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

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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.