Suppression Colitis and Colitis-Associated Colon Cancer by Anti-S100a9 Antibody in Mice.
Suppression Colitis and Colitis-Associated Colon Cancer by Anti-S100a9 Antibody in Mice.
复制标题
抗 S100a9 抗体在小鼠体内抑制结肠炎和结肠炎相关结肠癌
DOI：
10.3389/fimmu.2017.01774
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发表时间：
2017
影响因子：
7.3
通讯作者：
Ma J
中科院分区：
文献类型：
--
作者：
Zhang X;Wei L;Wang J;Qin Z;Wang J;Lu Y;Zheng X;Peng Q;Ye Q;Ai F;Liu P;Wang S;Li G;Shen S;Ma J
慢性炎症和癌症之间的联系早已被认识到。炎症性肠病溃疡性结肠炎经常进展为结肠癌;然而，其潜在机制仍不清楚。S100 a9在急性和慢性炎症中是一种重要的促炎介质，其异常表达也有助于肿瘤发生过程，如细胞增殖、血管生成、转移和免疫逃避。我们之前发现S100 a8和S100 a9是高度活化的，在结肠炎相关的癌变过程中起着重要作用，这表明溃疡性结肠炎和相关结肠癌有吸引力的治疗靶点。在此，我们报告了给予中和性抗S100 a9抗体显著改善了葡聚糖硫酸钠（DSS）诱导的结肠炎，并伴有先天免疫细胞（巨噬细胞、中性粒细胞和树突细胞）的细胞浸润减少和促炎细胞因子（TNFα、IL 1 β、IFNγ、IL 6、IL 17 a、IL 23 a、IL 4和IL 12 a）的产生减少。还在氧化偶氮甲烷（AOM）/DSS诱导的结肠炎相关癌症（CAC）小鼠模型中观察到抗S100 a9抗体治疗的保护作用。抗S100 a9抗体可抑制结肠组织中的炎症反应、肿瘤细胞增殖和免疫细胞浸润。基因表达谱分析表明，已知参与CAC发展的关键途径，如Wnt信号通路，PI 3 K-Akt信号通路，精氨酸-细胞因子受体相互作用和ECM-受体相互作用通路，在CAC小鼠中用抗S100 a9抗体治疗后被抑制。鉴于抗S100 a9中和抗体对DSS诱导的结肠炎和AOM/DSS诱导的CAC的保护作用，本研究表明抗S100 a9抗体可能为治疗溃疡性结肠炎提供新的治疗方法，并可能降低CAC的风险。
The association between chronic inflammation and cancer has long been recognized. The inflammatory bowel disease ulcerative colitis frequently progresses to colon cancer; however, the underlying mechanism is still unclear. S100a9 has been emerged as an important pro-inflammatory mediator in acute and chronic inflammation, and the aberrant expression of S100a9 also contributes to tumorigenic processes such as cell proliferation, angiogenesis, metastasis, and immune evasion. We previously revealed that S100a8 and S100a9 are highly activated and play an important role in the process of colitis-associated carcinogenesis, which suggests an attractive therapeutic target for ulcerative colitis and related colon cancer. Here, we report that administration of a neutralizing anti-S100a9 antibody significantly ameliorated dextran sulfate sodium (DSS)-induced colitis and accompanied by diminished cellular infiltrate of innate immunity cells (macrophages, neutrophils, and dendritic cells) and production of pro-inflammatory cytokines (Tnfα, Il1β, Ifnγ, Il6, Il17a, Il23a, Il4, and Il12a). The protective effect of anti-S100a9 antibody treatment was also observed in azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) mouse model. The inflammatory response, tumor cell proliferation, and immune cells infiltration in the colon tissues were suppressed by anti-S100a9 antibody. Gene expression profiling showed that key pathways known to be involved in CAC development, such as Wnt signaling pathway, PI3K–Akt signaling pathway, cytokine–cytokine receptor interaction, and ECM–receptor interaction pathway, were suppressed after treatment with anti-S100a9 antibody in CAC mice. In view of the protective effect of neutralizing anti-S100a9 antibody against DSS-induced colitis and AOM/DSS-induced CAC in mouse model, this study suggests that anti-S100a9 antibody may provide a novel therapeutic approach to treat ulcerative colitis and may decrease the risk for developing CAC.