The role of oxidative stress in cancer

Authors

Abstract

Oxidative stress (OS), resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, plays a critical and dual role in cancer biology. ROS, generated during cellular metabolism and in response to environmental stressors, act as signaling molecules at moderate levels, regulating processes such as cell proliferation, differentiation, and apoptosis. However, excessive ROS accumulation causes oxidative damage to DNA, proteins, and lipids, leading to genomic instability, mutations, and the activation of oncogenic pathways, which are essential for cancer initiation and progression. OS also influences the tumor microenvironment by promoting chronic inflammation, angiogenesis, and immune evasion, further supporting tumor growth and metastasis. The transcription factor NRF2, a master regulator of antioxidant responses, plays a context-dependent role: while it protects normal cells from oxidative damage, its dysregulation in cancer cells enhances their survival and resistance to therapy. Additionally, OS interacts with other cancer hallmarks, such as metabolic reprogramming and epigenetic alterations, creating a complex network that drives tumorigenesis. Antioxidants have shown potential in mitigating oxidative damage but may also protect cancer cells, while pro-oxidant therapies aim to exploit elevated ROS levels in cancer cells to induce selective cell death. This duality highlights the need for precise, context-specific interventions. Future research should focus on elucidating the nuanced roles of oxidative stress in different cancer types, identifying predictive biomarkers, and developing combination therapies that integrate redox modulation with other treatment modalities. In summary, OS is a central driver of cancer development and progression, offering both challenges and opportunities for innovative therapeutic strategies.

