Cancer-associated adipocyte-derived G-CSF promotes breast cancer malignancy via Stat3 signaling.
Cancer-associated adipocyte-derived G-CSF promotes breast cancer malignancy via Stat3 signaling.
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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
DOI：
10.1093/jmcb/mjaa016
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发表时间：
2020-09-01
影响因子：
5.5
通讯作者：
Yan X
中科院分区：
文献类型：
--
作者：
Liu L;Wu Y;Zhang C;Zhou C;Li Y;Zeng Y;Zhang C;Li R;Luo D;Wang L;Zhang L;Tu S;Deng H;Luo S;Chen YG;Xiong X;Yan X
摘要脂肪细胞是乳腺癌肿瘤微环境中最主要的细胞类型，在乳腺癌的发生发展中起着关键作用，但其潜在的机制和功能性介质仍不清楚。我们从人乳腺癌患者的乳腺脂肪垫中分离原代前脂肪细胞，并在体外产生成熟脂肪细胞和癌症相关脂肪细胞（CAAs）。通过转录组测序评估，CAA表现出显著不同的基因表达谱。粒细胞集落刺激因子（G-CSF）是CAAs中高表达的基因之一。在三阴性乳腺癌（TNBC）细胞系中用重组人G-CSF蛋白或稳定表达的人G-CSF处理通过激活Stat 3增强癌细胞的上皮-间充质转化、迁移和侵袭。相应地，用G-CSF中和抗体、化学抑制剂或Stat 3的siRNA靶向G-CSF/Stat 3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MMP 2和MMP 9被鉴定为TNBC细胞中G-CSF的靶基因。此外，在人乳腺癌组织中，脂肪细胞中升高的G-CSF表达与癌细胞中活化的Stat 3信号密切相关。总之，我们的研究结果提出了一种新的策略，通过靶向CAA衍生的G-CSF来干预浸润性乳腺癌。
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.
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DOI：
10.1186/s13058-016-0740-2
发表时间：
2016-08-11
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Bussard KM;Mutkus L;Stumpf K;Gomez-Manzano C;Marini FC
通讯作者：
Marini FC
影响因子：
3.1
作者：
Luo M;Brooks M;Wicha MS
通讯作者：
Wicha MS
影响因子：
15.9
作者：
Iyengar, P;Espina, V;Scherer, PE
通讯作者：
Scherer, PE
影响因子：
4.8
作者：
Benesch, Matthew G. K.;Tang, Xiaoyun;Brindley, David N.
通讯作者：
Brindley, David N.
影响因子：
11.2
作者：
Arendt LM;McCready J;Keller PJ;Baker DD;Naber SP;Seewaldt V;Kuperwasser C
通讯作者：
Kuperwasser C