The ROS-NOX connection in cancer and angiogenesis

Initially viewed as dangerous byproducts of aerobic life, reactive oxygen species (ROS) nowadays appear to be essential secondary messengers of many signaling cascades and cellular functions. The establishment of ROS as important signaling molecules has been confirmed by the existence of specialized ROS producing complexes expressed in nonphagocytic cells, the NADPH oxidase complex (NOX). Because of the diversity of their proteic targets (besides lipids and DNA), ROS have multiple and sometimes contradictory functions. In the present review, we focus on several different signaling pathways influenced by ROS and NOX in tumorigenesis, focusing on proliferation and angiogenesis. We review the ROS targets regulating proliferation, including cellular signaling (phosphatases, AP1, and nuclear factor-kappa B [NF-kappa B]) and cell cycle targets (CDC25, cyclin D, and forkhead proteins), and the role of NOX during proliferation. Finally, we review the direct and indirect involvement of ROS and NOX in (tumor) angiogenesis through the regulation of different biologic systems such as vascular endothelial growth factor, angiotensin II, hypoxia-inducible factor, AP1, and inflammation.