Keywords

Introduction

Cancer is one of the leading causes of death globally, with its prevalence steadily increasing in both developed and developing nations, posing a risk to roughly one in four individuals [1]. This condition arises predominantly from the uncontrolled growth and division of cells, bypassing the body’s normal regulatory processes [2]. The development of cancer, known as carcinogenesis, occurs through three distinct stages: initiation, promotion, and progression [3]. The initiation phase involves damage to the epigenome, chromosomes, and DNA, which govern gene expression. This phase is followed by a prolonged period where cells with genomic instability expand, often within an inflammatory environment. In the progression stage, these cells proliferate further, causing more genomic damage and eventually evolving into malignant tumors.
Cancer encompasses a diverse range of types, generally classified into hematologic and solid tumor cancers [4]. These categories vary significantly in terms of growth patterns, spread, and responses to treatment. While some cancers grow and metastasize rapidly, others progress at a slower pace [5]. Additionally, certain types aggressively invade distant parts of the body, whereas others remain localized. The causes of cancer are multifaceted, including genetic mutations, lifestyle factors, environmental exposures, and contact with carcinogenic substances [6]. It is well-documented that cancer cells can travel from their original site via the bloodstream or lymphatic system, reaching distant organs [7]. This phenomenon, known as metastasis, occurs when cancer cells settle in new locations, grow, and form secondary tumors [8].
In a healthy state, the body maintains a balance between free radicals and antioxidants. When this balance tilts in favor of free radicals, oxidative stress (OS) occurs, leading to significant harm to lipids, proteins, and nucleic acids [9, 10, 11]. OS has been identified as a major contributor to the development of cancer. For example, OS can cause structural damage to DNA, disrupt gene expression, and alter intercellular communication. These disruptions may either stimulate or inhibit cell proliferation, ultimately leading to further genomic changes in the affected cell population [12]. Consequently, oxidative stress is closely associated with both the initiation and progression of cancer.
Epidemiology, Genetics, and Pathophysiology of Cancer
Cancer is a complex disease with multiple contributing factors, exerting a significant impact on global health and ranking among the leading causes of illness and death worldwide [13]. Its epidemiology reveals pronounced variations based on geography, demographics, and socioeconomic conditions. The global burden of cancer continues to escalate, with approximately 19.3 million new cases and 10 million deaths recorded in 2020, as reported by the International Agency for Research on Cancer. The rates of cancer incidence and mortality differ widely across regions, influenced by factors such as age, gender, ethnicity, lifestyle habits, and environmental exposures. For example, lung cancer remains the most common cause of cancer-related mortality worldwide, largely attributed to tobacco use, while breast cancer is the most frequently diagnosed malignancy in women, with rising incidence in both high-income and low- to middle-income nations [14]. Environmental and lifestyle factors, including smoking, diet, physical inactivity, and infections like human papillomavirus (HPV) and hepatitis B and C, emphasize the need for tailored prevention and early detection strategies [15].
On the genetic front, cancer develops from the accumulation of mutations that disrupt normal cell growth and division. These genetic changes include the activation of oncogenes, such as KRAS and MYC, and the deactivation of tumor suppressor genes, such as TP53 and RB1 [16]. Mutations may occur sporadically due to environmental exposures, such as ultraviolet radiation or carcinogenic substances, or they may be inherited, as seen in hereditary cancer syndromes like BRCA1/2 mutations associated with breast and ovarian cancers [17, 18]. Genomic instability, a hallmark of cancer, often arises from defects in DNA repair systems, such as mismatch repair deficiencies linked to Lynch syndrome [19]. Advances in genomic technologies have also revealed the significance of epigenetic alterations, such as DNA methylation and histone modifications, in cancer progression. These genetic and epigenetic changes are further influenced by the tumor microenvironment, which comprises stromal cells, immune cells, and signaling molecules that drive tumor growth and spread [20].
The pathophysiology of cancer involves a series of interrelated processes that enable malignant cells to bypass the body’s regulatory mechanisms and form metastatic disease [21]. Cancer progression is often described using the “hallmarks of cancer,” which include sustained signaling for cell proliferation, evasion of cell death, resistance to growth suppression, replicative immortality, induction of angiogenesis, and activation of invasion and metastasis. Supporting characteristics such as genomic instability and inflammation promote these hallmarks. For instance, mutations in proto-oncogenes like EGFR result in continuous activation of growth signals, while the loss of tumor suppressor genes like PTEN undermines vital cell cycle checkpoints. Cancer cells also develop strategies to evade immune detection, such as overexpressing immune checkpoint proteins like PD-L1 to inhibit T-cell function [22]. Additionally, the tumor microenvironment aids cancer progression by fostering angiogenesis, metabolic changes, and immune suppression.
Metastasis, a defining feature of advanced cancer, is the leading cause of cancer-related deaths and involves multiple complex steps. These include the local invasion of surrounding tissues, entry into the bloodstream or lymphatic system, survival during circulation, extravasation into distant organs, and colonization at secondary sites [23]. Processes such as epithelial-to- mesenchymal transition (EMT) endow cancer cells with the ability to migrate and invade, while interactions with stromal cells and the extracellular matrix facilitate metastatic spread. Recent studies have highlighted the importance of circulating tumor cells (CTCs) and exosomes in driving metastasis and serving as biomarkers for tracking disease progression [24].
