Genetic suppression of inflammation blocks the tumor-promoting effects of TGF-β in gastric tissue.
Genetic suppression of inflammation blocks the tumor-promoting effects of TGF-β in gastric tissue.
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DOI：
10.1158/0008-5472.can-13-3404
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发表时间：
2014-05-01
期刊：
影响因子：
11.2
通讯作者：
Rifkin DB
中科院分区：
文献类型：
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作者：
Ota M;Horiguchi M;Fang V;Shibahara K;Kadota K;Loomis C;Cammer M;Rifkin DB
TGF-β信号对癌症的贡献是复杂的，但涉及炎症微环境和癌细胞本身。在编码TGF-β突变体的小鼠中，该突变体阻止了TGF-β与潜在TGF-β结合蛋白（Tgfb1−/C33S）的结合，我们观察到由于潜在TGF-β1向活性TGF-β1的转化受损，多器官炎症和各种类型胃肠道实体瘤的发生率升高。通过基因消除潜伏TGF-β1的激活因子，我们进一步降低TGF-β的数量，从而增加肿瘤发生频率和多器官炎症。利用该模型系统进一步研究TGF-β1在胃肠道肿瘤发生过程中对淋巴细胞介导炎症的相对贡献。为此，我们生成了Tgfb1−/C33S；Rag2−/−小鼠缺乏适应性免疫功能，从而消除肿瘤的产生。Tgfb1−/C33S小鼠的组织分析表明，与野生型动物相比，P-Smad3水平降低，而Tgfb1−/C33S；Rag2−/−小鼠P-Smad3水平正常。抑制炎症反应使IL-1β和IL-6水平正常化，减少肿瘤细胞增殖。此外,Tgfb1−/ C33S;Rag2−/−小鼠表现出由胃基质产生的肝细胞生长因子介导的上皮旁分泌信号减少。总之，我们的研究结果表明，与TGF-β1减少相关的胃组织的许多反应可能直接或间接受到炎症过程的影响，炎症过程伴随着TGF-β1的缺失，而不是细胞因子缺失的直接影响。
The contributions of TGF-β signaling to cancer are complex but involve the inflammatory microenvironment as well as cancer cells themselves. In mice encoding a TGF-β mutant that precludes its binding to the latent TGF-β binding protein (Tgfb1−/C33S), we observed multiorgan inflammation and an elevated incidence of various types of gastrointestinal solid tumors due to impaired conversion of latent to active TGF-β1. By genetically eliminating activators of latent TGF-β1, we further lowered the amount of TGF-β, which enhanced tumor frequency and multiorgan inflammation. This model system was used to further investigate the relative contribution of TGF-β1 to lymphocyte-mediated inflammation in gastrointestinal tumorigenesis. Toward this end, we generated Tgfb1−/C33S;Rag2−/− mice that lacked adaptive immune function, which eliminated tumor production. Analysis of tissue from Tgfb1−/C33S mice indicated decreased levels of P-Smad3 compared to wild type animals, whereas tissue from Tgfb1−/C33S;Rag2−/− mice had normal P-Smad3 levels. Inhibiting the inflammatory response normalized levels of IL-1β and IL-6 and reduced tumor cell proliferation. Additionally, Tgfb1−/C33S;Rag2−/− mice exhibited reduced paracrine signaling in the epithelia, mediated by hepatocyte growth factor produced by gastric stroma. Together, our results indicate that many of the responses of the gastric tissue associated with decreased TGF-β1 may be directly or indirectly affected by inflammatory processes, which accompany loss of TGF-β1, rather than a direct effect of loss of the cytokine.