Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Province, China.
Northewest Minzu University, Lanzhou 730030, Gansu Province, China.
Int Immunopharmacol. 2023 Jul;120:110235. doi: 10.1016/j.intimp.2023.110235. Epub 2023 May 16.
Neutrophil extracellular traps (NETs) have been implicated in many cancers, but the regulatory mechanisms in the context of breast cancer have not been thoroughly discussed. This study proposed a mechanism based on collagen-activated DDR1/CXCL5 for NET formation in breast cancer. Through TCGA and GEO-based bioinformatics analysis, we examined the DDR1 expression and the correlation of CXCL5 with immune cell infiltration in breast cancer. It was found that high DDR1 expression was correlated with poor prognosis of patients with breast cancer, and CXCL5 was positively correlated with neutrophil and Treg infiltration. Expression of DDR1 and CXCL5 was determined in collagen-treated breast cancer cells, the malignant phenotypes of which were evaluated by ectopic expression and knockdown methods. Collagen-activated DDR1 upregulated CXCL5 expression, resulting in augmented malignant phenotypes of breast cancer cells in vitro. The formation of NETs caused promotion in the differentiation and immune infiltration of Tregs in breast cancer. A in situ breast cancer mouse model was constructed, where NET formation and lung metastasis of breast cancer cells were observed. The differentiation of CD4+ T cells isolated from the mouse model was induced into Tregs, followed by Treg infiltration assessment. It was further confirmed in vivo that DDR1/CXCL5 induced the formation of NETs to promote immune infiltration of Tregs, driving tumor growth and metastasis. Accordingly, our results provided new mechanistic insights for an understanding of the role of collagen-mediated DDR1/CXCL5 in formation of NETs and Treg infiltration, revealing potential targets for therapeutic intervention of breast cancer.
中性粒细胞胞外诱捕网（NETs）已被牵涉到多种癌症中，但在乳腺癌背景下的调控机制尚未被充分讨论。本研究提出了一种基于胶原激活 DDR1/CXCL5 的机制，用于乳腺癌中 NET 的形成。通过 TCGA 和 GEO 数据库的生物信息学分析，我们检测了 DDR1 的表达以及 CXCL5 与乳腺癌中免疫细胞浸润的相关性。结果发现，高 DDR1 表达与乳腺癌患者的不良预后相关，并且 CXCL5 与中性粒细胞和 Treg 浸润呈正相关。我们在胶原处理的乳腺癌细胞中检测了 DDR1 和 CXCL5 的表达，并通过异位表达和敲低方法评估了其恶性表型。胶原激活的 DDR1 上调了 CXCL5 的表达，导致乳腺癌细胞体外恶性表型增强。NET 的形成促进了乳腺癌中 Treg 的分化和免疫浸润。构建了原位乳腺癌小鼠模型，观察了乳腺癌细胞 NET 的形成和肺转移。从模型中分离的 CD4+T 细胞被诱导分化为 Treg，然后评估 Treg 的浸润情况。进一步在体内证实了 DDR1/CXCL5 诱导 NET 的形成，从而促进 Treg 的免疫浸润，驱动肿瘤生长和转移。因此，我们的结果为理解胶原介导的 DDR1/CXCL5 在 NET 形成和 Treg 浸润中的作用提供了新的机制见解，揭示了乳腺癌治疗干预的潜在靶点。
