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. HO is a ROS with an important role in cell signaling, but how HO regulates tumor angiogenesis is still poorly understood. We have xenografted tumor cells with altered levels of HO 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 HO-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 HO regulates the expression of angiogenic factors and the formation of a vessel network. Understanding the molecular mechanisms that govern this multifunctional effect of HO on tumor angiogenesis could be important for the development of more efficient anti-angiogenic therapies.