Redox-based escape mechanism from death: the cancer lesson

We review here current evidence on the role of reactive oxygen species (ROS) and of the intracellular redox state in governing crucial steps of the metastatic process, from cell detachment from the primary tumor to final colonization of the distant site. In particular, we discuss the redox-dependent aspects of cell glycolytic metabolism (Warburg effect), of cell juggling between different motility styles (epithelial-to-mesenchymal and mesenchymal-to-amoeboid transition), of cell resistance to anoikis and of cell interaction with the stromal components of the metastatic niche. Central to this overview is the concept that metastasis can be viewed as an integrated "escape program" triggered by redox changes and instrumental at avoiding oxidative stress within the primary tumor. In this novel perspective, metabolic, motility, and prosurvival choices of the cell along the entire metastatic process can be interpreted as exploiting redox-signaling cascades to monitor oxidative/reductive environmental cues and escape oxidative damage. We also propose that this theoretic framework be applied to "normal" evasion/invasion programs such as in inflammation and development. Furthermore, we suggest that the intimate connection between metastasis, inflammation, and stem cells results, at least in part, by the sharing of a common redox-dependent strategy for infiltration, survival, dissemination, and patterning.