Understanding the interplay between epidemiology, genetics, and pathophysiology is crucial for addressing the complexity of cancer. Comprehensive knowledge of these factors is essential for developing effective strategies for prevention, early diagnosis, and treatment. Advances in molecular biology and genomic technologies have paved the way for precision medicine, enabling the identification of actionable genetic mutations and the creation of targeted therapies, such as tyrosine kinase inhibitors and immune checkpoint inhibitors [25, 26]. Public health measures, including smoking cessation programs, vaccination against oncogenic viruses, and promoting healthy behaviors, are integral components of cancer prevention efforts. Despite notable advancements, disparities in cancer care and outcomes persist, particularly in resource- constrained settings with limited access to diagnostic tools and treatments. Ongoing research must continue to explore the intricate interactions between genetic, environmental, and biological factors to enhance our understanding of cancer and improve patient outcomes.
Reactive Oxygen Species
Reactive oxygen species (ROS) are highly reactive molecules that originate from molecular oxygen and include superoxide anions (O₂•⁻), hydrogen peroxide (H₂O₂), hydroxyl radicals (•OH), and singlet oxygen (¹O₂). These molecules are naturally produced as byproducts of cellular metabolism, primarily during mitochondrial oxidative phosphorylation, but also through enzymatic activities involving NADPH oxidases, xanthine oxidase, and cytochrome P450 enzymes [27]. Under normal conditions, ROS play essential roles as signaling molecules, regulating key processes such as cell proliferation, differentiation, immune responses, and apoptosis [28]. However, excessive ROS production that surpasses the capacity of the body’s antioxidant defense system—which includes enzymes like superoxide dismutase (SOD), catalase, and glutathione peroxidase, as well as antioxidants like vitamins C and E—leads to OS. This imbalance results in damage to cellular components, including DNA, proteins, and lipids, causing mutations, functional impairments, and the activation of harmful pathways [29]. In cancer, ROS contributes to tumor development and progression by promoting genomic instability, triggering oncogenic signaling pathways such as MAPK and PI3K/AKT, and fostering a tumor-supportive environment through inflammation and angiogenesis [30]. Conversely, elevated ROS levels can also induce programmed cell death mechanisms, such as apoptosis and ferroptosis, illustrating their dual role in cell fate. Recent research highlights the importance of maintaining a delicate balance between ROS production and elimination, as well as the involvement of redox-sensitive transcription factors like NRF2 and NF-κB in preserving cellular homeostasis [31]. Advances in understanding ROS biology have led to new therapeutic strategies, including the use of antioxidants to reduce oxidative damage and pro-oxidant therapies aimed at selectively targeting cancer cells with high ROS levels. Despite these advancements, challenges remain in understanding the context-specific roles of ROS in health and disease, as well as in designing targeted interventions that modulate ROS without disrupting normal cellular functions. Future research seeks to unravel the complex interactions between ROS and cellular signaling pathways, identify biomarkers for oxidative stress-related conditions, and develop innovative therapies that leverage the dual nature of ROS to benefit clinical outcomes. In summary, ROS plays a pivotal role in both normal cellular functions and disease mechanisms, underscoring their importance as both signaling molecules and agents of cellular damage.
OS refers to a state where the production of reactive oxygen species (ROS) overwhelms the body’s antioxidant defenses. ROS, including superoxide anions, hydrogen peroxide, and hydroxyl radicals, are naturally produced during cellular metabolism, particularly in mitochondrial respiration. At controlled levels, ROS are vital for regulating processes like cell signaling, immune function, and maintaining cellular homeostasis. However, excessive accumulation of ROS can cause significant damage to cellular macromolecules, such as DNA, proteins, and lipids, leading to various pathological conditions, including cancer, neurodegenerative disorders, cardiovascular diseases, and aging. In the context of cancer, oxidative stress drives tumor initiation and progression by inducing DNA mutations, activating oncogenic pathways, and promoting genomic instability. It also shapes the tumor microenvironment by sustaining chronic inflammation, facilitating angiogenesis, and enabling immune evasion, all of which support tumor growth. On the other hand, oxidative stress can also induce cell death mechanisms like apoptosis and ferroptosis, highlighting its dual role in cancer biology. The transcription factor NRF2 is a key regulator of antioxidant responses, helping to maintain redox balance. While NRF2 activation protects normal cells from oxidative damage, its dysregulation in cancer cells can enhance their survival and resistance to therapy. Recent advancements in understanding OS have paved the way for therapeutic strategies targeting redox pathways, including the use of antioxidants to mitigate oxidative damage and pro-oxidant agents to selectively eliminate cancer cells. However, challenges persist in fully understanding the intricate relationships between OS and disease, as well as in developing treatments that exploit redox imbalances without harming normal tissues. Ongoing research aims to uncover the nuanced roles of OS in different diseases, identify predictive biomarkers, and create combination therapies that integrate redox modulation with other treatments. In conclusion, OS plays a central role in numerous diseases, acting as both a driver of pathology and a potential therapeutic target [32, 33, 34, 35, 36, 37, 38, 39, 40]. Continued exploration of its molecular mechanisms is essential for advancing clinical applications and improving patient outcomes.
What is Cancer?
