TGF-β receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms.
TGF-β receptor II loss promotes mammary carcinoma progression by Th17 dependent mechanisms.
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DOI：
10.1158/2159-8290.cd-11-0100
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发表时间：
2011-10
期刊：
影响因子：
28.2
通讯作者：
Moses HL
中科院分区：
文献类型：
--
作者：
Novitskiy SV;Pickup MW;Gorska AE;Owens P;Chytil A;Aakre M;Wu H;Shyr Y;Moses HL
我们报道，IL-17显著增加乳腺癌细胞分泌CXCL1和CXCL5，这一作用可被转化生长因子-β通过II型转化生长因子-β受体(T-βRII)下调。TβRII(Tgfbr2KO)条件性基因敲除的癌细胞在刺激趋化因子分泌的过程中对IL-17a的敏感性增强。在PYMT诱导的肿瘤进展过程中，PYMT/Tgfbr2KO肿瘤中Th17诱导的细胞因子转化生长因子β、IL-6、IL-23水平升高，并与Th17细胞数量增加有关。IL-17通过上调Arg、IDO和COX2，增强MDSCs对T细胞的抑制作用。用抗IL-17单抗治疗PYMT/Tgfbr2KO小鼠可降低肿瘤生长和转移负担。对人类乳腺癌转录组数据库的分析表明，IL-17基因的表达与淋巴结阳性、雌激素受体阴性或管腔B亚型的不良预后有很强的相关性，提示了潜在的治疗方法。
We report that IL-17 significantly increases the secretion of CXCL1 and CXCL5 from mammary carcinoma cells, which is downregulated by TGF-β through the type II TGF-β receptor (TβRII). Carcinoma cells with conditional knockout of TβRII (Tgfbr2KO) have enhanced sensitivity to IL-17a in the stimulation of chemokine secretion. During polyoma middle T (PyMT) induced tumor progression, levels of Th17 inducing cytokines TGF-β, IL-6, IL-23 were increased in PyMT/Tgfbr2KO tumors, which was associated with an increased number of Th17 cells. IL-17 increased the suppressive function of MDSCs on T cells through the upregulation of Arg, IDO, and COX2. Treatment of PyMT/Tgfbr2KO mice with anti-IL-17 Ab decreased carcinoma growth and metastatic burden. Analysis of human breast cancer transcriptome databases showed a strong association between IL-17 gene expression and poor outcome in lymph node positive, estrogen receptor negative or luminal B subtypes suggesting potential therapeutic approaches.