|
既往研究已经发现肿瘤相关巨噬细胞可以促进乳腺癌的生长和转移，并且已经确定肿瘤相关巨噬细胞分泌的多种细胞因子与不良临床结局相关。不过，肿瘤相关巨噬细胞与乳腺癌细胞之间存在的治疗靶点尚不明确。 2018年8月29日，英国《自然》旗下《细胞死亡与疾病》在线发表广州中医药大学、香港浸会大学的研究报告，发现肿瘤相关巨噬细胞分泌的趋化因子CXC配体1（CXCL1）通过激活NF-κB→SOX4通路信号转导可以促进乳腺癌转移。 该研究首先通过细胞因子阵列分析，证实CXCL1是肿瘤相关巨噬细胞分泌最多的趋化因子，可以促进乳腺癌的迁移和浸润能力，以及小鼠和人类乳腺癌细胞的上皮→间质转化。随后通过定量聚合酶链反应（QPCR）筛查，进一步证实SOX4是CXCL1分泌后应答水平最高的基因。机制研究表明，CXCL1与SOX4启动子结合并且通过细胞核因子κB（NF-κB）通路激活其转录。通过体内乳腺癌异种移植物，证实抑制肿瘤相关巨噬细胞分泌CXCL1可使乳腺癌的生长和转移显著减少。最后，生物信息学分析和临床研究表明，CXCL1高表达与乳腺癌淋巴结转移、总生存不良、基底样亚型（三阴性）乳腺癌显著相关。 因此，该研究结果表明，肿瘤相关巨噬细胞与CXCL1通过NF-κB→SOX4通路信号转导激活，可以促进乳腺癌转移，而CXCL1靶向治疗可能成为防止乳腺癌转移的新策略。 Cell Death Dis. 2018 Aug 29;9(8):880. CXCL1 derived from tumor-associated macrophages promotes breast cancer metastasis via activating NF-κB/SOX4 signaling. Neng Wang, Weiping Liu, Yifeng Zheng, Shengqi Wang, Bowen Yang, Min Li, Juxian Song, Fengxue Zhang, Xiaotong Zhang, Qi Wang, Zhiyu Wang. Guangzhou University of Chinese Medicine, Guangzhou, China; Hong Kong Baptist University, Hong Kong SAR, China. Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and multiple TAM-secreted cytokines have been identified associating with poor clinical outcomes. However, the therapeutic targets existing in the loop between TAMs and cancer cells are still required for further investigation. Here in, cytokine array validated that C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant chemokine secreted by TAMs, and CXCL1 can promote breast cancer migration and invasion ability, as well as epithelial-mesenchymal transition in both mouse and human breast cancer cells. QPCR screening further validated SOX4 as the highest responsive gene following CXCL1 administration. Mechanistic study revealed that CXCL1 binds to SOX4 promoter and activates its transcription via NF-κB pathway. In vivo breast cancer xenografts demonstrated that CXCL1 silencing in TAMs results in a significant reduction in breast cancer growth and metastatic burden. Bioinformatic analysis and clinical investigation finally suggested that high CXCL1 expression is significantly correlated with breast cancer lymph node metastasis, poor overall survival and basal-like subtype. Taken together, our results indicated that TAMs/CXCL1 promotes breast cancer metastasis via NF-κB/SOX4 activation, and CXCL1-based therapy might become a novel strategy for breast cancer metastasis prevention. DOI: 10.1038/s41419-018-0876-3
|
|
|
