Reactive oxygen species: Role in carcinogenesis, cancer cell signaling and tumor progression
Graphical abstract
Introduction
Cancer is a major health and economic world problem, being the first or second leading cause of premature death (among those 30–69 years of age) in 134 countries of the world. Assuming global rates remain unchanged, projections based on population aging and growth estimate that the global cancer burden will increase by more than 60% in 2040 to 29.4 million cases [1]. Importantly, cancer can be attributed to potentially modifiable risk factors [1], underscoring the need to understand the cellular targets of known carcinogenic agents to design therapeutic interventions that could halt the process of cellular transformation.
Oxidative damage is one of the main contributors to DNA mutations and disruptions in the pro-oxidant/ antioxidant balance have been reported in more than 200 clinical disorders, including chronic diseases like neurodegenerative diseases, inflammatory bowel disease and cancer [2]. Although cancer is a multi-factorial disease, a common consequence of exposure to several of the known cancer risk factors is the production of reactive oxygen species (ROS). Oxidative damage to proteins and DNA is likely to be one of the main contributors to the appearance of DNA mutations and, alterations in signaling pathways involved in the promotion of malignancy and ROS, are known to induce mutations in purines, pyrimidines and oxidate chromatin proteins, inducing genomic instability, affecting gene expression and contributing to carcinogenesis and cancer progression [2]. Here, we review recent evidence implicating changes in the oxidative balance in tumor progression and cancer cell signaling and discuss the role of oxidative damage in known cancer risk factors, as well as the implications of targeting ROS for cancer prevention or treatment.
Section snippets
Reactive oxygen species (ROS)
ROS are molecules formed by the partial reduction of molecular oxygen (O2) and its reaction products with other molecules [3] (Fig. 1). Reactive nitrogen species (RNS) are a subclass of ROS that contain nitrogen formed by the reaction of ROS with nitric oxide (NO) [4]. Both ROS and RNS participate in cell development, proliferation, differentiation, oxygen sensing and adaptive immunity through reversible oxidative modifications of macromolecules; but when present in excess, they can cause
ROS, cancer risk factors and carcinogenesis
The worldwide increase in cancer incidence has been attributed to population aging due to increased life expectancy [29], to increased exposure to risk factors [1] or to changing patterns of occurrence and exposure to them [30]. In this regard, cancer risk factors have been classified as follows: 1) intrinsic risk factors (unmodifiable random errors occurring during DNA replication and explained by the accumulation of cell divisions in normal tissue stem cells), 2) endogenous risk factors
ROS and the stages of cancer progression
Evidence supports both tumor-promoting and tumor-suppressive functions for ROS during transformation, reflecting a context and tissue-dependent role, as well as a differential effect of ROS in the different stages of cancer [76] (Table 1, Fig. 2). In general, in normal cells, the intracellular accumulation of ROS due to the exposure to carcinogens or carcinogenic conditions can be attenuated by antioxidant enzymes, such as CAT, SOD or the GSH system. Under these circumstances, if lipid, protein
Redox regulation of cancer signaling pathways
Physiologically, ROS are known to have important cellular functions since they regulate cellular proliferation, differentiation, migration and programmed cell death [5]. However, oxidative stress has been associated with diverse pathologies, such as neurodegenerative [119], [120], chronic inflammatory diseases [121], [122] and cancer [5]. Regarding cancer, multiple signaling pathways have been described in which ROS have an important role, acting as second messengers or modifying (activating or
Conclusions
ROS have a controversial and context-dependent role in cancer, where an antioxidant defense would be needed mostly for cancer prevention and supporting the idea that a healthy lifestyle and a high diet intake of fruits and vegetables to be associated with lower risks of cancer or death and cardiovascular disease [166]. However, once transformation has occurred, context, stage of transformation and cell type-dependent aspects should be considered regarding antioxidant or oxidant treatment.
CRediT authorship contribution statement
Fabiola Lilí Sarmiento-Salinas: Conceptualization, Writing – original draft, Writing – review & editing. Andrea Perez-Gonzalez: Conceptualization, Writing – original draft. Adilene Acosta-Casique: Conceptualization, Writing – original draft. Adrian Ix-Ballote: Writing – original draft. Alfonso Diaz: Conceptualization, Writing – original draft. Samuel Treviño: Conceptualization, Writing – original draft. Nora Hilda Rosas-Murrieta: Writing – review & editing. Lourdes Millán-Perez-Peña: Writing –
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by IMSS (FIS/IMSS/PROT/PRIO/15/049; CTFIS/1ORD/012/2011) and CONACYT (CB-2015-01 258123). FLSS received CONACYT (291137) and IMSS scholarships (97221301).
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