The Contribution of redox regulation in tumor angiogenesis and tumor growth: glutathione peroxidase 4 (GPx4) as a key regulator of 12/15-lipoxygenase activity

2004年，血管生成研究的突破导致了第一种抗血管生成药物的临床批准。然而，血管生成的详细分子机制，包括肿瘤和宿主来源的血管区室之间的多重相互作用尚未完全理解。已经鉴定了感测/转导缺氧和诱导肿瘤定向血管生成的关键参与者，例如HIF系统的成员以及VEGF和血管生成素家族。相比之下，在这些过程中的细胞氧化还原系统的贡献吸引了相当少的关注。这一现实反映了缺乏适当的体外和体内模型来研究氧化还原调节的非常短暂的性质。为了研究不同酶实体的特定作用，我们创建了一系列谷胱甘肽和硫氧还蛋白依赖性系统（PHGPx、胞质硫氧还蛋白还原酶和线粒体硫氧还蛋白还原酶的条件等位基因小鼠）中有针对性缺陷的小鼠品系，这两种途径控制细胞氧化还原平衡。花生四烯酸和亚油酸途径的成员包括环氧合酶-2（考克斯-2）和某些脂氧合酶（LOX）代表肿瘤血管生成的关键因子。PHGPx由于其调节细胞过氧化物张力的能力，被认为控制考克斯和LOX活性。我们最近建立的条件性PHGPx基因敲除小鼠模型将被证明是最适合定义LOX和考克斯途径的关键酶。从我们的条件小鼠离体分离的细胞模型将使我们能够表征PHGPx在内皮细胞中的特异性功能。最后，我们将能够通过删除肿瘤区室或宿主衍生的血管区室中的PHGPx来研究肿瘤-血管界面。

A break-through in angiogenesis research led to the first clinical approval of an anti-angiogenic drug in 2004. Yet, the detailed molecular mechanisms of angiogenesis including the multiple interactions between the tumor and the host-derived vascular compartment are not fully understood. Key players in sensing/transducing hypoxia and inducing tumor-directed angiogenesis, such as members of the HIF-system, as well as VEGF and the angiopoietin family, have been identified. In contrast, the contribution of the cellular redox systems in these processes has attracted considerably less attention. This reality reflects a lack of appropriate in vitro and in vivo models to investigate the very transient nature of redox regulation. To study the specific roles of the different enzymatic entities, we created a series of mouse lines with targeted deficiencies in the glutathione- and thioredoxin-dependent systems (mice with conditional alleles for PHGPx, cytosolic thioredoxin reductase and mitochondrial thioredoxin reductase), the two major pathways that control cellular redox balance. Members of the arachidonic and linoleic acid pathways including cyclooxygenase-2 (COX-2) and certain lipoxygenases (LOX) represent critical factors of tumor angiogenesis. PHGPx, due to its capability to regulate cellular peroxide tone, has been considered to govern COX and LOX activities. Our recently established, conditional PHGPx knockout mouse model will prove most suitable to define critical enzymes of the LOX and COX pathways. Cellular models isolated ex vivo from our conditional mice will allow us to characterize the specific function of PHGPx in endothelial cells. Finally, we will be able to investigate the tumor-vessel interface by deleting PHGPx either in the tumor compartment or in the host-derived vascular compartment.