文章：

英夫利西单抗，一种针对TNF-α的单克隆抗体，可抑制NF-κB活化、自分泌运动因子表达及乳腺癌肺转移

Infliximab, a Monoclonal Antibody against TNF-α, Inhibits NF-κB Activation, Autotaxin Expression and Breast Cancer Metastasis to Lungs

原文发布日期：21 December 2023

DOI: 10.3390/cancers16010052

类型: Article

开放获取: 是

英文摘要：

An inflammatory milieu in the tumor microenvironment leads to immune evasion, resistance to cell death, metastasis and poor prognosis in breast cancer patients. TNF-α is a proinflammatory cytokine that regulates multiple aspects of tumor biology from initiation to progression. TNF-α-induced NF-κB activation initiates inflammatory pathways, which determine cell survival, death and tumor progression. One candidate pathway involves the increased secretion of autotaxin, which produces lysophosphatidate that signals through six G-protein-coupled receptors. Significantly, autotaxin is one of the 40–50 most upregulated genes in metastatic tumors. In this study, we investigated the effects of TNF-α by blocking its action with a monoclonal antibody, Infliximab, and studied the effects on autotaxin secretion and tumor progression. Infliximab had little effect on tumor growth, but it decreased lung metastasis by 60% in a syngeneic BALB/c mouse model using 4T1 breast cancer cells. Infliximab-treated mice also showed a decrease in proliferation and metastatic markers like Ki-67 and vimentin in tumors. This was accompanied by decreases in NF-κB activation, autotaxin expression and the concentrations of plasma and tumor cytokines/chemokines which are involved in metastasis. We also demonstrated a positive correlation of TNF-α -NF-κB and ATX expression in breast cancer patients using cancer databases. Studies in vitro showed that TNF-α-induced NF-κB activation increases autotaxin expression and the clone forming ability of 4T1 breast cancer cells. This report highlights the potential role of Infliximab as an additional approach to attenuate signaling through the autotaxin–lysophosphatidate–inflammatory cycle and decrease mortality from metastatic cancer.

摘要翻译： 

肿瘤微环境中的炎症状态可导致免疫逃逸、细胞死亡抵抗、转移及乳腺癌患者预后不良。TNF-α作为促炎细胞因子，在肿瘤发生发展的多个环节发挥调控作用。TNF-α诱导的NF-κB活化启动炎症通路，进而决定细胞存活、死亡及肿瘤进展。其中一条潜在通路涉及自分泌运动因子分泌增加，该因子产生的溶血磷脂酸可通过六种G蛋白偶联受体传递信号。值得注意的是，自分泌运动因子在转移性肿瘤中属于上调最显著的前40-50个基因之一。本研究通过单克隆抗体英夫利昔单抗阻断TNF-α作用，探究其对自分泌运动因子分泌及肿瘤进展的影响。在4T1乳腺癌细胞构建的同源BALB/c小鼠模型中，英夫利昔单抗对肿瘤生长影响甚微，但使肺转移率降低60%。经英夫利昔单抗处理的小鼠肿瘤中，增殖标志物Ki-67和转移标志物波形蛋白表达均下降，同时伴随NF-κB活化减弱、自分泌运动因子表达降低，以及血浆和肿瘤中参与转移过程的细胞因子/趋化因子浓度下降。通过癌症数据库分析，我们进一步证实乳腺癌患者中TNF-α-NF-κB通路与自分泌运动因子表达呈正相关。体外实验表明，TNF-α诱导的NF-κB活化可增强4T1乳腺癌细胞的自分泌运动因子表达及克隆形成能力。本研究表明，英夫利昔单抗可能通过抑制自分泌运动因子-溶血磷脂酸-炎症循环信号通路，成为降低转移性癌症死亡率的潜在辅助治疗策略。

原文链接：

Infliximab, a Monoclonal Antibody against TNF-α, Inhibits NF-κB Activation, Autotaxin Expression and Breast Cancer Metastasis to Lungs