Shinde Anjali, Tang Xiaoyun, Singh Rajesh, Brindley David N
Department of Biochemistry, Faculty of Science, The MS University of Baroda, Vadodara 390002, Gujarat, India.
Cancer Research Institute of Northern Alberta, Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada.
Cancers (Basel). 2023 Dec 21;16(1):52. doi: 10.3390/cancers16010052.
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.
肿瘤微环境中的炎症环境会导致乳腺癌患者发生免疫逃逸、对细胞死亡产生抗性、发生转移并预后不良。肿瘤坏死因子-α（TNF-α）是一种促炎细胞因子，可调节肿瘤生物学从起始到进展的多个方面。TNF-α 诱导的核因子-κB（NF-κB）激活启动炎症信号通路，该通路决定细胞的存活、死亡和肿瘤进展。一条可能的信号通路涉及自分泌运动因子（autotaxin）分泌增加，自分泌运动因子可产生溶血磷脂酸，通过六种 G 蛋白偶联受体发出信号。值得注意的是，自分泌运动因子是转移性肿瘤中上调最明显的 40 - 50 个基因之一。在本研究中，我们通过使用单克隆抗体英夫利昔单抗阻断 TNF-α 的作用来研究其效果，并研究对自分泌运动因子分泌和肿瘤进展的影响。英夫利昔单抗对肿瘤生长影响不大，但在使用 4T1 乳腺癌细胞的同基因 BALB/c 小鼠模型中，它使肺转移减少了 60%。接受英夫利昔单抗治疗的小鼠肿瘤中的增殖和转移标志物（如 Ki-67 和波形蛋白）也有所减少。同时，NF-κB 激活、自分泌运动因子表达以及参与转移的血浆和肿瘤细胞因子/趋化因子浓度均降低。我们还利用癌症数据库证明了乳腺癌患者中 TNF-α - NF-κB 与自分泌运动因子（ATX）表达呈正相关。体外研究表明，TNF-α 诱导的 NF-κB 激活会增加自分泌运动因子表达以及 4T1 乳腺癌细胞的克隆形成能力。本报告强调了英夫利昔单抗作为一种额外方法的潜在作用，即通过自分泌运动因子 - 溶血磷脂酸 - 炎症循环减弱信号传导并降低转移性癌症的死亡率。
