf14(-/-) mice showed no significant bone loss or other changes in bone homeostasis associated with this model. These data indicate LIGHT is a key control mechanism for regulating bone homeostasis during metastatic invasion. Thus, LIGHT may be a novel therapeutic target in osteolytic bone metastases. (c) 2019 American Society for Bone and Mineral Research.