Abstract 6430: Untangling the link between chronic stress and colorectal cancer

Abstract Cancer patients experience high levels of stress, which is known to increase the risk of metastasis and decrease survival rates. Chronic stress can worsen inflammatory bowel disease (IBD), a pre-malignant condition for colorectal cancer (CRC). CRC is the third most common malignancy and the second leading cause of cancer-related deaths in the United States. Colitis-associated cancer (CAC) is a subtype of CRC associated with IBD and has a high mortality rate. Within 30 years of disease onset, over 20% of IBD patients develop CAC, and more than 50% of these cases result in death. Stress can break down the protective barrier in the intestines and cause a leaky gut, leading to persistent chronic inflammation, DNA damage, and oncogenic mutations that contribute to the development of cancer. Disruption of gut homeostasis and breakdown of the gut barrier are associated with various diseases, including obesity, diabetes, and colitis, all of which can contribute to the development of tumors. Our recent study using mouse models showed that stress, via glucocorticoids, significantly enhances breast cancer lung metastasis through neutrophil-mediated changes. Mechanistically, chronic stress shifted the normal circadian rhythm of neutrophils and, via glucocorticoid release, caused increased neutrophil extracellular trap (NET) formation through the glucocorticoid receptor (GR) signaling pathway. However, the effects of stress on IBD and CRC are not yet well understood. A critical question remains: How does stress-induced leaky gut regulate gut homeostasis and tumorigenesis? To address this question, we used a well-established mouse model of physical restraint and chronic stress, which we had previously validated in our research. Our findings showed that stress induces a leaky gut in mice. Additionally, in a mouse model of dextran sodium sulfate (DSS)-induced colitis, we discovered that stress significantly delayed the healing process from colitis by inducing senescence in the cells of the enteric nervous system, thereby generating a pro-inflammatory microenvironment. Dual treatment with senolytic drugs dasatinib and quercetin significantly accelerated healing from colitis in stressed mice. Colitis-associated colorectal cancer (CAC) is a classic cancer type associated with inflammation, and mouse models have been instrumental in elucidating the underlying mechanisms linking inflammation to cancer. In a well-established azoxymethane (AOM)/DSS-induced CAC model, we found that restraint stress increases colorectal tumor numbers by two-fold compared to control ones with more tumor innervation. Perineural invasion of CRC has been recognized as a strong and independent predictor of prognosis. Therefore, our findings will enhance our understanding of the systemic effects of stress on CRC development, thereby enabling novel therapeutics to improve the efficacy of CRC treatment. Citation Format: Xiaoxiao Zhou, Chen Chen, Steven Chi, Xue-Yan He. Untangling the link between chronic stress and colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6430.