Mechanisms of ROS in Colorectal Cancer Initiation

The mechanisms by which ROS contribute to CRC initiation are multifaceted and involve various cellular processes. Elevated levels of ROS can lead to DNA damage via the formation of oxidative DNA lesions, such as 8-oxoguanine, which can cause mutations if not repaired properly. This accumulation of mutations can trigger oncogenic pathways, particularly the activation of growth-promoting signals such as the Wnt/β-catenin pathway, a critical pathway in CRC development (Catalano et al., 2025).

In addition to direct DNA damage, ROS also influence signaling pathways that regulate cell proliferation and apoptosis. For instance, ROS can activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), promoting the expression of pro-inflammatory cytokines that further enhance tumor growth (Catalano et al., 2025). Furthermore, cancer cells exhibit metabolic reprogramming to adapt to high levels of ROS, thereby fostering an environment conducive to tumor growth and progression.

The Role of Oxidative Stress in Colorectal Cancer Progression

As CRC progresses, cancer cells develop mechanisms to cope with and exploit oxidative stress. The tumor microenvironment becomes increasingly hypoxic, leading to a further increase in ROS levels. This enhanced oxidative environment can stimulate angiogenesis, the formation of new blood vessels, which is essential for tumor growth and metastasis. Moreover, CRC cells can upregulate antioxidant defenses, allowing them to survive therapeutic interventions that would typically induce cell death via ROS (Catalano et al., 2025).

The interplay between ROS and the immune response is also critical in CRC progression. While ROS can promote inflammation, chronic inflammation can lead to increased ROS production, creating a vicious cycle that facilitates tumor growth. Tumor-associated macrophages (TAMs) and other immune cells can produce ROS, which in turn influences the behavior of cancer cells, promoting survival and resistance to therapies (Catalano et al., 2025).

Therapeutic Approaches Targeting ROS in Colorectal Cancer

Given the pivotal role of ROS in CRC, targeting oxidative stress presents a promising therapeutic strategy. Several approaches are being explored, including:

Antioxidant Therapies: The administration of antioxidants aims to neutralize excessive ROS levels in the tumor microenvironment. Compounds such as vitamin C, vitamin E, and various polyphenols have shown potential in preclinical studies to enhance the efficacy of conventional therapies by reducing oxidative damage to normal tissues while selectively targeting cancer cells.
Chemotherapy and Radiotherapy: Both treatment modalities induce ROS production as a mechanism to kill cancer cells. For instance, chemotherapeutic agents can increase ROS levels, leading to cellular apoptosis. Enhancing ROS production through these therapies may improve treatment outcomes, particularly in patients exhibiting resistance to traditional treatments.
Immunotherapy: Strategies that augment the immune response against cancer cells may also leverage ROS. Immune checkpoint inhibitors, which enhance T cell activity, can induce ROS production in tumor cells, rendering them more susceptible to immune-mediated destruction (Catalano et al., 2025).
Theranostic Approaches: The integration of diagnostic imaging with therapeutic interventions, termed theranostics, allows for personalized treatment strategies based on the unique redox status of the tumor. This approach can facilitate the selection of patients who might benefit most from ROS-targeted therapies (Catalano et al., 2025).

Future research must focus on elucidating the complex roles of ROS in CRC. Key areas of interest include:

Understanding ROS Dynamics: Investigating how ROS levels fluctuate in response to various treatments can reveal potential biomarkers for therapy response and resistance.
Developing ROS Modulating Agents: Innovative compounds that selectively modulate ROS levels in cancer cells without affecting normal tissues could enhance treatment efficacy and reduce side effects.
Exploring the Tumor Microenvironment: The interactions between tumor cells and the surrounding stroma are crucial for CRC progression. Understanding how ROS influence these interactions can lead to novel therapeutic targets.
Personalized Medicine: The incorporation of ROS status into clinical decision-making can guide tailored therapies that consider individual patient characteristics and tumor biology.

Frequently Asked Questions (FAQ)

What are Reactive Oxygen Species (ROS)?

Reactive Oxygen Species (ROS) are highly reactive molecules containing oxygen that can cause damage to cells if produced in excess. They play a dual role in cancer, acting as both mediators of tumor initiation and potential therapeutic targets.

How do ROS contribute to colorectal cancer?

ROS can induce DNA damage, activate oncogenic signaling pathways, and promote tumor progression. They also influence the tumor microenvironment and immune responses, leading to enhanced cancer cell survival.

What therapeutic strategies target ROS in colorectal cancer?

Strategies include antioxidant therapies, enhancing the efficacy of chemotherapy and radiotherapy, utilizing immunotherapy, and employing theranostic approaches that combine diagnostics and therapeutics.

Why is understanding ROS important for colorectal cancer?

Understanding ROS dynamics can lead to better predictive biomarkers, improve therapeutic strategies, and facilitate personalized medicine approaches in CRC treatment.

What are the future directions for ROS research in colorectal cancer?

Future research should focus on elucidating ROS’s complex roles, developing selective modulating agents, exploring tumor microenvironment interactions, and personalizing treatment based on ROS status.

References

Catalano, T., Selvaggi, F., Cotellese, R., & Aceto, G. M. (2025). The Role of Reactive Oxygen Species in Colorectal Cancer Initiation and Progression: Perspectives on Theranostic Approaches. Cancers (Basel). Retrieved from https://doi.org/10.3390/cancers17050752
Fletcher, J., Lung, P., Van Eetvelde, E., Bertelsen, C. A., Stearns, A., Storli, K., & Miskovic, D. (2025). Inter‐rater and intra‐rater reliability of multi‐slice CT and three‐dimensional reconstructed imaging analysis of mesenteric vascular anatomy for planning and performing complete mesocolic excision. Colorectal Disease
Yangi, K., On, T. J., Xu, Y., Gholami, A. S., Hong, J., Reed, A. G., Puppalla, P., Chen, J., Tangsrivimol, J. A., Li, B., Santello, M., Lawton, M. T., & Preul, M. C. (2025). Artificial intelligence integration in surgery through hand and instrument tracking: a systematic literature review. Frontiers in Surgery. Retrieved from https://doi.org/10.3389/fsurg.2025.1528362