Granulocyte colony stimulating factor (G-CSF), an essential cytokine regulating granulopoiesis, is expressed in a substantial proportion of breast cancers, and it has been implicated in cancer progression. Here, we examined effects of G-CSF on the development of bone metastases of breast cancer using immunocompetent mouse models. The expression of CXC chemokine ligand 12 (CXCL12) in bone marrow stromal cells, which plays a critical role in the maintenance of hematopoietic stem cells and also in cancer cell homing to bone, was markedly decreased in mice treated with G-CSF. Flow cytometric analysis revealed that pretreatment of mice with G-CSF reduced the number of bone-homing cancer cells. G-CSF also increased the population of myeloid-derived suppressor cells (MDSCs) in bone marrow. Depletion of MDSCs using anti–Gr-1 antibody treatment significantly decreased the metastatic tumor burden in bone. The overall effects of G-CSF on bone metastases were finally examined using two different treatment protocols. When mice were treated with G-CSF prior to the tumor cell inoculation, G-CSF did not change bone metastatic-tumor burden. In contrast, when G-CSF treatment was started after the tumor cells had homed to bone, G-CSF significantly accelerated bone metastases formation. These results suggest that G-CSF suppressed cancer cell homing to bone by downregulating CXCL12 expression in bone marrow stromal cells, whereas G-CSF stimulated the progression of bone metastases at least in part by MDSC-mediated mechanisms. Implications: G-CSF had opposing effects on the initiation and progression of bone metastases of breast cancer and the balance may regulate the metastatic tumor burden.

中文翻译：

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粒细胞集落刺激因子对乳腺癌骨转移发生和进展的拮抗作用

粒细胞集落刺激因子 (G-CSF) 是一种调节粒细胞生成的重要细胞因子，在相当大比例的乳腺癌中表达，并且与癌症进展有关。在这里，我们使用免疫活性小鼠模型检查了 G-CSF 对乳腺癌骨转移发展的影响。在用 G-CSF 治疗的小鼠中，CXC 趋化因子配体 12 (CXCL12) 在骨髓基质细胞中的表达显着降低，它在造血干细胞的维持和癌细胞归巢中起关键作用。流式细胞仪分析显示，用 G-CSF 预处理小鼠可减少骨归巢癌细胞的数量。G-CSF 还增加了骨髓中髓源性抑制细胞 (MDSCs) 的数量。使用抗 Gr-1 抗体治疗去除 MDSC 显着降低了骨中的转移性肿瘤负荷。最终使用两种不同的治疗方案检查了 G-CSF 对骨转移的总体影响。当小鼠在肿瘤细胞接种前用 G-CSF 治疗时，G-CSF 没有改变骨转移肿瘤负荷。相反，当肿瘤细胞归巢到骨后开始 G-CSF 治疗时，G-CSF 显着加速了骨转移的形成。这些结果表明，G-CSF 通过下调骨髓基质细胞中 CXCL12 的表达来抑制癌细胞归巢，而 G-CSF 至少部分通过 MDSC 介导的机制刺激了骨转移的进展。影响：