Inflammatory gastrointestinal (GI) diseases and malignancies are associated with growing morbidity and cancer-related mortality worldwide. GI tumor and inflammatory cells contain activated sphingolipid-metabolizing enzymes, including sphingosine kinase 1 (SphK1) and SphK2, that generate sphingosine-1-phosphate (S1P), a highly bioactive compound. Many inflammatory responses, including lymphocyte trafficking, are directed by circulatory S1P, present in high concentrations in both the plasma and the lymph of cancer patients. High fat and sugar diet, disbalanced intestinal flora, and obesity have recently been linked to activation of inflammation and SphK/S1P/S1P receptor (S1PR) signaling in various GI pathologies, including cancer. SphK1 overexpression and activation facilitate and enhance the development and progression of esophageal, gastric, and colon cancers. SphK/S1P axis, a mediator of inflammation in the tumor microenvironment, has recently been defined as a target for the treatment of GI disease states, including inflammatory bowel disease and colitis. Several SphK1 inhibitors and S1PR antagonists have been developed as novel anti-inflammatory and anticancer agents. In this review, we analyze the mechanisms of SphK/S1P signaling in GI tissues and critically appraise recent studies on the role of SphK/S1P/S1PR in inflammatory GI disorders and cancers. The potential role of SphK/S1PR inhibitors in the prevention and treatment of inflammation-mediated GI diseases, including GI cancer, is also evaluated.

中文翻译：

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鞘氨醇激酶和鞘氨醇-1-磷酸受体信号转导通路在炎性胃肠疾病和癌症中：一种新型治疗靶点。

炎性胃肠道疾病和恶性肿瘤与全球范围内发病率增加和与癌症有关的死亡率有关。胃肠道肿瘤和炎性细胞含有活化的鞘氨醇代谢酶，包括鞘氨醇激酶1（SphK1）和SphK2，它们会产生具有高生物活性的鞘氨醇-1-磷酸（S1P）。许多炎症反应（包括淋巴细胞运输）都是由循环S1P指导的，S1P在癌症患者的血浆和淋巴中均以高浓度存在。高脂肪和高糖饮食，肠道菌群失调和肥胖症最近与各种胃肠道疾病（包括癌症）中的炎症激活和SphK / S1P / S1P受体（S1PR）信号传导有关。SphK1的过度表达和激活促进并增强了食管，胃，和结肠癌。SphK / S1P轴是肿瘤微环境中炎症的介体，最近已被定义为治疗GI疾病状态的靶标，包括炎症性肠病和结肠炎。已经开发了几种SphK1抑制剂和S1PR拮抗剂作为新型抗炎和抗癌药。在这篇综述中，我们分析了胃肠道组织中SphK / S1P信号传导的机制，并严格评估了SphK / S1P / S1PR在炎症性胃肠疾病和癌症中的作用的最新研究。还评估了SphK / S1PR抑制剂在预防和治疗炎症介导的GI疾病（包括GI癌症）中的潜在作用。包括炎症性肠病和结肠炎。已经开发了几种SphK1抑制剂和S1PR拮抗剂作为新型抗炎和抗癌药。在这篇综述中，我们分析了胃肠道组织中SphK / S1P信号传导的机制，并严格评估了SphK / S1P / S1PR在炎症性胃肠疾病和癌症中的作用的最新研究。还评估了SphK / S1PR抑制剂在预防和治疗炎症介导的GI疾病（包括GI癌症）中的潜在作用。包括炎症性肠病和结肠炎。已经开发了几种SphK1抑制剂和S1PR拮抗剂作为新型抗炎和抗癌药。在这篇综述中，我们分析了胃肠道组织中SphK / S1P信号传导的机制，并严格评估了SphK / S1P / S1PR在炎症性胃肠疾病和癌症中的作用的最新研究。还评估了SphK / S1PR抑制剂在预防和治疗炎症介导的GI疾病（包括GI癌症）中的潜在作用。