Immunization With RANKL Inhibits Osteolytic Bone Metastasis in Breast Cancer
Immunization With RANKL Inhibits Osteolytic Bone Metastasis in Breast Cancer
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DOI：
10.1097/cji.0000000000000393
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发表时间：
2022-01-01
影响因子：
3.9
通讯作者：
Lim, Wonbong
中科院分区：
文献类型：
--
作者：
Kim, Bora;Cho, Yong Jin;Lim, Wonbong
乳腺癌细胞经常转移至骨骼。越来越多的证据表明，抑制核因子κB配体受体激活剂（RANKL）不仅可以减少乳腺癌骨转移，而且还具有抗肿瘤作用。在这里，我们使用核因子-κB配体突变型受体激活剂（RANKL(M)）作为主动免疫疫苗，诱导抗体用于骨转移癌的免疫治疗。我们在体外和小鼠模型中研究了抗 RANKL 抗体是否抑制溶骨性骨转移。 MDA-MB-231 培养基刺激的 MC3T3 细胞分泌生长分化因子-15 (GDF-15)。诱导核因子-κ B 信号级联反应。此外。 RANKL(M)治疗诱导的MDA-MB-231细胞骨内生长减少与GDF-15表达减少、溶骨性病变数量减少和肿瘤进展减慢相关。此外，接种 RANKL(M) 疫苗可显着改善荷瘤小鼠的总体生存率和骨骼转移。 RANKL(M)诱导抗RANKL抗体通过使核因子-κB信号失活来减少GDF-15的产生，从而抑制MDA-MB-231细胞向骨的转移。总而言之，结果证明了 RANKL(M) 免疫在预防乳腺癌骨转移中的作用。
Breast cancer cells often metastasize to bone. Accumulating evidence suggests that inhibiting the receptor activator of nuclear factor-kappa B ligand (RANKL) not only leads to reduced bone metastasis of breast cancer but also has antitumoral effects. Here, we used mutant receptor activator of nuclear factor-kappa B ligand (RANKL(M)) as a vaccine for active immunization to induce antibodies for immunotherapy of bone metastatic cancer. We investigated whether anti-RANKL antibodies inhibit osteolytic bone metastasis in vitro and in a murine model. MC3T3 cells stimulated by MDA-MB-231 culture medium secreted growth differentiation factor-15 (GDF-15). which induced the nuclear factor-kappa B signaling cascade. In addition. RANKL(M) treatment-induced reduction of intraosseous growth of MDA-MB-231 cells correlated with decreased GDF-15 expression, a reduced number of osteolytic lesions, and slower tumor progression. In addition, vaccination with RANKL(M) led to significant improvement in overall survival and skeletal metastasis in tumor-bearing mice. Induction of anti-RANKL antibodies by RANKL(M) decreased GDF-15 production by deactivating nuclear factor-kappa B signaling, which in turn inhibited metastasis of MDA-MB-231 cells to bone. Taken together, the results demonstrate a role for RANKL(M) immunization in preventing bone metastasis of breast cancer.