BACKGROUND Mechanisms driving the progression of castration-resistant prostate cancer are believed to relate substantially to the tumor microenvironment. However, the cross-talks between tumor epithelial cell, stromal cells, and immune cells are yet to be fully elucidated. The present study aims to determine the role of chemokine and neutrophil derived cytokine paracrine axis in mediating the interaction between tumor cells, stromal myofibroblasts, and neutrophils in the tumor microenvironment of prostate cancer. METHODS To identify myofibroblasts and neutrophil derived specific proteins affecting progression of prostate cancer, bioinformatics analyses were firstly performed in independent human prostate cancer gene expression data sets from the GEO data bank. Expression of stromal myofibroblasts secretory chemokine CXCL1 and neutrophil derived cytokine LCN2 was evaluated in prostate tissues via immunohistochemistry assay. We further investigated the effect of CXCL1 and LCN2 on prostate cancer using in vivo and in vitro models, and explored the underlying signal transduction pathways. RESULTS A CXCL1-LCN2 paracrine network was confirmed in prostate cancer tissue samples, which was correlated with the biochemical recurrence of prostate cancer. Of note, CXCL1-LCN2 axis activates Src signaling, triggers the epithelial-mesenchymal transition (EMT), consequently promotes the migration of prostate cancer cells, leading to enhanced tumor metastasis. CONCLUSIONS Our findings may provide enhanced insight into the interactions of carcinoma-stromal cells and immune cells linked to prostate cancer progression, wherein CXCL1-LCN2 axis is a key contributor to prostate cancer cells migration. These data indicate tumor microenvironment and Src signaling pathway may be potential therapeutic targets of prostate cancer treatment.

中文翻译：

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CXCL1-LCN2 旁分泌轴通过 Src 激活和上皮间质转化促进前列腺癌的进展。

背景技术据信驱动去势抵抗性前列腺癌进展的机制与肿瘤微环境显着相关。然而，肿瘤上皮细胞、基质细胞和免疫细胞之间的相互作用尚未完全阐明。本研究旨在确定趋化因子和中性粒细胞衍生的细胞因子旁分泌轴在介导前列腺癌肿瘤微环境中肿瘤细胞、基质肌成纤维细胞和中性粒细胞之间相互作用中的作用。方法 为了鉴定影响前列腺癌进展的肌成纤维细胞和中性粒细胞衍生的特定蛋白质，首先对来自 GEO 数据库的独立人类前列腺癌基因表达数据集进行生物信息学分析。通过免疫组织化学测定评估前列腺组织中基质肌成纤维细胞分泌趋化因子 CXCL1 和中性粒细胞衍生细胞因子 LCN2 的表达。我们利用体内和体外模型进一步研究了CXCL1和LCN2对前列腺癌的影响，并探讨了潜在的信号转导途径。结果前列腺癌组织样本中证实存在CXCL1-LCN2旁分泌网络，该网络与前列腺癌的生化复发相关。值得注意的是，CXCL1-LCN2轴激活Src信号传导，触发上皮间质转化（EMT），从而促进前列腺癌细胞的迁移，从而增强肿瘤转移。结论我们的研究结果可能有助于深入了解与前列腺癌进展相关的癌基质细胞和免疫细胞的相互作用，其中CXCL1-LCN2轴是前列腺癌细胞迁移的关键因素。这些数据表明肿瘤微环境和Src信号通路可能是前列腺癌治疗的潜在治疗靶点。