Extracellular Matrix Induction of Intracellular Reactive Oxygen Species

Significance: The extracellular matrix (ECM) is the noncellular component secreted by cells and is present within all tissues and organs. The ECM provides the structural support required for tissue integrity and also contributes to diseases, including cancer. Many diseases rich in ECM are characterized by changes in reactive oxygen species (ROS) levels that have been shown to have important context-dependent functions. Recent Advances: Many studies have found that the ECM affects ROS production through integrins. The activation of integrins by ECM ligands results in stimulation of multiple pathways that can generate ROS. Furthermore, control of ECM-integrin interaction by matricellular proteins is an underappreciated pathway that functions as an ROS rheostat in remodeling tissues. Critical Issues: A better understanding of how the ECM affects the generation of intracellular ROS is required for advances in the development of therapeutic strategies that affect or exploit oxidative stress. Future Directions: Targeting ROS generation can be therapeutic or can promote disease progression in a context-dependent manner. Many ECM proteins can impact ROS generation. However, given the breadth of different proteins that constitute the ECM and the cell surface receptors that interact with ECM proteins, there are likely many tissue and microenvironmental-specific ROS-generating pathways that have yet to be investigated in depth. Identifying canonical pathways of ECM-induced ROS generation should be a priority for the field.