Discipline of Surgical Specialties, Adelaide Medical School, University of Adelaide, The Queen Elizabeth Hospital, Woodville South, SA 5011, Australia.
Robinson Research Institute, University of Adelaide, Adelaide, SA 5006, Australia.
Int J Mol Sci. 2023 Apr 17;24(8):7385. doi: 10.3390/ijms24087385.
CCL2 is an inflammatory cytokine that regulates macrophage activity and is implicated in increased mammographic density and early breast tumorigenesis. The role of CCL2 in mediating stromal interactions that contribute to breast tumorigenesis has yet to be fully elucidated. THP-1-derived macrophages and mammary fibroblasts were co-cultured for 72 h. Fibroblasts and macrophages were analysed for phenotype, expression of inflammatory and ECM-regulatory genes and collagen production. Mice overexpressing CCL2 in the mammary glands were analysed for global gene expression by RNAseq at 12 weeks of age. These mice were cross-bred with PyMT mammary tumour mice to examine the role of CCL2 in tumorigenesis. The co-culture of macrophages with fibroblasts resulted in macrophage polarization towards an M2 phenotype, and upregulated expression of CCL2 and other genes associated with inflammation and ECM remodelling. CCL2 increased the production of insoluble collagen by fibroblasts. A global gene expression analysis of CCL2 overexpressing mice revealed that CCL2 upregulates cancer-associated gene pathways and downregulates fatty acid metabolism gene pathways. In the PyMT mammary tumour model, CCL2 overexpressing mice exhibited increased macrophage infiltration and early tumorigenesis. Interactions between macrophages and fibroblasts regulated by CCL2 can promote an environment that may increase breast cancer risk, leading to enhanced early tumorigenesis.
CCL2 是一种炎症细胞因子，可调节巨噬细胞活性，并与乳腺密度增加和早期乳腺癌发生有关。CCL2 在调节促进乳腺癌发生的基质相互作用中的作用尚未完全阐明。将 THP-1 衍生的巨噬细胞和乳腺成纤维细胞共培养 72 小时。分析成纤维细胞和巨噬细胞的表型、炎症和 ECM 调节基因的表达以及胶原蛋白的产生。在 12 周龄时，通过 RNAseq 分析过表达 CCL2 的乳腺中的小鼠的全基因表达。这些小鼠与 PyMT 乳腺肿瘤小鼠杂交，以研究 CCL2 在肿瘤发生中的作用。巨噬细胞与成纤维细胞共培养导致巨噬细胞向 M2 表型极化，并上调 CCL2 和其他与炎症和 ECM 重塑相关的基因的表达。CCL2 增加了成纤维细胞不溶性胶原蛋白的产生。CCL2 过表达小鼠的全基因表达分析显示，CCL2 上调了癌症相关基因途径，下调了脂肪酸代谢基因途径。在 PyMT 乳腺肿瘤模型中，过表达 CCL2 的小鼠表现出巨噬细胞浸润增加和早期肿瘤发生。CCL2 调节的巨噬细胞和成纤维细胞之间的相互作用可以促进可能增加乳腺癌风险的环境，从而导致早期肿瘤发生增强。
