Recent studies have demonstrated that cancer-associated adipocytes (CAAs) in the tumor microenvironment are involved in the malignant progression of breast cancer. However, the underlying mechanism of CAA formation an...Recent studies have demonstrated that cancer-associated adipocytes (CAAs) in the tumor microenvironment are involved in the malignant progression of breast cancer. However, the underlying mechanism of CAA formation and its effects on the development of breast cancer are still unknown. Here, we show that CSF2 is highly expressed in both CAAs and breast cancer cells. CSF2 promotes inflammatory phenotypic changes of adipocytes through the Stat3 signaling pathway, leading to the secretion of multiple cytokines and proteases, particularly C–X–C motif chemokine ligand 3 (CXCL3). Adipocyte-derived CXCL3 binds to its specific receptor CXCR2 on breast cancer cells and activates the FAK pathway, enhancing the mesenchymal phenotype, migration, and invasion of breast cancer cells. In addition, a combination treatment targeting CSF2 and CXCR2 shows a synergistic inhibitory effect on adipocyte-induced lung metastasis of mouse 4T1 cells in vivo. These findings elucidate a novel mechanism of breast cancer metastasis and provide a potential therapeutic strategy for breast cancer metastasis.展开更多
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 isolat...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.展开更多
基金supported by grants from the National Natural Science Foundation of China(NSFC)(82260531 and 81760509)the Natural Science Foundation of Jiangxi Province of China(20181BAB205043 and 20224BAB206057)to X.X.
文摘Recent studies have demonstrated that cancer-associated adipocytes (CAAs) in the tumor microenvironment are involved in the malignant progression of breast cancer. However, the underlying mechanism of CAA formation and its effects on the development of breast cancer are still unknown. Here, we show that CSF2 is highly expressed in both CAAs and breast cancer cells. CSF2 promotes inflammatory phenotypic changes of adipocytes through the Stat3 signaling pathway, leading to the secretion of multiple cytokines and proteases, particularly C–X–C motif chemokine ligand 3 (CXCL3). Adipocyte-derived CXCL3 binds to its specific receptor CXCR2 on breast cancer cells and activates the FAK pathway, enhancing the mesenchymal phenotype, migration, and invasion of breast cancer cells. In addition, a combination treatment targeting CSF2 and CXCR2 shows a synergistic inhibitory effect on adipocyte-induced lung metastasis of mouse 4T1 cells in vivo. These findings elucidate a novel mechanism of breast cancer metastasis and provide a potential therapeutic strategy for breast cancer metastasis.
基金This work was supported by grants from the National Natural Science Foundation of China(NSFC31871378 and 31671460 to X.Y.and 81760509 to X.X.)the Natural Science Foundation of Jiangxi Provinee of China(20171ACB21004 to X.Y.and 20181BAB205043 to X.X.).
文摘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.
