Microenvironmental Reactive Oxygen Species in Colorectal Cancer: Involved Processes and Therapeutic Opportunities

SIMPLE SUMMARY: Colorectal cancer is a disease associated with a high mortality rate. During the tumorigenic process, several factors and signaling molecules produced by tumor cells and the cells that surround them (forming the tumor microenvironment) regulate and modify cancer proliferation and metastasis. These regulatory agents include reactive oxygen species (ROS), which are involved in different metabolic networks and in the maintenance of cell homeostasis. Their excess, however, can cause oxidative stress and be detrimental to the cell. In fact, oxidative stress has been linked to several processes related to colorectal cancer initiation and progression. The different activities where ROS are involved suggest that ROS level modulators could be used to benefit cancer patients. ABSTRACT: Colorectal cancer (CRC) is the fourth most common cause of cancer deaths worldwide. Although screening programs have reduced mortality rates, there is a need for research focused on finding the main factors that lead primary CRC to progress and metastasize. During tumor progression, malignant cells modify their habitat, corrupting or transforming cells of different origins and creating the tumor microenvironment (TME). Cells forming the TME like macrophages, neutrophils, and fibroblasts generate reactive oxygen species (ROS) that modify the cancer niche. The effects of ROS in cancer are very diverse: they promote cellular proliferation, epithelial-to-mesenchymal transition (EMT), evasion of cell death programs, migration, and angiogenesis. Due to the multifaceted role of ROS in cancer cell survival and function, ROS-modulating agents such as antioxidants or pro-oxidants could have therapeutic potential in cancer prevention and/or as a complement to systemic treatments. In this review, we will examine the main ROS producer cells and their effects on cancer progression and metastasis. Furthermore, we will enumerate the latest clinical trials where pro-oxidants and antioxidants have therapeutic uses in CRC.