Selective PGE(2) suppression inhibits colon carcinogenesis and modifies local mucosal immunity.
Selective PGE(2) suppression inhibits colon carcinogenesis and modifies local mucosal immunity.
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DOI：
10.1158/1940-6207.capr-11-0188
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Rosenberg DW
中科院分区：
文献类型：
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作者：
Nakanishi M;Menoret A;Tanaka T;Miyamoto S;Montrose DC;Vella AT;Rosenberg DW
前列腺素E2(PGE2)是一种生物活性脂质，具有广泛的生理调节作用，在炎症和癌症中发挥重要作用。PGE2是由花生四烯酸通过环氧合酶(Coxs)和末端合成酶(PGES)的顺序作用而产生的。在结直肠癌(CRC)中经常发现COX-2水平升高，并伴随PGE2的升高，这为使用COX-2抑制剂进行化学预防提供了理论基础。然而，尽管COX-2抑制剂在癌症预防中被证明是有效的，但它们表现出剂量依赖的毒性，部分是通过它们对必需前列腺素的非特异性减少而介导的，从而限制了它们的化学预防益处。为了实现更高的特异性，最近的努力针对的是PGE2生产中的可诱导末端合酶，微粒体pGES(mPGES-1)。在目前的研究中，我们表明mPGES-1的基因缺失对致癌物诱导的结肠癌具有显著的保护作用。MPGES-1基因缺失导致偶氮甲烷(AOM)处理的小鼠远端结肠肿瘤多样性下降~80%，肿瘤负荷下降90%。与显著的癌症抑制相关，我们发现PGE2在控制结肠引流的肠系膜淋巴结内免疫调节细胞(FoxP3阳性调节性T细胞)的扩张中发挥关键作用，提供了一种潜在的机制，通过抑制PGE2可以预防结直肠癌。这些结果为PGE2如何控制抗肿瘤免疫提供了新的见解。
Prostaglandin E2 (PGE2) is a bioactive lipid that mediates a wide range of physiological effects and plays a central role in inflammation and cancer. PGE2 is generated from arachidonic acid by the sequential actions of the cyclooxygenases (COXs) and terminal synthases (PGES). Increased levels of COX-2, with a concomitant elevation of PGE2, are often found in colorectal cancers (CRC), providing the rationale for the use of COX-2 inhibitors for chemoprevention. Despite their proven efficacy in cancer prevention, however, COX-2 inhibitors exhibit dose-dependent toxicities that are mediated in part by their non-specific reduction of essential prostanoids, thus limiting their chemopreventive benefit. To achieve enhanced specificity, recent efforts have been directed towards targeting the inducible terminal synthase in the production of PGE2, microsomal PGES (mPGES-1). In the present study, we show that genetic deletion of mPGES-1 affords significant protection against carcinogen-induced colon cancer. mPGES-1 gene deletion results in an ~80% decrease in tumor multiplicity and up to a 90% reduction in tumor load in the distal colon of azoxymethane (AOM)-treated mice. Associated with the striking cancer suppression, we have identified a critical role for PGE2 in the control of immunoregulatory cell expansion (FoxP3-positive regulatory T cells) within the colon-draining mesenteric lymph nodes, providing a potential mechanism by which suppression of PGE2 may protect against CRC. These results provide new insights into how PGE2 controls anti-tumor immunity.