Chronic Stress and its Contribution to the Metastatic Spread of Cancer
Chronic Stress and its Contribution to the Metastatic Spread of Cancer
Sana Sawhney Thomas Jefferson High School for Science and Technology
This article placed 4th in the 2022 Teknos Summer Writing Contest.
A patient sits in her doctor’s office, hands tightly clasping the edge of her seat. She doesn’t notice, but her knuckles are turning white. She squeezes her eyes shut so that she doesn’t have to see the doctor’s mouth moving. She stopped listening after hearing the words “lung cancer.” Her heart rate speeds up, so fast that she can feel it almost beating out of her chest. She releases her hands from the chair only to rub them down her jeans, desperately trying to get rid of the sweat that is now coating her palms. It is almost as if her body is foreshadowing the months, possibly years, that lie ahead. Constant medications and therapy. Radiation to control the tumor. Surgery to remove it. Tests to measure recovery. And hovering over it all, like a cruel cherry on top… stress. The stress of not knowing what comes next, the stress of hope collapsing, the constant stress of being diagnosed with one of the greatest medical mysteries of all time.
Chronic stress is different from what the “normal” person experiences from day to day. Acute or short-term stress is what the typical human being is most familiar with. The stress of a big test at school or an important presentation at work. The stress of being stuck in traffic or even losing your job. All of these are examples of stress that last for a short period of time; one runs into a problem and experiences stress while trying to fix it. Once the problem is solved, the stress is gone, and an individual moves on with their life. Many people even argue that acute stress can be healthy or motivating. Chronic stress, however, tends to lack these redeeming qualities.
Chronic stress is defined as stress that is constant and experienced over a long period of time [5]. This is when stress seeps from its psychological borders into the physical well being of a human, with common symptoms including aches, pains, and insomnia. Because the treatment for a condition like cancer is lengthy and intense, often leaving the patient extremely weak, chronic stress has unsurprisingly become a theme among patients [3]. But what effect can this have on an individual?
When one experiences stress, the hypothalamic-pituitary-adrenal axis (HPA axis) and the sympathetic nervous system (SNS) are activated [7]. This activation results in the release of stress hormones, most notably catecholamines and glucocorticoids [7]. Low levels of these hormones are normal for the body, and tend to have almost no effect on the well being of an individual. However, as previously mentioned, chronic stress is prolonged. This extended amount of stress leads to the constant activation of the HPA axis and SNS, consequently leading to long-lasting, elevated levels of these hormones [5]. Oncologists and other researchers have begun to notice an important consequence of these increasing levels.
In studies on both mice and human subjects, elevated levels of stress hormones have been shown to lead to tumorigenesis (the production/formation of tumors), tumor progression, metastasis (the spread of cancer from the initial local site), and drug resistance [7]. These elevated hormone levels negatively alter the tumor microenvironment (TME), which consists of tumor cells, cancer stromal cells, and some non-cellular components, and the immune system [7].
In the immune system, increased exposure to stress hormones has the overall effect of decreasing the number and function of immune-supportive cells and increasing the number of exhausted and immuno-suppressive cells [4]. For example, dendritic cells, a special type of immune cell found in tissues, boost immune responses. Exposure to stress hormones disables the full maturation of immature dendritic cells, inhibiting their production (fully mature cells are unaffected) [7]. Another example can be seen in T lymphocytes, which develop from stem cells in the bone marrow and help protect against infection and cancer. Hormones, however, contribute to the reduction and dysfunction of immune-supportive T cells, while raising the number of immunosuppressive T cells [7].
Additionally, chronic stress is directly related to the overexpression of angiogenic factors, leading to the angiogenesis of solid tumors [2]. Angiogenesis is the development of new blood vessels, and thus plays a key role in the spread of cancer, since tumors need blood as fuel to grow beyond a few millimeters in size [1]. These effects were observed in ovarian cancer, oral cancer, and lung cancer, where enhanced angiogenesis was induced by the development of chronic stress [7].
While there are few therapies that have been discovered or even researched to solve the issue of chronic stress, studies have been conducted on mice in hopes of discovering a possible solution. One of these studies involved using a beta blocker, which inhibits stress hormones, preventing dormant cancer cells from forming tumors [6]. Similar effects were observed in another study when a drug, tasquinimod, blocks the activity of S100 proteins (high levels of S100 proteins have been noted in stressed mice) [6]. This drug has also been tested in people with prostate cancer [6].
Researchers have noticed a strong potential link between chronic stress, the release of stress hormones, and the spread of cancer. The mechanism behind this observed link, however, requires more studies and research to become clear to the oncology community. Scientists look towards possibly combined treatments to better control cancer, by suppressing stress hormones and proteins [6]. Until then, making stressful situations less intense and improving mental health is a mission that must be furthered in the community of those both physically and mentally exhausted from the rigorous treatments of this deadly disease. Mental health and physical health are not as separate as they may seem. In fact, they often influence each other in a cyclical way that could, in extreme circumstances, mean life or death. The true journey of cancer begins not when the disease first develops in your body, but when you are the patient sitting in a room being diagnosed with cancer. Stress is there when the journey begins, but overcoming it is important in easing the long road ahead.
References
[1] Angiogenesis Inhibitors. (2018, April 2). National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet
[2] Cole, S. W., Nagaraja, A. S., Lutgendorf, S. K., Green, P. A., & Sood, A. K. (2015). Sympathetic nervous system regulation of the tumor microenvironment. Nature reviews. Cancer, 15(9), 563–572. https://doi.org/10.1038/nrc3978
[3] CTCA. (2019, July 10). What is the relationship between stress and cancer? Cancer Treatment Centers of America. https://www.cancercenter.com/community/blog/2019/07/what-is-the-relationship-between-stress-and-cancer
[4] Kochanowska, M. (2020, March 29). The biology of stress. Reliably about psychology and neurobiology. https://neuroskoki.pl/en/biology-of-stress/
[5] Peck, M. (2022, April 22). Is there a connection between chronic stress and cancer? (with videos). City of Hope. https://www.cityofhope.org/living-well/is-there-a-connection-between-chronic-stress-and-cancer
[6] Staff, N. (2021, January 14). Study Suggests a Link between Stress and Cancer Coming Back. National Cancer Institute. Retrieved August 1, 2022, from https://www.cancer.gov/news-events/cancer-currents-blog/2021/cancer-returning-stress-hormones
[7] Tian, W., Liu, Y., Cao, C., Zeng, Y., Pan, Y., Liu, X., Peng, Y., & Wu, F. (2021). Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments. Frontiers in cell and developmental biology, 9, 777018. https://doi.org/10.3389/fcell.2021.777018
