Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Breast Cancer Res. 2023 Mar 15;25(1):27. doi: 10.1186/s13058-023-01629-0.
Inflammatory alterations of the extracellular matrix shape the tumor microenvironment and promote all stages of carcinogenesis. This study aims to determine the impact of cellular fibronectin on inflammatory facets of tumor-associated macrophages (TAMs) in breast cancer. Cellular fibronectin (FN) harboring the alternatively spliced extra domain A (FN-EDA) was determined to be a matrix component produced by the triple-negative breast cancer (TNBC) cells. High levels of FN-EDA correlated with poor survival in breast cancer patients. The proinflammatory cytokine IL-1β enhanced the expression of cellular fibronectin including FN-EDA. TAMs were frequently observed in the tumor areas rich in FN-EDA. Conditioned media from TNBC cells induced the differentiation of CD206CD163 macrophages and stimulated the STAT3 pathway, ex vivo. In the macrophages, the STAT3 pathway enhanced FN-EDA-induced IL-1β secretion and NF-κB signaling. In conclusion, our data indicate a self-reinforcing mechanism sustained by FN-EDA and IL-1β through NF-κB and STAT3 signaling in TAMs which fosters an inflammatory environment in TNBC.
细胞外基质的炎症改变塑造了肿瘤微环境，并促进了癌症发生的所有阶段。本研究旨在确定细胞纤维连接蛋白对乳腺癌中肿瘤相关巨噬细胞（TAMs）炎症方面的影响。细胞纤维连接蛋白（FN）含有交替剪接的额外结构域 A（FN-EDA），被确定为三阴性乳腺癌（TNBC）细胞产生的基质成分。高水平的 FN-EDA 与乳腺癌患者的不良预后相关。促炎细胞因子 IL-1β 增强了细胞纤维连接蛋白（包括 FN-EDA）的表达。在富含 FN-EDA 的肿瘤区域中经常观察到 TAMs。TNBC 细胞的条件培养基诱导 CD206CD163 巨噬细胞的分化，并在体外刺激 STAT3 通路。在巨噬细胞中，STAT3 通路增强了 FN-EDA 诱导的 IL-1β 分泌和 NF-κB 信号转导。总之，我们的数据表明，在 TNBC 中，FN-EDA 和 IL-1β 通过 NF-κB 和 STAT3 信号转导维持了一种自我强化的机制，促进了炎症环境。
