PO.PR02.01 · 预防研究
EPA与萘普生联合可阻止iCAF极化并减轻与Pirc肿瘤发生相关的炎症
The combination of EPA and Naproxen prevents iCAF polarization and attenuates inflammation associated with Pirc tumor development
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摘要 Abstract
中文摘要
我们最近报道，二十碳五烯游离脂肪酸（EPA-FFA）或化学稳定的EPA类似物（TP-252）在饮食中与萘普生联合使用时，在高外显率的Pirc大鼠模型中可将结肠肿瘤发生减少高达98%。癌症抑制部分依赖于类二十烷酸生物合成的改变。以下研究在这些初步发现的基础上，采用全基因组RNA测序（RNA-seq）分析，以鉴定Pirc肿瘤中受药物治疗影响的特定分子通路。从维持AIN93G饮食的未治疗对照Pirc大鼠中分离的结肠肿瘤，表现出与炎症性癌症相关成纤维细胞（iCAFs）存在相关的基因表达谱。经过二十周EPA-FFA（2% w/w）和萘普生（200 ppm）联合饮食治疗后，炎症和增殖基因特征显著减少。对这些药物联合治疗肿瘤的进一步分析显示，其表达谱类似于炎症性较低的成纤维细胞表型，提示存在肌成纤维细胞（myCAFs）。为进一步确立潜在机制，我们从未治疗Pirc大鼠的结肠肿瘤中分离出CAFs。随后用单个细胞因子（TNF-a、IL-1beta或IL-6）刺激CAFs 12小时以促进iCAF活化。在IL-1beta活化的CAFs中测定的一组炎症细胞因子（IL-6、Cxcl2、Csf3和Nos2）的分泌，与未治疗Pirc饮食对照结肠肿瘤的RNA-seq分析结果相似。此外，EPA-FFA与萘普生的联合治疗减弱了IL-1beta刺激下CAFs向iCAF表型的极化。本研究进一步深化了我们对饮食性EPA与萘普生联合所提供的肠道肿瘤保护作用的理解。这些发现进一步揭示了可在未来临床化学预防研究中加以利用的潜在机制。
查看英文原文 English abstract
We recently reported that eicosapentaenoic free fatty acid (EPA-FFA) or a chemically stable EPA analog (TP-252), when combined in the diet with naproxen, reduces colon tumor development by up to 98% in the highly penetrant Pirc rat model. Cancer suppression is dependent, in part, upon modifications of eicosanoid biosynthesis. The following study expands upon these initial findings using genome-wide RNA-sequencing (RNA-seq) analysis to identify specific molecular pathways in Pirc tumors affected by drug treatment. Colon tumors isolated from untreated control Pirc rats maintained on AIN93G diet exhibited gene expression profiles associated with the presence of inflammatory cancer-associated fibroblasts (iCAFs). Following a twenty-week treatment with a combination diet of EPA-FFA (2% w/w) and naproxen (200 ppm), there was a marked reduction in inflammatory and proliferative gene signatures. Further analysis of these drug combination-treated tumors showed expression profiles resembling a less inflammatory fibroblast phenotype, suggesting the presence of myofibroblasts (myCAFs). To further establish potential mechanisms, we isolated CAFs from colon tumors of untreated Pirc rats. CAFs were then stimulated for 12 hours with individual cytokines (TNF-a, IL-1beta or IL-6) to promote iCAF activation. The secretion of a panel of inflammatory cytokines (IL-6, Cxcl2, Csf3 and Nos2) determined in IL-1beta activated CAFs were similar to those found by RNA-seq analysis of colon tumors from untreated Pirc diet controls. In addition, the combination treatment of EPA-FFA and naproxen attenuated polarization of CAFs towards an iCAF phenotype upon IL-1beta stimulation. The present work contributes further to our understanding of intestinal tumor protection afforded by a combination of dietary EPA and naproxen. These findings further uncover potential mechanisms that can be exploited in future clinical chemoprevention studies.
利益披露 Disclosure
N. Jani, None..
M. Martinez, None.