The majority of us intuitively recognize the link between stress and the immune system. How many times in your life have you come down with a cold or other viral infection shortly after periods of high-stress? Now, imagine what your body goes through when exposed to stress over years. Substantial evidence suggests that exposure to long periods of stress increases rates of cancer development and growth. How is this possible, you ask?
New research indicates that stress can cause permanent changes to our genes. One hypothesis of how stress impacts on cancer development or growth is that these genetic changes could develop in key control points in the cancer process.
Another hypothesis involves the connection between the brain, the peripheral nervous system and the body (called “psychoneuroimmunology.”)
**Also be sure to read our recent posts related to this topic: “Can Coping with Anxiety, Depression and Stress Increase Remission and Survival? What Every Cancer Patient Needs to Know” and “Engaging Our Mind And Emotions To Change Our Biology: Anti-Cancer Strategies For Stacking The Deck In Your Favor.”**
Stress and cancer development:
Scientists (psychoneuroimmunologists), believe that this is the end result of our chronically stressed-out brains sending stimulatory signals to our adrenal glands to produce stress hormones (like cortisol and epinephrine.) Long-term exposure of our cells to these hormones causes:
- Stress hormones increase the production of free radicals–>DNA damage and impaired immune function
- Stress hormones increase inflammation through the production of inflammatory proteins (cytokines) –>impair immune function and promote cancer growth
- Stress hormones directly impair immune cell function
- Stress hormones reduce the ability of abnormal cells to undergo apoptosis (cell death) and DNA repair, important self-regulating anticancer mechanisms
- Stress hormones stimulate the production of IGF-1 (insulin-like growth factor-1), VEGF (vascular endothelial growth factor) and other growth factors that can promote tumor cell growth
The immune surveillance theory (or, immunosurveillance theory) postulates that at any one time within an individual, there are numerous cells (precancerous and malignant) that have the potential to become a tumor if not detected and destroyed by the immune system. Fortunately, in the presence of a healthy immune system, immune cells (i.e. white blood cells, natural killer cells, macrophages) protect us by detecting and eliminate these precancerous and cancer cells as soon as they identified. Our immune system is also constantly protecting us from viruses that can cause cancer (i.e. Epstein-Barr virus, human papilloma virus, hepatitis C virus, hepatitis B virus, human herpes virus 8 and human T-cell leukemia virus.) If our immune system is weakened or suppressed, precancerous and cancer cells and cancer-causing viruses are able to wreak havoc and eventually lead to the development of uncontrolled cancer cell growth.
Severe stress, such as occurs in individuals diagnosed with post-traumatic stress disorder (PTSD), appears to lead to permanent changes to genes (DNA) that control immune function. In a study (published in May 2010, in the Proceedings of the National Academy of Sciences) investigators have discovered that individuals with PTSD have 6-7 times as many changes to genes that control immune function compared to individuals without PTSD. Although the precise mechanism(s) to explain how these genetic changes take place is(are) not yet known, we now have data that show that PTSD can permanently change one’s DNA, reducing the function of their immune system.
Further complicating this picture, it is well-recognized that stress is associated with various high-risk behaviors that may increase the risk of developing cancer (i.e. smoking and excessive alcohol use, poor diet, lack of exercise, obesity, etc.) Sleep is commonly affected as a consequence of stress, and emerging data correlate disturbed circadian rhythms with increased incidence of certain cancers. Altered circadian (sleep-wake cycle) rhythms have been shown to affect the neurohormal axis, and thus modify the regulation of the immune system. The pineal hormone melatonin has been linked to numerous mechanisms attributed to immune enhancement (i.e. increased T and B cell immunity, increased monocyte activity, increased NK cell activity, increased secretion of cytokines), reduction of oxidative stress (free radicals), tumor cell apoptosis (cell death/suicide) and reduction of blood vessel growth in tumors.
Stress and Cancer Progression:
Once a tumor has developed, stress may modulate neuroendocrine pathways and affect numerous mechanisms that potentially lead to the progression of cancer:
- Stress hormone stimulation of beta-adrenergic receptors (present on all cells) increases tumor growth rates
- Stress hormones increase tumor cell invasiveness and metastatic activity
- Stress hormones increase tumor blood vessel growth
- Stress hormones suppress natural killer (NK) cell activity (immune suppression)
- Stress hormones reduce the cancer-killing effects of chemotherapy on tumor cell apoptosis (cell death/suicide)
Stress may be present from diagnosis to the survivorship period, and can be associated with behavioral comorbidities and diminished quality of life (i.e. depression, fatigue, sleep disturbances, and cognitive dysfunction.) Medical complications or side effects of cancer and treatment can further exacerbate these symptoms.
