骨轉(zhuǎn)移是乳腺癌死亡的主要原因。缺乏有效的治療表明，疾病機(jī)制在很大程度上仍然未知。作為腫瘤微環(huán)境的關(guān)鍵組成部分，巨噬細(xì)胞促進(jìn)腫瘤進(jìn)展和轉(zhuǎn)移。在這項(xiàng)研究中，我們發(fā)現(xiàn)巨噬細(xì)胞在人和小鼠乳腺癌骨轉(zhuǎn)移中含量豐富。巨噬細(xì)胞被清除/耗竭（Liposoma，CP-005-005）顯著抑制骨轉(zhuǎn)移生長(zhǎng)。譜系追蹤實(shí)驗(yàn)表明，這些巨噬細(xì)胞主要來(lái)源于 Ly6C⁺CCR2⁺ 炎性單核細(xì)胞。趨化因子受體 CCR2 的消融顯著抑制了骨轉(zhuǎn)移的生長(zhǎng)并延長(zhǎng)了生存期。免疫表型分析發(fā)現(xiàn)，骨轉(zhuǎn)移相關(guān)巨噬細(xì)胞表達(dá)高水平的 CD204 和 IL4R。此外，單核細(xì)胞/巨噬細(xì)胞限制性 IL4R 消融顯著抑制骨轉(zhuǎn)移生長(zhǎng)，IL4R 無(wú)效突變單核細(xì)胞未能促進(jìn)骨轉(zhuǎn)移生長(zhǎng)。總之，這項(xiàng)研究確定了以 IL4R 依賴(lài)性方式促進(jìn)乳腺癌骨轉(zhuǎn)移的單核細(xì)胞衍生巨噬細(xì)胞亞群。這表明 IL4R 和巨噬細(xì)胞抑制對(duì)乳腺癌骨病具有潛在的治療益處。

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.

論文信息：

論文題目： Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth

期刊名稱(chēng)：JEM- J Exp Med

時(shí)間期卷：J Exp Med (2020) 217 (11): e20191820.

在線時(shí)間：2020年8月11日

DOI： doi.org/10.1084/jem.20191820

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見(jiàn)刊于JEM：

JEM期刊巨噬細(xì)胞促進(jìn)乳腺癌細(xì)胞骨轉(zhuǎn)移模型巨噬細(xì)胞清除解決方案

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體的材料和方法：

JEM期刊巨噬細(xì)胞促進(jìn)乳腺癌細(xì)胞骨轉(zhuǎn)移模型巨噬細(xì)胞清除解決方案

JEM期刊巨噬細(xì)胞促進(jìn)乳腺癌細(xì)胞骨轉(zhuǎn)移模型巨噬細(xì)胞清除解決方案

Experimental metastasis assay and treatment

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.

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