In the fast-paced modern world, chronic stress has become an almost pervasive element in many people’s lives. Beyond its well-known effects on mental health, emerging research suggests that chronic stress may extend its influence to physical health, potentially impacting cancer risk and recurrence.
Recent studies have indicated an association between chronic stressed and an increased susceptibility to cancer, as well as a potential influence on cancer recurrence in individuals with a history of the disease. Chronic stress triggers a cascade of physiological responses, including the release of stress hormones like cortisol and adrenaline, which, when prolonged, may create an environment conductive to cancer development and progression. Figure 1 illustrates the close association between stress and the neuroendocrine pathways, specifically the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Stress hormones could induce DNA damage, which includes increasing p53 degradation, and maintaining the tumor microenvironment. Additionally, chronic stress may exacerbate neuroinflammation, hindering the brain's cognitive processing of stress. In a cyclical manner, chronic stress can inhibit the activity of type 1 helper T cells (Th1), suppress cytotoxic T cells (CTL)-mediated cellular immunity and interferon production, and compromise immune surveillance and other vital processes. Consequently, this increases the susceptibility to cancer invasion and metastasis while diminishing the efficacy of anti-tumor therapies. Chronic stress facilitates tumorigenesis and oncogenesis by inducing the production of stress hormones, triggering inflammation, and suppressing immunity.
Figure 1: The persistent stress experienced in chronic stress situations triggers the release of stress hormones through the activation of the neuroendocrine system, involving the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system.
Courtesy of Frontier Oncology
Insights from Mouse Studies on Cancer Recurrence
Recent research has cast a spotlight on the profound influence of stress, specifically depression, on the recurrence of cancer. Researchers at The Wistar Institute of Cancer Center, aimed to explore the impact of stress on mice and its connection to cancer recurrence. When mice experienced stress from being confined, certain changes occurred in their bodies. Neutrophils, which are a type of white blood cell, increased in their lungs and spleens. Neutrophils are the body’s first responders, rushing to the site of infection or injury to help fight off harmful invaders. The researchers then took a step further to test potential solutions. When stressed mice were treated with a beta blocker, a type of medication often used for high blood pressure that also blocks stress hormones, the dormant cancer cells couldn't form tumors. Similar positive effects were observed when the mice were treated with tasquinimod, a drug designed to block the activity of S100 proteins. This evidence not only highlights the intricate link between stress and cancer recurrence but also suggests potential avenues for intervention to mitigate these effects. The study's findings open doors for further exploration into targeted therapies and treatments that could positively impact individuals facing the challenges of cancer.
The Stress-BC Connection
According to the 2023 Stress in America survey by the APA, women consistently report higher stress levels than men. This aligns with the fact that approximately 40% of women experience the recurrence of Breast Cancer (BC). Despite advancements in early diagnosis and improved treatments, BC still maintains a grim prognosis, boasting a 5-year survival rate of merely 27%. A comprehensive review delving into the intricate relationship between stress and BC reveals that stress plays a significant role in modulating BC progression and metastasis, primarily through the sympathetic nervous system (SNS). The prolonged exposure to chronic stress heightens SNS activity, resulting in the release of catecholamines like norepinephrine (NE) and epinephrine (EP). These stress-induced neurotransmitters directly impact BC cells and the tumor microenvironment, triggering an accelerated tumor growth, heightened risk of metastases, and contributing to increased chemoresistance.
The Potential Role of β-Blockers
In the battle against stress-induced cancer recurrence, a pivotal strategy revolves around utilizing medications known as β-blockers. Specifically, these medications target and inhibit β-adrenergic receptors, key players in stress-related signaling. β-blockers work by blocking the effects of adrenaline, a stress hormone that typically binds to these receptors. This interference disrupts stress-related signals, potentially thwarting the spread of cancer cells.
Figure 2: The potential anti-cancer effects of the repurposed β-blocker propranolol in osteosarcoma, highlighting its ability to inhibit cancer cell growth and complement chemotherapy by hindering angiogenesis and promoting tumor necrosis.
Courtesy of Scientific Reports
Insights from Propranolol: A Promising Ally
A significant study conducted using the Longitudinal Health Insurance Database delves into the effects of propranolol, a nonselective β-blocker, on various types of cancers. The study compared outcomes between a propranolol-treated group and a non-propranolol group, revealing a noteworthy reduction in the risk of cancer, particularly in head and neck, esophagus, stomach, colon, and prostate cancers. Intriguingly, the protective effect of propranolol was most pronounced with prolonged exposure exceeding 1000 days. These findings indicate a 25% reduction in the risk of cancer among propranolol-treated patients, with older age groups experiencing a particularly prominent protective effect. This not only sheds light on the mechanics of β-blockers in disrupting stress-related signals but also presents promising insights from a specific β-blocker, propranolol. Figure 2 demonstrates the potential of the repurposed β-blocker propranolol in inhibiting cancer cell growth in osteosarcoma. The β-adrenergic receptor (β-AR) signaling, which plays a role in cancer progression, is heightened in osteosarcoma. Activation of β-AR by stress-related hormones in tumor cells and other supporting cells accelerates cell growth, angiogenesis, and immune-permissive environments, contributing to tumor progression. Propranolol counteracts these effects by inhibiting the growth-stimulating actions of stress hormones, leading to a slowdown in cellular growth and movement. Additionally, propranolol complements chemotherapy by hindering osteosarcoma-induced angiogenesis and promoting tumor necrosis, potentially delaying disease progression. The findings suggest a potential role for β-blockers in reducing the risk of specific cancers, emphasizing the need for further prospective research to validate and build upon these encouraging results. As we delve into the protective effects of propranolol, it becomes clear that β-blockers could emerge as valuable allies in the ongoing quest to prevent stress-induced cancer recurrence.
References:
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