Stress and Colon Cancer

Chronic stress has been increasingly recognized as a significant risk factor for various cancers, including colorectal cancer (CRC). Here are three studies that looked at the role of chronic stress in colorectal cancer progression, focusing on the mechanisms through which stress exacerbates cancer growth and potential therapeutic interventions.

Study 1: The Impact of Stress on Gut Microbiota and CRC Progression

In a study by McCollum and colleagues, chronic stress was shown to have a marked impact on colorectal cancer progression across multiple models, including chemically induced, genetically engineered, and xenograft tumor models. This study revealed a critical mechanistic link between stress and CRC development through alterations in the gut microbiota. Chronic stress led to the depletion of beneficial bacteria, particularly Lactobacillus johnsonii, which was inversely correlated with tumor load.

The study identified protocatechuic acid (PCA), a metabolite produced by L. johnsonii, as a key factor in mitigating stress-induced cancer progression. PCA was found to suppress β-catenin signaling, a pathway linked to cancer stemness and tumor aggressiveness. Supplementation of PCA or the restoration of L. johnsonii in mice effectively blocked the effects of chronic stress, reducing tumor growth. These findings suggest that stress-induced alterations in the gut microbiota promote CRC progression, and restoring microbial balance or supplementing beneficial metabolites like PCA could be a therapeutic strategy to counteract stress-induced CRC progression.

Study 2: Stress-Induced Metabolic Reprogramming in CRC

The second study by Guan et al. (2023) looked at the metabolic effects of chronic stress on colorectal cancer. The authors demonstrated that chronic stress facilitated CRC tumor growth by activating the β2-adrenergic receptor (β2-AR)/cAMP/CREB1 signaling pathway, which enhanced glycolysis in cancer cells. Chronic stress elevated the levels of catecholamines such as epinephrine and norepinephrine, which in turn activated β2-AR signaling. This pathway increased the expression of glycolytic enzymes like GLUT1, HK2, and PFKP, promoting glucose uptake and lactate production.

Metabolomics analysis revealed that stressed tumors exhibited enhanced glycolysis, which supported tumor growth under stressful conditions. The administration of a glycolysis inhibitor (2-deoxyglucose, 2-DG) or a β2-AR antagonist (ICI118,551) reversed the tumor-promoting effects of chronic stress, highlighting glycolysis as a key mediator of stress-induced CRC progression. This study underscores the importance of metabolic reprogramming in cancer cells under chronic stress. It suggests that targeting glycolysis could be an effective therapeutic approach for CRC patients experiencing chronic stress.

Study 3: Chronic Stress Linked to Accelerated Colorectal Cancer Progression Through Gut Microbiota Disruption

Research presented at UEG Week 2024 has shown that chronic stress accelerates colorectal cancer (CRC) progression by disrupting the balance of gut microbiota, specifically depleting Lactobacillus species. Dr. Qing Li's study showed that eliminating gut bacteria in mice, followed by fecal microbiota transplantation, confirmed the necessity of a healthy microbiota to curb stress-related tumor growth.

The findings highlight that stress-induced depletion of Lactobacillus, particularly Lactobacillus plantarum, weakens the immune system’s response to cancer, as these bacteria play a key role in regulating CD8+ T cells, which are vital for anti-tumor immunity. Mice supplemented with L. plantarum during stress exhibited reduced tumor formation.

Dr. Li emphasized the potential of combining L. plantarum with traditional therapies to enhance immune function and slow CRC progression, particularly in patients affected by chronic stress. The research team plans to further investigate changes in gut microbiota among CRC patients with and without stress, exploring the therapeutic potential of restoring beneficial bacteria like Lactobacillus to strengthen the body's natural defenses against cancer.

These studies highlight the complex relationship between chronic stress, gut microbiota, and colorectal cancer progression. Chronic stress not only alters microbial composition but also reprograms tumor cell metabolism and enhances cancer stemness, creating a more aggressive cancer phenotype. Therapeutic strategies that target these pathways, such as microbiota modulation, glycolysis inhibition, or β-catenin suppression, offer promising avenues to mitigate the detrimental effects of chronic stress on colorectal cancer outcomes. These findings stress the importance of addressing psychological stress in cancer patients as part of a comprehensive treatment strategy to improve survival rates and treatment efficacy.

References

McCollum SE, Shah YM. Stressing Out Cancer: Chronic Stress Induces Dysbiosis and Enhances Colon Cancer Growth. Cancer Res. 2024 Mar 4;84(5):645-647. doi: 10.1158/0008-5472.CAN-23-3871. PMID: 38437637.

Guan Y, Yao W, Yu H, Feng Y, Zhao Y, Zhan X, Wang Y. Chronic stress promotes colorectal cancer progression by enhancing glycolysis through β2-AR/CREB1 signal pathway. Int J Biol Sci. 2023 Apr 2;19(7):2006-2019. doi: 10.7150/ijbs.79583. PMID: 37151872; PMCID: PMC10158030.