Receptor activator of NF-κB (RANK)-mediated induction of metastatic spread and association with poor prognosis in renal cell carcinoma
Receptor activator of NF-κB (RANK)-mediated induction of metastatic spread and association with poor prognosis in renal cell carcinoma
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DOI：
10.1016/j.urolonc.2018.07.013
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发表时间：
2018-11-01
影响因子：
2.7
通讯作者：
Kroeger, Nils
中科院分区：
文献类型：
--
作者：
Steven, Andre;Leisz, Sandra;Kroeger, Nils
背景资料：抑制NF-κ B配体受体激活剂（RANKL）已成为预防癌症患者骨骼相关事件的标准护理支持性治疗。此外，RANKL抑制与肺癌中更好的生存结局有关，而RANKL表达在乳腺癌中诱导肿瘤进展和体内转移扩散。RANK/RANKL是否可能对肾透明细胞癌（ccRCC）的发病机制产生影响目前尚不清楚，患者和方法：进行了回顾性组织微阵列（TMA）研究，确定了306例ccRCC患者原发肿瘤中RANK/RANKL的表达。此外，我们还对24个ccRCC细胞系进行了RANK/RANKL轴的体外分析，包括细胞增殖、迁移和锚定非依赖性生长。（6.3 vs. 1.3年; p < 0.001）和无复发生存期（RFS）（9.9 vs. 5.8年; p < 0.001）。RANK（+）（HR 2.21; p < 0.001）是CSS和RFS的独立预后因素（HR 4.98; p < 0.001）。RANKL处理导致RANK（+）RCC细胞系的增殖、软琼脂生长和集落形成增加，这可以通过用NF-κ B抑制剂和骨保护素和RANKL的组合处理在体外逆转。结论：RANK在ccRCC组织中表达，与临床病理特征、生存结果相关，并且当用RANKL刺激时可以在体外诱导ccRCC进展。因此，RANKL抑制与标准治疗相结合可能是改善ccRCC患者生存的有希望的方法。(C)2018爱思唯尔公司All rights reserved.
Background: Inhibition of the receptor activator of NF-kappa B ligand (RANKL) has become a standard of care supportive treatment to prevent skeletal related events in cancer patients. Moreover, RANKL inhibition has been implicated with better survival outcome in lung cancer, while RANKL expression induces tumor progression and metastatic spread in vivo in breast cancer. Whether RANK/RANKL may have an impact on the pathogenesis of clear cell renal cell carcinoma (ccRCC) is currently unknown.Patients and Methods: A retrospective tissue micro array (TMA)-study was carried out determining the expression of RANK/RANKL in primary tumors of 306 ccRCC patients. Additionally, 24 ccRCC cell lines were employed for in vitro analyses of the RANK/RANKL axis including cell proliferation, migration and anchorage independent growth.Results: RANK (+) vs. RANK (-) tumors had both worse cancer specific survival (CSS) (6.3 vs. 1.3 years; p < 0.001) and recurrence free survival (RFS) (9.9 vs. 5.8 years; p < 0.001). RANK (+) (HR 2.21; p < 0.001) was an independent prognostic factor for CSS and RFS (HR 4.98; p < 0.001). RANKL treatment resulted in increased proliferation, soft agar growth, and colony formation of RANK (+) RCC cell lines, which could be reversed by treatment with an NF-KB inhibitor and with a combination of osteoprotegrin and RANKL in vitro.Conclusions: RANK is expressed in ccRCC tissue, correlates with clinicopathological features, survival outcome, and when stimulated with RANKL can induce ccRCC progression in vitro. Consequently, RANKL inhibition combined with standard of care treatment may be a promising approach to improve ccRCC patient's survival. (C) 2018 Elsevier Inc. All rights reserved.