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

结直肠癌患者的免疫状况是影响患者生存率的重要预后因素。因此，肠肿瘤中适应性免疫细胞亚群的相对存在标志着良好的预后（细胞毒性CD 8 + T细胞，TH 1极化的CD 4 + T细胞）或不良的预后（TH 17极化的CD 4 + T细胞）。结直肠癌发生中的淋巴细胞可塑性取决于髓系细胞中的主要炎症调节因子，如NF-κ B、STAT 3或STAT 1，及其下游介质，包括促进癌发生的细胞因子IL-1 β、IL-6、IL-23和TNF-α，以及限制癌发生的IL-12或I型干扰素。这些细胞因子的产生最初由外源性或内源性危险信号触发。通过识别这种危险信号的模式识别受体的信号传导通过其他信号传导途径接收大量的调节输入。我们遵循这样的假设，即鞘脂鞘氨醇-1-磷酸（S1 P）通过特异性G蛋白偶联受体（S1 PRs）的信号传导来严格调节结直肠癌中的炎性细胞因子。增强的S1 P水平先前与结肠癌发生有关。自己的数据表明，特别是S1 PR 1和S1 PR 4参与肿瘤相关炎症。乳腺癌和纤维肉瘤中肿瘤相关巨噬细胞中S1 PR 1的表达通过分泌IL-1 β促进淋巴管生成和转移。S1 PR 4促进乳腺肿瘤中TH 17的发育，并限制I型干扰素的产生。基于这些证据，我们提出了S1 PR 4的肿瘤促进作用和S1 PR 1信号在结直肠癌转移中的主导作用。具体而言，我们研究了在转移性结肠癌模型中，巨噬细胞表达S1 PR 1是否通过IL-1 β促进淋巴结转移。此外，我们询问S1 PR 4-/-小鼠是否显示结肠炎相关癌症的发病率较低，并分析潜在的细胞因子网络和骨髓细胞/淋巴细胞可塑性的改变。我们的研究将确定肿瘤相关炎症的新调节因子，并可能提示潜在的药理学靶点，以干扰促进结肠癌发生和转移的炎症事件。

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.