EMT and Oxidative Stress: A Bidirectional Interplay Affecting Tumor Malignancy

Significance: Epithelial-mesenchymal transition (EMT) is emerging as a driving force in tumor progression, enabling cancer cells to evade their "homeland" and to colonize remote locations. In this review, we focus on the emerging views dealing with a redox control of EMT and with the importance of a pro-oxidant environment, both in cancer and stromal cells, to attain an improvement in tumor malignancy. Recent Advances: The variety of signals able to promote EMT is large and continuously growing, ranging from soluble factors to components of the extracellular matrix. Compelling evidence highlights reactive oxygen species (ROS) as crucial conspirators in EMT engagement. Critical Issues: Tumor microenvironment exploits a fascinating role in ensuring EMT outcome within the primary tumor, granting for the achievement of an essential selective advantage for cancer cells. Cancer-associated fibroblasts, macrophages, and hypoxia are major players in this scenario, exerting a propelling role for EMT, as well as for invasiveness, stemness, and dissemination of metastatic cells. Future Directions: Future research focused on EMT should address some key points that are still unclear. They include: i) the role of the reverse phenomenon (i. e., mesenchymal-epithelial transition) that is likely regulated in the final stages of tumor progression, or that of mesenchymal-amoeboid transition, a plasticity program of cancer cells, which often follows EMT and offers a further metastatic advantage, and ii) the molecular basis of the correlation between stemness, EMT and ROS content. Antioxid. Redox Signal. 16, 1248-1263.