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，血管生成研究取得突破，导致抗血管生成药物首次获得临床批准。然而，血管生成的详细分子机制，包括肿瘤与宿主来源的血管间隔之间的多重相互作用，尚不完全清楚。在感知/转导缺氧和诱导肿瘤导向的血管生成方面的关键角色，如HIF系统的成员，以及血管内皮生长因子和血管生成素家族，已经被确定。相比之下，细胞氧化还原系统在这些过程中的贡献却引起了相当少的关注。这一现实反映了缺乏合适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，我们创建了一系列在谷胱甘肽和硫氧还蛋白依赖系统(具有PHGPx、胞浆硫氧还蛋白还原酶和线粒体硫氧还蛋白还原酶条件等位基因的小鼠)中有针对性缺陷的小鼠系，这两个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(COX-2)和某些脂氧合酶(LOX)是肿瘤血管生成的关键因子。PHGPx由于其调节细胞过氧化应激的能力，一直被认为控制COX和LOX的活性。我们最近建立的条件性PHGPx基因敲除小鼠模型将被证明最适合定义LOX和COX途径的关键酶。从我们的条件性小鼠分离的体外细胞模型将使我们能够表征PHGPx在内皮细胞中的特定功能。最后，我们将能够通过删除肿瘤间隔室或宿主来源的血管间隔室中的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.