Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.
German Centre for Cardiovascular Research (DZHK) Partner Site RheinMain, Frankfurt, Germany.
Cancer Metastasis Rev. 2018 Sep;37(2-3):425-438. doi: 10.1007/s10555-018-9732-2.
Angiogenesis and inflammation are hallmarks of cancer. Arachidonic acid and other polyunsaturated fatty acids (PUFAs) are primarily metabolized by three distinct enzymatic systems initiated by cyclooxygenases, lipoxygenases, and cytochrome P450 enzymes (CYP) to generate bioactive eicosanoids, including prostanoids, leukotrienes, hydroxyeicosatetraenoic acids, and epoxyeicosatrienoic acids. As some of the PUFA metabolites playing essential roles in inflammatory processes, these pathways have been widely studied as therapeutic targets of inflammation. Because of their anti-inflammatory effects, these pathways were also proposed as anti-cancer targets. However, although the eicosanoids were linked to endothelial cell proliferation and angiogenesis almost two decades ago, it is only recently PUFA metabolites, especially those generated by CYP enzymes and the soluble epoxide hydrolase (sEH), have been recognized as important signaling mediators in physiological and pathological angiogenesis. Despite the fact that tumor growth and invasion are heavily dependent on inner-tumor angiogenesis and influenced by vascular stability, the role played by PUFA metabolites in tumor angiogenesis and vessel integrity has been largely overlooked. This review highlights current knowledge on the function of PUFA metabolites generated by the CYP/sEH pathway in angiogenesis and vascular stability as well as their potential involvement in cancer development.
血管生成和炎症是癌症的标志。花生四烯酸和其他多不饱和脂肪酸（PUFAs）主要通过三种不同的酶促系统代谢，这些系统由环氧化酶、脂氧合酶和细胞色素 P450 酶（CYP）启动，生成生物活性类二十烷酸，包括前列腺素、白三烯、羟二十碳四烯酸和环氧二十碳三烯酸。由于一些 PUFAs 代谢物在炎症过程中发挥着重要作用，这些途径已被广泛研究为炎症的治疗靶点。由于其抗炎作用，这些途径也被提出作为抗癌靶点。然而，尽管大约二十年前就已经发现类二十烷酸与内皮细胞增殖和血管生成有关，但直到最近，PUFA 代谢物，特别是由 CYP 酶和可溶性环氧化物水解酶（sEH）生成的代谢物，才被认为是生理和病理血管生成中重要的信号转导介质。尽管肿瘤的生长和侵袭在很大程度上依赖于肿瘤内血管生成，并受到血管稳定性的影响，但 PUFAs 代谢物在肿瘤血管生成和血管完整性中的作用在很大程度上被忽视了。本综述强调了 CYP/sEH 途径生成的 PUFAs 代谢物在血管生成和血管稳定性中的功能，以及它们在癌症发展中的潜在作用。
