Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis.
Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis.
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DOI：
10.18632/oncotarget.8488
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发表时间：
2016-05-10
期刊：
影响因子：
--
通讯作者：
Kuo PL
中科院分区：
文献类型：
--
作者：
Hsu YL;Hung JY;Chiang SY;Jian SF;Wu CY;Lin YS;Tsai YM;Chou SH;Tsai MJ;Kuo PL
癌细胞与其微环境之间的交流在癌症发展中起着重要作用，但癌症相关成纤维细胞（CAF）影响肺癌中抗癌免疫和癌症进展的确切机制尚不清楚。在这里，我们报告了肺成纤维细胞在被肺癌细胞激活时产生色氨酸代谢物犬尿氨酸（Kyn），其抑制树突状细胞的分化并诱导癌症生长以及迁移。我们确定TDO 2（色氨酸2，3-双加氧酶）为能够进行色氨酸代谢的成纤维细胞中表达的主要酶。在机制上，CAF或外源性犬尿氨酸刺激肺癌细胞中的AKT，而没有赖氨酸1（WNK 1）和cAMP反应元件结合蛋白（CREB）磷酸化。抑制AKT/CREB通路可防止癌症增殖，而抑制AKT/WNK 1可逆转犬尿氨酸诱导的上皮-间充质转化和癌症迁移。此外，我们还证明了肺癌衍生的半乳糖凝集素-1有助于通过AKT依赖性途径上调CAF中的TDO 2。肺癌手术标本的免疫组织化学分析显示，TDO 2在癌旁成纤维细胞中的表达增加。此外，体内研究表明，施用TDO 2抑制剂显著改善小鼠中的DC功能和T细胞应答，并降低肿瘤转移。总之，我们的数据确定了反馈回路，由癌症衍生的半乳糖凝集素-1和产生CAF的犬尿氨酸组成，维持肺癌进展。这些发现表明，靶向这一途径可能是一种有前途的治疗策略。
Communication between cancer cells and their microenvironment plays an important role in cancer development, but the precise mechanisms by which cancer-associated fibroblasts (CAF) impact anti-cancer immunity and cancer progression in lung cancer are poorly understood. Here, we report that lung fibroblasts when activated by lung cancer cells produce tryptophan metabolite kynurenine (Kyn) that inhibits dendritic cells' differentiation and induces cancer growth as well as migration. We identified TDO2 (tryptophan 2,3-dioxygenase) as the main enzyme expressed in fibroblasts capable of tryptophan metabolism. Mechanistically, condition medium of CAF or exogenous kynurenine stimulated AKT, with no lysine 1 (WNK1) and cAMP response element-bindingprotein (CREB) phosphorylation in lung cancer cells. Inhibition of the AKT/CREB pathway prevents cancer proliferation, while inhibition of the AKT/ WNK1 reverted epithelial-to-mesenchymal transition and cancer migration induced by kynurenine. Moreover, we also demonstrate that lung cancer-derived galectin-1 contributes to the upregulation of TDO2 in CAF through an AKT-dependent pathway. Immunohistochemical analysis of lung cancer surgical specimens revealed increased TDO2 expression in the fibroblasts adjacent to the cancer. Furthermore, in vivo studies showed that administration of TDO2 inhibitor significantly improves DCs function and T cell response, and decreases tumor metastasis in mice. Taken together, our data identify the feedback loop, consisting of cancer-derived galectin-1 and CAF-producing kynurenine, that sustains lung cancer progression. These findings suggest that targeting this pathway may be a promising therapeutic strategy.
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