Multiple studies demonstrate that chronic stress increases the rate of tumor metastases in animals with cancer. For example, norepinephrine (stress hormone) has been shown to increase the migration of breast, prostate, and colon carcinoma cells (in-vitro) and increase the incidence of prostate carcinoma lymph node metastases (in-vivo.) This phenomenon seems likely to be related to the chronic stimulation of beta-adrenergic receptors (stress hormone receptor):
- In a study (published in Cancer Research, September 2010), investigators from UCLA examined the effects of chronic stress in mice injected with breast cancer cells. The mice were subjected to a chronic stress model by being confined to a small cage for 2-hours each day for 20-days. During this time, they underwent injection of fluorescent-labeled breast cancer cells and then observed for metastatic spread. They compared the results to a control group of mice that were not subjected to chronic stress. The results were significantly different. The stressed mice had a 30-fold increase in the development of metastases compared to the non-stressed mice. The authors found, in the stressed mice, that cells in their immune system (i.e. macrophages) were genetically altered by the activity of stress hormones in such a way that increased the ability of the injected cancer cells to gain access to the blood system and thereby spread around the body.
- Interestingly, the researchers also tested the effects of a stress hormone blocking medication (“beta-blocker”, propranolol) on the stressed mice. What they found was incredible…propronalol completely blocked the effects of stress hormones on causing the rapid progression of cancer metastases! As propranolol is an inexpensive and widely available blood pressure medication, the authors have suggested that it may have a future role in helping to reduce the risk of cancer progression.
- Similar findings have also been reported by other groups.
Stress reduces the effectiveness of cancer drugs.
- In a 2013 study, researchers discovered that mice implanted with prostate cancer cells and treated with a prostate cancer drug (ZSTK474) had much slower tumor growth when the mice were kept calm compared with a group of mice who were placed under stress. It appeared that in the stressed mice, the cancer cells didn’t die and the drug did not slow tumor growth. In a second experiment, mice genetically modified to develop prostate cancer were used. When these mice were repeatedly stressed, the size of prostate tumors increased. When the mice were treated with a commonly used prostate cancer drug (bicalutamide), their prostate tumors decreased in size. However, if mice were subjected to repeated stress, the prostate tumors didn’t respond as well to the drug.
Stress is often associated with sleeping disturbances.
- direct effects of altered hormone levels on tumor cells
- effects on tumor versus host metabolism
- neuroimmune effects resulting in cell mediated immune suppression
- increase cortisol release and expression of pro-inflammatory cytokines (i.e. IL-6, tumor growth factor-alpha), which can stimulate tumor development and progression
Why is stress reduction so important?
It is a well-known fact that chronic stress negatively impacts the health of individuals with a variety of medical conditions (cardiovascular disease, diabetes, obesity, chronic pain, autoimmune diseases, depression, inflammatory bowel syndromes/disorders, etc.) Helping individuals with these conditions learn how to cope with and reduce stress has been demonstrated in numerous studies to not only reverse the physiologic effects of stress hormone exposure, but also significantly improve disease, overall health outcomes and quality of life. Okay, but what about the impact of stress reduction on cancer?
Stress reduction may improve cancer survival rates:
The effects of long-term exposure of stress hormones on our cells has not been definitely linked to the development or progression of cancer, but the evidence supporting this potential association is very compelling. It seems highly unlikely that chronic stress exacerbates nearly every other disease except for cancer.
An important meta-analysis (published in 1998, in Nature Reviews Clinical Oncology), of 165 studies on the topic of stress and cancer statistics (incidence & outcomes), reported that stress was associated with higher cancer incidence in initially healthy populations (6-21% higher) and higher cancer mortality (29-133% higher). The following study is one of the strongest pieces of evidence ever reported on the positive impact of stress reduction on cancer progression and recurrence:
- In a study (published in June 2010, in Clinical Cancer Research), investigators update the results of a fascinating experiment in which 227 breast cancer patients were randomly assigned to two groups: group 1 (received psychological interventions such as relaxation training and advice on minimizing stress in 39 therapy hours, over 12 months), group 2 (received no psychological interventions). The patients have been followed for over 11 years since their initial enrollment. Patients were reassessed every four months during year one, every six months during years two to five, and annually thereafter. In their initial publication, the authors previously reported that patients in the intervention group had a 45% reduced risk of breast cancer recurrence, improvements in multiple immune function measurements, and improvements in various quality of life outcomes.
- In this paper, the authors analyzed the patients who recurred in both groups. Incredibly, they found that those in the intervention group had a 59% reduced risk of death from breast cancer!!
