Department of Histology and Cell Biology, Matsumoto Dental University, Shiojiri-shi, Nagano, Japan.
Division of Instrumental Analysis, Research Center for Human and Environmental Sciences, Shinshu University, Matsumoto-shi, Nagano, Japan.
Mol Cancer Res. 2021 Dec;19(12):2110-2119. doi: 10.1158/1541-7786.MCR-21-0243. Epub 2021 Aug 31.
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.
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，在相当一部分乳腺癌中表达，并与癌症进展有关。在这里，我们使用免疫活性小鼠模型研究了 G-CSF 对乳腺癌骨转移发展的影响。骨髓基质细胞中 CXC 趋化因子配体 12（CXCL12）的表达明显降低，CXCL12 在维持造血干细胞和癌细胞归巢到骨中起着关键作用。流式细胞术分析显示，G-CSF 预处理可减少归巢到骨的癌细胞数量。G-CSF 还增加了骨髓中髓源抑制细胞（MDSCs）的数量。用抗 Gr-1 抗体耗竭 MDSCs 可显著减少骨转移瘤的负荷。最后使用两种不同的治疗方案研究了 G-CSF 对骨转移的整体影响。当在肿瘤细胞接种前用 G-CSF 处理小鼠时，G-CSF 并未改变骨转移瘤的负荷。相比之下，当 G-CSF 治疗在肿瘤细胞归巢到骨后开始时，G-CSF 显著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 的表达抑制癌细胞归巢到骨，而 G-CSF 通过 MDSC 介导的机制至少部分刺激了骨转移的进展。意义：G-CSF 对乳腺癌骨转移的起始和进展有相反的影响，平衡可能调节转移瘤的负荷。
