Reading time: 5 minutes
Hema Saranya Ilamathi
It’s Monday morning! The alarm goes off, and your mind immediately floods with thoughts: meetings with the boss, deadlines to meet, the week’s workload, and the rush to get to work on time. The stress is already kicking in—sound familiar?. In a competitive and fast-paced world, stress has become a part of everyone’s life. However, stress is one of the important factors that increase the risk of different diseases including cancer.
Stress has become an inevitable part of today’s life. There are different kinds of stress depending on the duration and its effect including eustress, acute stress, chronic stress and episodic acute stress. For instance, certain stresses are temporary, and stress hormone levels increase transiently and then return to normal. Imagine that you see a crazy dog running towards you. Your body senses danger and activates the part of the brain to release fight-or-flight hormones (adrenaline, noradrenaline) and other hormones (cortisol) to sustain the stress response. Once the danger is gone, hormone levels return to normal. These hormonal changes are accompanied by changes in energy mobilization to essential organs such as the brain, heart, and muscles, enhanced alertness and attention, and elevated immune response.
On the other hand, chronic stress is a prolonged stress response that could last for weeks, months, or years and it is detrimental to the health. Chronic stress can be triggered by intense job pressure, financial insecurities, emotional strain, unstable living conditions, or illness of loved ones or oneself. Chronic stress alters the body’s functioning by increasing heart rate, and blood pressure, altering the sleep cycle, and affecting the appetite. Furthermore, prolonged elevated stress hormones in the blood suppress immune response thereby increasing the susceptibility to infection1.
Although stress is considered one of the potential risk factors for cancer there is no direct evidence available so far to confirm its role in cancer formation. However, stress-induced habits such as smoking, drinking, altered eating and sleeping patterns could indirectly influence cancer formation. A meta-study supported that psychosocial factors influence cancer incidence, especially in the case of lung tumors2. Some of the known psychosocial factors such as poor quality of life, weaker stress management style, and negative emotions are highly associated with cancer incidence2.
Unlike limited knowledge of stress-induced cancer formation, there are multiple evidence suggesting a positive correlation between chronic stress and cancer development. Different stress-hormones-mediated mechanisms have been proposed to alleviate tumorigenesis. One such mechanism includes attenuation of the cell’s DNA repair system and alleviating DNA mutations. This in turn enhances DNA damage and tumorigenesis3,4. Cells perceive the hormonal signal through the adrenergic receptors (alpha and beta receptors), the protein that binds with the hormone. This in turn activates the cellular proliferation pathway downstream thereby enhancing cancer development5.
Graphical abstract: Is stress a key factor for tumor formation and spread? Image created using biorender.
In addition to these effects, chronic stress remodels the tumor microenvironment, favoring tumor development. Multiple pieces of evidence suggest the differential impact of chronic stress on immune cells. For instance, Stress-induced hormones suppress the presentation of cancer antigens to the cytotoxic killer T-cells thereby blocking the anti-tumor immune response6. In addition to this, stress hormones can stimulate pro-inflammatory macrophages present in the tumor environment to anti-inflammatory macrophages thereby aiding the tumor cells to evade immune response7. Thus, stress hormones play an important role in tumorigenesis by creating a conducive environment for tumor growth.
Stress hormones facilitate the spread of tumor cells. For instance, stress hormones enhance the expression of factors in the cancer cells necessary for colonizing the lungs. Arresting the expression of metastatic factors reduces metastasis and increases survival in the animal model8. Chronic stress alters the immune profile of the metastatic site thus favoring the growth of disseminated cancer cells9. Moreover, stress activates the formation of new blood vessels and induces lymphatic remodeling to facilitate the spread of tumor10,11.
Advancements in the medical field have increased the number of patients recovering from primary tumors. However, the 5-year survival rate after treatment is still less than 20% worldwide. Some cancer cells enter hibernation during the treatment called dormant cancer cells. Recent studies suggest that stress could be one of the factors resulting in tumor recurrence. Stress hormones activate the immune cells that support the reestablishment of tumors12. Thus, stress retunes the microenvironment around the dormant cancer cells, and results in the resurrection of tumors highly resistant to treatment.
Various chemotherapeutic drugs, radiation therapy, and immunotherapy are available to treat patients with different cancer stages and types. However, in many cases, patients develop resistance to the treatment, especially in advanced stages or recurrent tumors. Chronic stress has been reported to be one of the factors associated with treatment resistance13,14. Blocking the receptors through which the cell perceives the stress signal has been reported to benefit treatment outcomes in multiple clinical studies15. The inclusion of beta-adrenergic receptor blockers increases the overall survival of colorectal cancer patients16. Beta-blockers reduce the recurrence of breast cancer and reduce the mortality among breast cancer patients17,18. In contrast, the other studies reported no beneficial effect of using beta-blockers in cancer patients19-21. Though beta-blockers per se have inconsistent positive effects on cancer patients, combining them with conventional treatments reduces the development of resistance and improves the outcome22-24.