Cancer is a diverse and complex group of diseases defined by the uncontrolled growth and spread of abnormal cells, driven by genetic and epigenetic changes that disrupt normal cellular functions [5]. These changes may result from a combination of inherited genetic mutations, environmental factors such as tobacco smoke, ultraviolet radiation, and exposure to carcinogens, as well as lifestyle factors like diet and physical inactivity. Hanahan and Weinberg identified the hallmarks of cancer, which include continuous proliferative signaling, avoidance of growth suppressors, resistance to programmed cell death, limitless replicative potential, promotion of angiogenesis, invasion and metastasis, metabolic alterations, and evasion of immune destruction. These features are supported by genomic instability and chronic inflammation, which foster a favorable environment for tumor development [6]. Cancer encompasses a wide range of diseases, each with distinct molecular, histological, and clinical characteristics. For example, carcinomas originate from epithelial tissues, sarcomas from connective tissues, leukemias and lymphomas from hematopoietic cells, and central nervous system cancers from neural tissues [41, 42].
The heterogeneity of cancer is further reflected in the variety of driver mutations, such as those affecting TP53, KRAS, and EGFR, which differ across cancer types and even within individual tumors [43]. This variability presents significant challenges in diagnosing, predicting outcomes, and developing effective treatments. In addition to its direct impact, cancer often coexists with other conditions, including cardiovascular diseases, diabetes, and cachexia, which can worsen patient outcomes and complicate treatment strategies. For instance, cancer-associated inflammation and OS can lead to cardiovascular dysfunction, while metabolic shifts in cancer cells may cause insulin resistance. Moreover, cancer therapies like chemotherapy and radiotherapy can result in long-term side effects, including secondary cancers and organ damage [44]. Recent advances in precision medicine, including the development of targeted therapies and immunotherapies, have transformed cancer treatment by utilizing the molecular and immune profiles of individual tumors. Despite these advancements, therapy resistance remains a major obstacle, driven by tumor evolution and the influence of the tumor microenvironment. Current research is investigating the roles of the microbiome, extracellular vesicles, and epigenetic changes in cancer progression and resistance to treatment, offering new opportunities for intervention [45]. In summary, cancer is a dynamic and multifaceted disease with significant global health implications. Its interactions with related conditions and the complexity of its underlying biology highlight the necessity of multidisciplinary approaches to enhance prevention, early detection, and treatment. By combining insights from genomics, immunology, and systems biology, the field is advancing toward more personalized and effective strategies to address cancer and its associated challenges.
Oxidative Stress and Cancer
Oxidative stress, which arises from an imbalance between the generation of reactive oxygen species (ROS) and the body’s antioxidant defenses, plays a crucial role in cancer development [9]. ROS, including molecules like superoxide anions, hydrogen peroxide, and hydroxyl radicals, are natural byproducts of cellular metabolism, primarily produced in mitochondria during oxidative phosphorylation. At physiological levels, ROS act as signaling molecules, regulating key processes such as cell proliferation, differentiation, and apoptosis. However, when ROS levels become excessive, they cause oxidative damage to vital cellular components like DNA, proteins, and lipids, leading to genomic instability, mutations, and disruptions in cellular signaling—all of which are hallmarks of cancer [27]. For instance, oxidative damage to DNA can activate oncogenes like RAS and MYC or inactivate tumor suppressor genes such as TP53, thereby driving tumor formation. Moreover, OS influences the tumor microenvironment by promoting chronic inflammation, angiogenesis, and immune evasion, which collectively facilitate cancer progression and metastasis [46].
Recent studies emphasize the dual role of OS in cancer. While prolonged OS promotes cancer initiation and progression, acute OS can trigger cell death mechanisms, such as ferroptosis, a form of iron-dependent programmed cell death [47]. This paradox has spurred interest in targeting OS pathways for cancer therapy. Antioxidants, such as N-acetylcysteine and vitamin E, have been explored to mitigate oxidative damage and prevent cancer. Conversely, pro-oxidant therapies, which aim to elevate ROS levels or inhibit antioxidant defenses selectively in cancer cells, are under investigation for their ability to exploit the heightened ROS levels often found in tumors. The transcription factor NRF2, a key regulator of antioxidant responses, plays a complex role in this context. While NRF2 activation protects normal cells from oxidative damage, its overactivation in cancer cells can enhance their survival and resistance to therapies, highlighting the challenges of targeting OS in cancer treatment.
Furthermore, OS interacts with other cancer hallmarks, such as altered metabolism and epigenetic modifications, creating a complex network that drives tumorigenesis. For instance, cancer cells frequently exhibit the “Warburg effect,” preferring glycolysis over oxidative phosphorylation even in oxygen-rich environments, which not only supports rapid growth but also influences ROS levels [48]. Additionally, epigenetic changes, such as DNA methylation and histone acetylation, can be modulated by OS, leading to altered gene expression that promotes cancer progression. Despite significant advances in understanding these mechanisms, challenges persist in developing therapies that leverage OS without causing harm to normal cells. Future research should focus on identifying context-specific roles of OS across different cancer types and stages, discovering predictive biomarkers, and creating combination therapies that integrate OS modulation with other treatment approaches.
In conclusion, OS is a central factor in cancer biology, influencing tumor initiation, progression, and therapy resistance. Its dual role as both a driver and inhibitor of cancer underscores the need for a nuanced understanding of its mechanisms and therapeutic potential. By integrating insights from molecular biology, genomics, and clinical research, the development of innovative strategies to target OS could significantly improve cancer prevention and treatment outcomes.

