Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands.
Department of Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands.
Cancer Treat Rev. 2018 Jan;62:18-28. doi: 10.1016/j.ctrv.2017.10.010. Epub 2017 Nov 2.
At present, accumulating evidence suggests that inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL) does not only induce an increase in bone mass and strength, but also has anti-tumor effects. Denosumab, an antibody targeting RANKL, is used to treat osteoporosis and to prevent skeletal related events (SREs) in patients with bone metastases originating from solid tumors. However, expression of RANKL and its receptor activator of nuclear factor kappa-B (RANK) is not solely restricted to cells involved in homeostasis of the bone and RANKL-RANK signalling appears to play a substantial role in many other processes in the body like mammary physiology, mammary tumorigenesis and the immune system. In pre-clinical models, RANKL inhibition has been shown to reduce skeletal tumor burden and distant metastases as well as to decrease mammary carcinogenesis. Clinically, RANKL inhibition improves bone-metastasis free survival in patients with prostate cancer and disease-free survival in patients with breast cancer. In addition, RANKL treatment may form a preventative strategy in patients at high risk for malignancies of the breast. Current clinical studies are evaluating the effect of denosumab on survival, the immune system and other biomarkers into a greater extent. To that purpose, a systematic review of the literature was performed and a narrative review synthesized, describing the present pre-clinical and clinical evidence of an anti-tumor effect of RANKL inhibition and the potential role of the immune system as one of the underlying mechanisms.
目前，越来越多的证据表明，核因子κ B 受体激活剂配体（RANKL）的抑制不仅会导致骨量和骨强度增加，而且还具有抗肿瘤作用。靶向 RANKL 的抗体地舒单抗用于治疗骨质疏松症，并预防源自实体瘤的骨转移患者的骨骼相关事件（SREs）。然而，RANKL 和其核因子κ B 受体激活剂（RANK）的表达不仅限于参与骨骼内稳态的细胞，并且 RANKL-RANK 信号似乎在身体的许多其他过程中发挥重要作用，如乳腺生理学、乳腺肿瘤发生和免疫系统。在临床前模型中，已经表明 RANKL 抑制可减少骨骼肿瘤负担和远处转移，并减少乳腺致癌作用。临床上，RANKL 抑制可改善前列腺癌患者的无骨转移生存和乳腺癌患者的无病生存。此外，RANKL 治疗可能成为高风险乳腺癌患者的预防策略。目前的临床研究正在更广泛地评估地舒单抗对生存、免疫系统和其他生物标志物的影响。为此，对文献进行了系统评价，并进行了叙述性综述，描述了 RANKL 抑制的抗肿瘤作用的目前临床前和临床证据，以及免疫系统作为潜在机制之一的潜在作用。
