Tumorigenic cytokine networks during colon carcinogenesis depend on sphingosine-1-phosphate receptor signalling

结肠癌发生过程中的致瘤细胞因子网络依赖于 1-磷酸鞘氨醇受体信号传导

• 批准号: 319412472
• 负责人: Professor Dr. Bernhard Brüne
• 金额: --
• 依托单位: Institut für Biochemie I: Pathobiochemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/319412472?language=en
• 关键词: Tumorigenic; cytokine; networks; during; colon

The immune contexture in colorectal cancer emerges as an important prognostic factor for patient survival. Accordingly, the relative presence of adaptive immune cell subpopulations in intestinal tumors marks either good prognosis (cytotoxic CD8+ T cells, TH1-polarized CD4+ T cells) or bad prognosis (TH17-polarized CD4+ T cells). Lymphocyte plasticity in colorectal carcinogenesis depends on master inflammatory regulators in myeloid cells such as NF-kappaB, STAT3 or STAT1, and their downstream mediators, including the cytokines IL-1beta, IL-6, IL-23, and TNF-alpha, which promote, and IL-12 or type I interferons, which restrict carcinogenesis. The production of these cytokines is initially triggered by exogenous or endogenous danger signals. Signaling through pattern recognition receptors recognizing such danger signals receives substantial regulatory input through other signaling pathways. We follow the hypothesis that the sphingolipid sphingosine-1-phosphate (S1P) critically regulates inflammatory cytokines in colorectal cancer by signaling through specific G protein-coupled receptors (S1PRs). Enhanced S1P levels were previously connected to colon carcinogenesis. Own data suggest that particularly S1PR1 and S1PR4 are involved in tumor-associated inflammation. S1PR1 expression in tumor-associated macrophages in mammary carcinoma and fibrosarcoma promoted lymphangiogenesis and metastasis through IL-1beta secretion. S1PR4 promoted TH17 development in breast tumors and limited type I interferon production. Based on this evidence, we propose a tumor-promoting role for S1PR4 and a dominating role of S1PR1 signaling in colorectal cancer metastasis. Specifically, we investigate if S1PR1 expression by macrophages promotes lymph node metastasis via IL-1beta in a model of metastatic colon cancer. Additionally we ask whether S1PR4-/- mice show a lower incidence of colitis-associated cancer and analyze the underlying altered cytokine networks and myeloid cell/lymphocyte plasticity. Our studies will identify new regulators of tumor-associated inflammation and may suggest potential pharmacological targets to interfere with inflammatory events that promote colon carcinogenesis and metastasis.

结直肠癌的免疫环境是影响患者生存的重要预后因素。因此，肠道肿瘤中适应性免疫细胞亚群的相对存在标志着预后良好(细胞毒性CD8+T细胞，TH1极化的CD4+T细胞)或预后不良(TH17极化的CD4+T细胞)。淋巴细胞在结直肠癌发生中的可塑性依赖于髓系细胞中的主要炎症调节因子，如核因子-kappaB、STAT3或STAT1，以及它们的下游介质，包括促进肿瘤发生的细胞因子IL-1β、IL-6、IL-23和TNF-α，以及限制肿瘤发生的IL-12或I型干扰素。这些细胞因子的产生最初是由外源性或内源性危险信号触发的。通过识别这种危险信号的模式识别受体发出的信号，通过其他信号通路得到大量的调节输入。我们遵循的假设是，鞘磷脂-1-磷酸鞘氨醇(S1P)通过特异性G蛋白偶联受体(S1PR)对结直肠癌中的炎性细胞因子进行关键调节。此前，S1P水平升高与结肠癌的发生有关。自己的数据表明，特别是S1PR1和S1PR4参与了肿瘤相关的炎症。乳腺癌和纤维肉瘤中肿瘤相关巨噬细胞S1PR1的表达通过分泌IL-1β促进淋巴管生成和转移。S1PR4促进TH17在乳腺肿瘤中的发展，并限制I型干扰素的产生。基于这一证据，我们提出了S1PR4的促肿瘤作用和S1PR1信号在结直肠癌转移中的主导作用。具体地说，我们研究了在转移性结肠癌模型中，巨噬细胞表达S1PR1是否通过IL-1β促进淋巴转移。此外，我们询问S1PR4-/-小鼠是否表现出较低的结肠炎相关癌症发病率，并分析潜在的细胞因子网络变化和髓系细胞/淋巴细胞可塑性。我们的研究将确定肿瘤相关炎症的新调节因素，并可能建议潜在的药物靶点来干预促进结肠癌发生和转移的炎症事件。