中文摘要：
骨转移是乳腺癌死亡的主要原因。缺乏有效的治疗表明，疾病机制在很大程度上仍然未知。作为肿瘤微环境的关键组成部分，巨噬细胞促进肿瘤进展和转移。在这项研究中，我们发现巨噬细胞在人和小鼠乳腺癌骨转移中含量丰富。巨噬细胞被清除/耗竭（Liposoma，CP-005-005）显著抑制骨转移生长。谱系追踪实验表明，这些巨噬细胞主要来源于 Ly6C+CCR2+ 炎性单核细胞。趋化因子受体 CCR2 的消融显着抑制了骨转移的生长并延长了生存期。免疫表型分析发现，骨转移相关巨噬细胞表达高水平的 CD204 和 IL4R。此外，单核细胞/巨噬细胞限制性 IL4R 消融显着抑制骨转移生长，IL4R 无效突变单核细胞未能促进骨转移生长。总之，这项研究确定了以 IL4R 依赖性方式促进乳腺癌骨转移的单核细胞衍生巨噬细胞亚群。这表明 IL4R 和巨噬细胞抑制对乳腺癌骨病具有潜在的治疗益处。
英文摘要：
Bone metastasis is the major cause of death in breast cancer. The lack of effective treatment suggests that disease mechanisms are still largely unknown. As a key component of the tumor microenvironment, macrophages promote tumor progression and metastasis. In this study, we found that macrophages are abundant in human and mouse breast cancer bone metastases. Macrophage ablation（Liposoma，CP-005-005） significantly inhibited bone metastasis growth. Lineage tracking experiments indicated that these macrophages largely derive from Ly6C+CCR2+ inflammatory monocytes. Ablation of the chemokine receptor, CCR2, significantly inhibited bone metastasis outgrowth and prolonged survival. Immunophenotyping identified that bone metastasis–associated macrophages express high levels of CD204 and IL4R. Furthermore, monocyte/macrophage-restricted IL4R ablation significantly inhibited bone metastasis growth, and IL4R null mutant monocytes failed to promote bone metastasis outgrowth. Together, this study identified a subset of monocyte-derived macrophages that promote breast cancer bone metastasis in an IL4R-dependent manner. This suggests that IL4R and macrophage inhibition can have potential therapeutic benefit against breast cancer bone disease.
论文信息：
论文题目： Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth
期刊名称：JEM- J Exp Med
时间期卷：J Exp Med (2020) 217 (11): e20191820.
在线时间：2020年8月11日
DOI： doi.org/10.1084/jem.20191820
Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于JEM：
Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体的材料和方法：
JEM期刊巨噬细胞促进乳腺癌细胞骨转移模型巨噬细胞清除解决方案
Bone metastasis was generated through intracardiac injection of 105 tumor cells into 4-wk-old female mice of strains described above. Bioluminescent signal was recorded twice a week using the Photon IMAGER Optima system (Biospace) or IVIS spectrum (PerkinElmer). The region of interest was quantified by Photon IMAGER software or IVIS Living Imaging v4.3.1. Macrophage depletion was performed by i.v. injection of liposome-encapsulated clodronate (1 mg/mouse; Liposoma) twice a week. BLZ945 was given as daily gavage (200 mg/kg body weight; MedChemExpress). CCL2-neutralizing antibody or the control antibody (20 mg/kg body weight; Ortho BiotechOncology) was administered twice a week. Osteoclast depletion was performed by i.p. injections of free clodronate (dichloromethylenediphosphonic acid disodium salt; Sigma-Aldrich; 1 mg/mouse) on day 0, day 1, and then twice a week after tumor was detected.
For adoptive transfer, 1 × 106 monocytes (CD45+CD11b+CSF1R+Ly6C+) from the bone of WT, Ccr2−/−, or Il4ra−/− were sorted and injected via intracaudal injection to mice with detectable bone metastasis. Mice were imaged right before monocyte transfer and on day 1, 3, 7, and 10 for quantification of tumor growth. For lineage tracking, 1 × 106 GFP+ monocytes (from FVB-eGFP or Csf1r-EGFP mice) were injected i.v. into mice with late-stage bone metastasis. Bone and blood were collected 48 h after injection.
