Abstract

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.

中文翻译：

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癌症相关脂肪细胞衍生的 G-CSF 通过 Stat3 信号传导促进乳腺癌恶性肿瘤

摘要

脂肪细胞是乳腺癌肿瘤微环境中最主要的细胞类型，在癌症进展中发挥着关键作用，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，并在体外产生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 表现出显着不同的基因表达谱。CAAs 中高表达的基因之一是粒细胞集落刺激因子 (G-CSF)。在三阴性乳腺癌 (TNBC) 细胞系中使用重组人 G-CSF 蛋白或稳定表达人 G-CSF 进行治疗，可通过激活 Stat3 来增强癌细胞的上皮-间质转化、迁移和侵袭。因此，用 G-CSF 中和抗体、化学抑制剂或 Stat3 的 siRNA 靶向 G-CSF/Stat3 信号传导都可以消除 CAA 或 G-CSF 诱导的乳腺癌细胞的迁移和侵袭。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，我们的结果提出了一种通过靶向 CAA 衍生的 G-CSF 来干预浸润性乳腺癌的新策略。