Conclusion

To summarize, OS, resulting from an imbalance between reactive oxygen species (ROS) production and the body’s antioxidant defenses, plays a critical and multifaceted role in cancer. ROS, which arise from normal metabolic activities and external stressors, function as double-edged swords in cellular biology. At moderate levels, they regulate essential processes such as cell proliferation, differentiation, and apoptosis. However, when ROS levels exceed the antioxidant system’s capacity, oxidative damage ensues, leading to genomic instability, mutations, and activation of oncogenic pathways, key features of cancer development and progression. OS also shapes the tumor microenvironment by sustaining inflammation, encouraging angiogenesis, and enabling immune evasion, further supporting cancer growth.
The transcription factor NRF2, which regulates antioxidant responses, illustrates the dual nature of OS. While NRF2 protects normal cells from damage, its dysregulation in cancer cells enhances their ability to resist OS and therapies, complicating treatment strategies. Additionally, OS interacts with other cancer hallmarks, such as metabolic reprogramming and epigenetic changes, adding to its complexity in tumor biology.
For instance, the Warburg effect, a metabolic shift favoring glycolysis over oxidative phosphorylation, supports rapid tumor growth and impacts ROS levels. Despite advancements in understanding the link between OS and cancer, therapeutic approaches remain challenging. While antioxidants have been tested to mitigate damage, their efficacy is controversial as they may inadvertently shield cancer cells. On the other hand, pro-oxidant strategies aim to exploit the elevated ROS levels in cancer cells to induce selective cell death, but their application requires precision to avoid harming normal tissues.
Looking ahead, future research should aim to uncover the nuanced roles of OS across various cancer contexts, identify biomarkers to predict therapeutic responses, and develop combination treatments that integrate OS targeting with other therapeutic modalities. In conclusion, OS is a key player in cancer biology, with its dual roles highlighting the need for sophisticated and context-specific therapeutic interventions. By combining insights from multiple disciplines, researchers can harness the potential of OS modulation to enhance cancer prevention and treatment, ultimately improving patient outcomes.

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