The results of this important study suggest that a relatively short and inexpensive psychosocial stress reduction program may be effective in improving the survival of breast cancer patients.
The authors hypothesize that the mechanism for this improvement in survival and reduction in recurrence is due to the positive effects of stress reduction on the immune system.
To satisfy the skeptics out there, I want to emphasize (dare I say ‘stress’) the point that the direct association between chronic stress, the immune system and cancer has not been definitively established, but increasingly the evidence seems to support this.
While the concept of stress is universal and readily understood, it is often a challenge to operationalize it for research. Perhaps one of the reasons for why linkages between cancer and psychological stress is not well-defined is due to the lack of clear understanding on what constitutes stress, and how stress is measured and defined. Stress is a not a distinct state of mind, but is in fact a combination of various psychological components (i.e. depression, anxiety, frustration, fear, hopelessness, etc.) resulting from exposure to adversity, cognitive appraisal, behavioral characteristics and coping style, personality, social support, and emotional responses. Each of these components may be activated by different emotional or physical experiences and can involve different neural pathways, ultimately leading to complex downstream physiological effects.
Stress reduction improves quality of life:
Regardless of whether stress reduction techniques are able to improve cancer outcomes, there is no doubt that they can greatly improve quality of life. Stress reduction techniques can involve any of variety of effective options, such as: massage therapy, meditation, guided imagery, yoga, cognitive based therapies, prayer, walking on the beach, and many others. Here are three studies looking at just one of these stress reducing modalities, yoga:
- A recent study reported that breast cancer survivors who practiced yoga for 3-months had a significant reduction in cancer related fatigue and improved vigor. This reduction in fatigue is thought to be due to yoga’s effects on the immune and neuroendocrine systems (likely through increased physical activity and stress reduction).
- A short, 4-week yoga course has also been reported to improve sleep quality and fatigue after cancer treatment.
- An 8-week yoga course was reported to reduce salivary cortisol (stress hormone) levels, improve emotional well-being and reduce fatigue after cancer treatment.
- Anxiety (Oncology Nursing Society)
- Caregiver Strain/Burden (Oncology Nursing Society)
- Coping with Emotional and Physical Concerns (a great reference by Cancer.Net)
- Integrative Oncology: Complementary Therapies for Pain, Anxiety, and Mood Disturbance
- Stress, Depression, The Immune System and Cancer (Lancet Oncology, in 2004. Excellent review.)
- Psychological stress and cancer (National Cancer Institute)
- Acupuncture has many beneficial effects in managing a variety of symptoms experienced in patients with cancer
- Acupuncture significantly reduces anxiety with a simple 5 minute treatment. (My blog entry on the use of acupuncture for relaxation)
- Anxiety, Fear and Depression (American Cancer Society)
- Posttraumatic Stress Disorder and Cancer
- Learn About The Impact Of Stress On Your Health & Techniques To Reduce It: Education & Self-Assessment (A fantastic reference from the University of Minnesota, Center for Spirituality and Healing and the Life Science Foundation. Not directed specifically for cancer patients, but the information is useful for everyone.)
- Stress Management (Useful tips and supplements for helping with stress, from Life Extension.org)
- Nutrients to Combat The Modern Stress Epidemic (Excellent article on the use of supplements for helping to manage stress, from Life Extension.org)
- Biofeedback Devices Help To Reduce Stress (My blog entry on the use of relaxation gizmos)
- Cannabis and Cancer (My blog entry on the use of cannabis in cancer care)
Great technique for relaxing: “The 4-7-8 (or Relaxing Breath) Exercise”
I highly recommend this relaxation technique as a very simple and effective way to get you into a relaxed state quickly. You can learn the “relaxing breath” in a short amount of time and it is very easy to do. This can be done before going to bed, before going to the doctors office (if that makes you nervous) or in any stressful situation.
Instructions (from DrWeil.Com)
“Place the tip of your tongue against the ridge of tissue just behind your upper front teeth, and keep it there through the entire exercise. You will be exhaling through your mouth around your tongue; try pursing your lips slightly if this seems awkward.”
- Exhale completely through your mouth, making a whoosh sound.
- Close your mouth and inhale quietly through your nose to a mental count of four.
- Hold your breath for a count of seven.
- Exhale completely through your mouth, making a whoosh sound to a count of eight.
- This is one breath. Now inhale again and repeat the cycle three more times for a total of four breaths.
The figure (below) illustrates some of the mechanisms that have linked the development and progression of cancer with stress
(“The Influence On Bio-Behavioural Factors On Tumour Biology: Pathways & Mechanisms”, Antoni, M.H., et. al., Nature Reviews, March 2006)