Liu Li, Wu Yudong, Zhang Cheng, Zhou Chong, Li Yining, Zeng Yi, Zhang Chunbo, Li Rong, Luo Daya, Wang Lieliang, Zhang Long, Tu Shuo, Deng Huan, Luo Shiwen, Chen Ye-Guang, Xiong Xiangyang, Yan Xiaohua
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang 330006, China.
Department of Breast Surgery, Jiangxi Provincial Cancer Hospital, Nanchang 330029, China.
J Mol Cell Biol. 2020 Sep 1;12(9):723-737. doi: 10.1093/jmcb/mjaa016.
Adipocyte is the most predominant cell type in the tumor microenvironment of breast cancer and plays a pivotal role in cancer progression, yet the underlying mechanisms and functional mediators remain elusive. We isolated primary preadipocytes from mammary fat pads of human breast cancer patients and generated mature adipocytes and cancer-associated adipocytes (CAAs) in vitro. The CAAs exhibited significantly different gene expression profiles as assessed by transcriptome sequencing. One of the highly expressed genes in CAAs is granulocyte colony-stimulating factor (G-CSF). Treatment with recombinant human G-CSF protein or stable expression of human G-CSF in triple-negative breast cancer (TNBC) cell lines enhanced epithelial-mesenchymal transition, migration, and invasion of cancer cells, by activating Stat3. Accordantly, targeting G-CSF/Stat3 signaling with G-CSF-neutralizing antibody, a chemical inhibitor, or siRNAs for Stat3 could all abrogate CAA- or G-CSF-induced migration and invasion of breast cancer cells. The pro-invasive genes MMP2 and MMP9 were identified as target genes of G-CSF in TNBC cells. Furthermore, in human breast cancer tissues, elevated G-CSF expression in adipocytes is well correlated with activated Stat3 signal in cancer cells. Together, our results suggest a novel strategy to intervene with invasive breast cancers by targeting CAA-derived G-CSF.
脂肪细胞是乳腺癌肿瘤微环境中最主要的细胞类型，在癌症进展中起关键作用，但其潜在机制和功能介质仍不清楚。我们从人类乳腺癌患者的乳腺脂肪垫中分离出原代前脂肪细胞，并在体外生成成熟脂肪细胞和癌症相关脂肪细胞（CAA）。通过转录组测序评估，CAA表现出显著不同的基因表达谱。CAA中高表达的基因之一是粒细胞集落刺激因子（G-CSF）。用重组人G-CSF蛋白处理或在三阴性乳腺癌（TNBC）细胞系中稳定表达人G-CSF，通过激活Stat3增强癌细胞的上皮-间质转化、迁移和侵袭。相应地，用G-CSF中和抗体、化学抑制剂或针对Stat3的小干扰RNA靶向G-CSF/Stat3信号传导，均可消除CAA或G-CSF诱导的乳腺癌细胞迁移和侵袭。促侵袭基因MMP2和MMP9被确定为TNBC细胞中G-CSF的靶基因。此外，在人类乳腺癌组织中，脂肪细胞中G-CSF表达升高与癌细胞中激活的Stat3信号密切相关。总之，我们的结果表明了一种通过靶向CAA衍生的G-CSF干预侵袭性乳腺癌的新策略。