Studies highlight the important role of chronic stress in cancer development, dissemination of cancer cells to other organs, suppression of anti-tumor immune response, and treatment resistance. Cancer can be prevented in the first place by following a healthy lifestyle including good food habits, proper sleep-wakeup cycle, regular exercise, and meditation. Cancer patients face intense emotional stress resulting in anxiety and depression, which can affect treatment outcomes. In addition to conventional cancer treatment, psychological intervention programs must become an integral part of the regimen from diagnosis to post-treatment. Regular meditation, yoga, mild physical exercise, and other mind-relaxing activities should be recommended to the patients. While stress is an unavoidable part of modern life, we can still control it by prioritizing our well-being.
Edited by Susan Egbert
Reference
1 Dhabhar, F. S. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res 58, 193-210 (2014). https://doi.org:10.1007/s12026-014-8517-0
2 Chida, Y., Hamer, M., Wardle, J. & Steptoe, A. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat Clin Pract Oncol 5, 466-475 (2008). https://doi.org:10.1038/ncponc1134
3 Feng, Z. et al. Chronic restraint stress attenuates p53 function and promotes tumorigenesis. Proc Natl Acad Sci U S A 109, 7013-7018 (2012). https://doi.org:10.1073/pnas.1203930109
4 Hara, M. R. et al. A stress response pathway regulates DNA damage through beta2-adrenoreceptors and beta-arrestin-1. Nature 477, 349-353 (2011). https://doi.org:10.1038/nature10368
5 Thaker, P. H. et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 12, 939-944 (2006). https://doi.org:10.1038/nm1447
6 Figueroa, C. et al. Inhibition of dopamine receptor D3 signaling in dendritic cells increases antigen cross-presentation to CD8(+) T-cells favoring anti-tumor immunity. J Neuroimmunol 303, 99-107 (2017). https://doi.org:10.1016/j.jneuroim.2016.12.014
7 Xie, Y. et al. Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration. Dis Model Mech 12 (2019). https://doi.org:10.1242/dmm.037887
8 Obradovic, M. M. S. et al. Glucocorticoids promote breast cancer metastasis. Nature 567, 540-544 (2019). https://doi.org:10.1038/s41586-019-1019-4
9 He, X. Y. et al. Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment. Cancer Cell 42, 474-486 e412 (2024). https://doi.org:10.1016/j.ccell.2024.01.013
10 Yang, E. V. et al. Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res 66, 10357-10364 (2006). https://doi.org:10.1158/0008-5472.CAN-06-2496
11 Le, C. P. et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat Commun 7, 10634 (2016). https://doi.org:10.1038/ncomms10634
12 Perego, M. et al. Reactivation of dormant tumor cells by modified lipids derived from stress-activated neutrophils. Sci Transl Med 12 (2020). https://doi.org:10.1126/scitranslmed.abb5817
13 Zeng, Y. et al. Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer. Nat Med 30, 1680-1688 (2024). https://doi.org:10.1038/s41591-024-02929-4
14 Chen, M. et al. Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation. Nat Commun 11, 1821 (2020). https://doi.org:10.1038/s41467-020-15676-0
15 Udumyan, R. et al. Beta-Blocker Drug Use and Survival among Patients with Pancreatic Adenocarcinoma. Cancer Res 77, 3700-3707 (2017). https://doi.org:10.1158/0008-5472.CAN-17-0108
16 Jansen, L., Hoffmeister, M., Arndt, V., Chang-Claude, J. & Brenner, H. Stage-specific associations between beta blocker use and prognosis after colorectal cancer. Cancer 120, 1178-1186 (2014). https://doi.org:10.1002/cncr.28546
17 Powe, D. G. et al. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 1, 628-638 (2010). https://doi.org:10.18632/oncotarget.197
18 Botteri, E. et al. Therapeutic effect of beta-blockers in triple-negative breast cancer postmenopausal women. Breast Cancer Res Treat 140, 567-575 (2013). https://doi.org:10.1007/s10549-013-2654-3
19 Weberpals, J. et al. Pre- and post-diagnostic beta-blocker use and lung cancer survival: A population-based cohort study. Sci Rep 7, 2911 (2017). https://doi.org:10.1038/s41598-017-02913-8
20 Shah, S. M. et al. Does beta-adrenoceptor blocker therapy improve cancer survival? Findings from a population-based retrospective cohort study. Br J Clin Pharmacol 72, 157-161 (2011). https://doi.org:10.1111/j.1365-2125.2011.03980.x
21 Huang, T., Townsend, M. K., Dood, R. L., Sood, A. K. & Tworoger, S. S. Antihypertensive medication use and ovarian cancer survival. Gynecol Oncol 163, 342-347 (2021). https://doi.org:10.1016/j.ygyno.2021.09.009
22 Nilsson, M. B. et al. Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with beta-blockers. Sci Transl Med 9 (2017). https://doi.org:10.1126/scitranslmed.aao4307
23 Chaudhary, K. R. et al. Effects of beta-Adrenergic Antagonists on Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer. J Clin Med 8 (2019). https://doi.org:10.3390/jcm8050575
24 Gandhi, S. et al. Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity. Clin Cancer Res 27, 87-95 (2021). https://doi.org:10.1158/1078-0432.CCR-20-2381
OncoBites 
Leave a comment