Hydrogen peroxide regulates angiogenesis-related factors in tumor cells

Tumor angiogenesis is required for tumor development and growth, and is regulated by several factors including ROS. H₂O₂ is a ROS with an important role in cell signaling, but how H₂O₂ regulates tumor angiogenesis is still poorly understood. We have xenografted tumor cells with altered levels of H₂O₂ by catalase overexpression into zebrafish embryos to study redox-induced tumor neovascularization. We found that vascular recruitment and invasion were impaired if catalase was overexpressed. In addition, the overexpression of catalase altered the transcriptional levels of several angiogenesis-related factors in tumor cells, including TIMP-3 and THBS1. These two anti-angiogenic factors were found to be H₂O₂-regulated by two different mechanisms: TIMP-3 expression in a cell-autonomous manner; and, THBS1 expression that was non-cell-autonomous. Our work shows that intracellular H₂O₂ regulates the expression of angiogenic factors and the formation of a vessel network. Understanding the molecular mechanisms that govern this multifunctional effect of H₂O₂ on tumor angiogenesis could be important for the development of more efficient anti-angiogenic therapies.