CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages
CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages
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CD137通过增强单核/巨噬细胞迁移和破骨细胞分化促进乳腺癌骨转移
DOI：
10.7150/thno.29617
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Li, Na
中科院分区：
文献类型：
--
作者：
Jiang, Pengling;Gao, Wenjuan;Li, Na
基本原理：骨是乳腺癌最常见的转移部位之一。CD137（4 - 1BB）是肿瘤坏死因子（TNF）受体超家族成员，主要表达于活化的白细胞。先前的研究证实了CD137-CD137L双向信号通路对RANKL介导的破骨细胞生成的影响。但CD137在乳腺癌骨转移中的作用还有待进一步研究。方法：建立稳定的Cd137过表达和沉默的单核/巨噬细胞系。采用Western blot、real-time PCR、transwell和抗酒石酸酸性磷酸酶染色法检测CD137对单核/巨噬细胞迁移和破骨细胞生成的调节作用。建立小鼠自发性骨转移模型，通过生物发光成像、免疫组化和组织学检测，检测CD137在体内骨转移中的作用。结果：CD137通过上调Fra1的表达促进单核/巨噬细胞向肿瘤微环境迁移。同时还促进单核/巨噬细胞向破骨细胞分化，从而为乳腺癌细胞在骨中的定植和生长提供了有利的微环境。基于这些发现，合成了一种新型的F4/80靶向脂质体纳米粒，其包裹抗CD137阻断抗体（NP-α CD137 Ab-F4/80）。该纳米颗粒可以在体内高效地抑制4T1乳腺癌细胞的骨和肺转移。此外，它增加了Fra1抑制剂对肿瘤转移的治疗效果。结论：综上所述，这些发现揭示了巨噬细胞/单核细胞CD137对骨转移的促进作用，并为乳腺癌转移提供了有希望的治疗策略。
Rationale: Bone is one of the most common metastatic sites of breast cancer. CD137 (4-1BB), a member of the tumor necrosis factor (TNF) receptor superfamily, is mainly expressed in activated leukocytes. Previous study demonstrates the effect of CD137-CD137L bidirectional signaling pathway on RANKL-mediated osteoclastogenesis. However, the role of CD137 in bone metastasis of breast cancer needs further study. Methods: Stable monocyte/macrophage cell lines with Cd137 overexpression and silencing were established. Western blot, real-time PCR, transwell and tartrate-resistant acid phosphatase staining were used to detect the regulatory effect of CD137 on migration and osteoclastogenesis of monocytes/macrophages in vitro. Spontaneous bone metastasis mouse model was established, bioluminescent images, immunohistochemistry and histology assay were performed to detect the function of CD137 in bone metastasis in vivo. Results: We found that CD137 promotes the migration of monocytes/macrophages to tumor microenvironment by upregulating the expression of Fra1. It also promoted the differentiation of monocytes/macrophages into osteoclasts at the same time, thus providing a favorable microenvironment for the colonization and growth of breast cancer cells in bone. Based on these findings, a novel F4/80-targeted liposomal nanoparticle encapsulating the anti-CD137 blocking antibody (NP-αCD137 Ab-F4/80) was synthesized. This nanoparticle could inhibit both bone and lung metastases of 4T1 breast cancer cells with high efficacy in vivo. In addition, it increased the therapeutic efficacy of Fra1 inhibitor on tumor metastasis. Conclusions: Taken together, these findings reveal the promotion effect of macrophage/monocyte CD137 on bone metastases and provide a promising therapeutic strategy for metastasis of breast cancer.