Cancer preventive effect of recombinant TRAIL by ablation of oncogenic inflammation in colitis-associated cancer rather than anticancer effect.
Cancer preventive effect of recombinant TRAIL by ablation of oncogenic inflammation in colitis-associated cancer rather than anticancer effect.
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DOI：
10.18632/oncotarget.23083
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发表时间：
2018-01-05
期刊：
影响因子：
--
通讯作者：
Hong S
中科院分区：
文献类型：
--
作者：
Kim JY;Kim YM;Park JM;Han YM;Lee KC;Hahm KB;Hong S
肿瘤坏死因子相关凋亡诱导配体（TRAIL）在诱导细胞凋亡中的潜力是癌症治疗中的标志，此后其实现针对癌细胞的细胞死亡途径的选择性能力导致了重组TRAIL在癌症治疗中的希望。来自氧化偶氮甲烷引发的、葡聚糖硫酸钠促进的结肠炎相关癌症（CAC）模型的当前数据强烈地表明rTRAIL在癌症预防中而不是在癌症治疗中的潜力。rTRAIL的早期治疗通过抑制巨噬细胞向受损粘膜中的募集并激活具有巨噬细胞增多的清除剂活性和几种生长因子的产生来显著减少结肠炎和CAC。与此相反，晚期给予rTRAIL的抗癌作用并没有减少CAC的发生和发展。发现了rTRAIL的显著的癌症预防机制。在CAC模型中，通过TRAIL治疗6天诱导抗炎、再生和红细胞增多，在4周时显著的抑制活性是明显的，并且在12周时注意到抗氧化和抗炎诱导。最重要的是，TRAIL通过激活NLRP3炎性体途径增强病理性炎症的消退来促进组织再生。结果表明，TRAIL通过抑制促炎信号传导和促进组织修复来减少结肠炎的诱导和CAC的启动，以通过NLRP 3炎性体的激活来维持肠内稳态。因此，TRAIL可以作为抗CAC的化学预防剂，而不是作为赋予细胞凋亡的治疗药物。
The potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in inducing apoptosis is a hallmark in cancer therapeutics, after which its selective ability to achieve cell death pathways against cancer cells led to hope for recombinant TRAIL in cancer therapeutics. The present data from azoxymethane-initiated, dextran sulfate sodium-promoted colitis associated cancer (CAC) model strongly indicate the potential of rTRAIL in cancer prevention rather than in cancer therapeutics. Early treatment of rTRAIL significantly reduced colitis and CAC by inhibiting the recruitment of macrophages into the damaged mucosa and activating the scavenger activity with efferocytosis and the production of several growth factors. In contrast, late administration of rTRAIL as for anti-cancer effect did not decrease the initiation and development of CAC at all. Significant cancer preventing mechanisms of rTRAIL were identified. In the CAC model, anti-inflammation, regeneration, and efferocytosis was induced by treatment of TRAIL for 6 days, significant inhibitory activity was evident at 4 weeks and anti-oxidative and anti-inflammatory induction were noted at 12 weeks. Most importantly, TRAIL promoted tissue regeneration by enhancing the resolution of pathological inflammation through the activation of the NLRP3 inflammasome pathway. The results indicate that TRAIL reduces the induction of colitis and the initiation of CAC by inhibiting pro-inflammatory signaling and promoting tissue repair to maintain intestinal homeostasis through activation of the NLRP3 inflammasome. Therefore, TRAIL can be used as a chemopreventive agent against CAC, rather than as a therapeutic drug endowing apoptosis.
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DOI：
10.1084/jem.186.8.1365
发表时间：
1997-10-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Katsikis PD;Garcia-Ojeda ME;Torres-Roca JF;Tijoe IM;Smith CA;Herzenberg LA;Herzenberg LA
通讯作者：
Herzenberg LA
影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
15.9
作者：
Ghosh, Arnab;Dogan, Yildirim;van den Brink, Marcel R. M.
通讯作者：
van den Brink, Marcel R. M.
影响因子：
45.3
作者：
Soria, Jean-Charles;Smit, Egbert;Blackhall, Fiona
通讯作者：
Blackhall, Fiona
影响因子：
4.4
作者：
Lum, JJ;Bren, G;Badley, AD
通讯作者：
Badley, AD