Abstract
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 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.
骨转移是导致乳腺癌患者死亡的主要原因。缺乏有效的治疗方法表明，乳腺癌的发病机制在很大程度上仍然未知。作为肿瘤微环境的重要组成部分，巨噬细胞会促进肿瘤的进展和转移。本研究发现，巨噬细胞在人类和小鼠乳腺癌骨转移灶中含量丰富。巨噬细胞消除可明显抑制骨转移癌的生长。系谱追踪实验表明，这些巨噬细胞主要来源于Ly6C+ CCR2+炎性单核细胞。消除趋化因子受体CCR2可明显抑制骨转移瘤的生长并延长存活时间。免疫分型发现，骨转移相关巨噬细胞表达高水平的CD204和IL4R。此外，单核细胞/巨噬细胞受限的IL4R敲除能显著抑制骨转移癌生长，而IL4R无效突变的单核细胞不能促进骨转移癌生长。总之，这项研究发现了单核细胞衍生的巨噬细胞亚群，它们以依赖 IL4R 的方式促进乳腺癌骨转移。这些研究表明抑制IL4R和巨噬细胞对乳腺癌骨转移有潜在的治疗作用。
