Abstract
Simple SummaryColorectal 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.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.
Highlights
In this type of Colorectal cancer (CRC) cells, another set of experiments performed with resveratrol showed chemopreventive cancer properties, as this compound activated cell apoptosis through a reactive oxygen species (ROS)-dependent mitochondrial mechanism [101]
Bortezomib was ineffective in controlling metastatic CRC disease, but a significant accumulation of HIF-1α was seen in tumor specimens and xenograft models, suggesting that proteasome inhibition could alter the response to tumor hypoxia [124]
A phase I/II clinical trial was designed to analyze whether the pretreatment with calmangafodipir could decrease the frequency and severity of side effects derived from FOLFOX6 administration in patients with metastatic CRC (NCT01619423)
Summary
Cells from the TME, like macrophages, neutrophils, and fibroblasts, are sources of growth factors, cytokines, proteases, and reactive oxygen species (ROS) that modify the cancer niche, acting on multiple cell types and matrix components [4]. We present an overview of the origin and influence of ROS (with a focus on those produced by TME cells) on cancer progression and metastasis. Due to the dual role of ROS in both cell survival and cell death, there is therapeutic potential for the use of both pro-oxidants and antioxidants in CRC. In this regard, we have reviewed the latest clinical trials where these interventions have been applied
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