Biological Impact of Stress on Cancer Patients

Without question, receiving a cancer diagnosis is life altering, and may bring with it more fear than any other diagnosis. Patients may fear for their life, fear telling their family, friends and coworkers, and fear what the treatment will be like. This has a huge psychological impact, and stress levels are drastically increased. Much is known about the ways in which increased psychological stress can negatively affect disease processes, and cancer is no exception. The ways in which stress affects cancer progression is a well researched topic, and there are some interesting emerging treatment options. What follows a cancer diagnosis can be overwhelming. Patients are trying to understand the disease, attempting to learn new medical terminology, and learning to navigate the health care system, while still attending to the other responsibilities we each have in this busy day and age. It could seem that stress management is not a priority, but as we will explore in the following article, it should be a critical aspect of standard cancer care.

BIOLOGICAL EFFECTS OF STRESS ON CANCER

Two major pathways mediate the human stress response. The first involves the sympathetic nervous system (SNS), using the catecholamines epinephrine (EP) and norepinephrine (NE) as its messengers. The second is the hypothalamic-pituitary (HPA) axis, which mainly involves the hormone cortisol, released from the adrenal cortex. Almost all cells in the human body have receptors for these hormones, including cancer cells. Psychological stress activates both the SNS and HPA axis, resulting in systemic increases in cortisol and catecholamines. In vitro studies have shown that cells exposed to EP and NE have significantly increased amounts of DNA damage compared to controls ^[1]. The hypothesis is that stress not only increases the production of reactive oxygen species (ROS) leading to DNA damage, but also actually impairs DNA repair mechanisms ^[2]. Stress as an etiological factor in cancer is not well supported in the literature, but stress as a factor in cancer progression and mortality does in fact have significant positive research. A recent meta-analysis reported a positive significant correlation to high stress and poorer survival as well as increased mortality, but not to increased incidence ^[3]. In vitro experiments have shown that gastric cancer cell lines exposed to NE had elevated levels of interleukin-6 (IL-6), which is associated with cancer progression ^[4]. Colon cancer cells exposed to EP had increased expression of genes associated with accelerated growth rate, and also had more resistance to cisplatin induced apoptosis ^[5]. Lung cancer patients with high levels of stress have a higher mortality and less favourable clinical outcomes ^[6].

Tumour tissue and its stroma are innervated by sympathetic nerve fibers, and upon their stimulation, for instance by psychological stress, catecholamines are released. In experimental models of disease, elevated NE and EP have been associated with increased angiogenesis, invasion and metastasis, and protection from anoikis (programmed cell death when a cell detaches from its extracellular matrix (ECM) ^[7]. In one mouse model, elevated NE was found to activate signalling pathways that led to the inhibition of apoptosis ^[8]. In addition to SNS effects, there is a plethora of research showing that glucocorticoids, mainly cortisol, affect proliferation, differentiation and effector functions of immune cells and modulate the expression of many cytokines, chemokines and adhesion molecules ^[9].

Adrenergic signalling, primarily via beta-adrenergic receptors, has been implicated as the mediators of many of these effects by modulating several growth factors, such as vascular endothelial growth factor (VEGF), IL-6, IL-8 and matrix metalloproteinase-9 (MMP-9), the latter being involved in metastasis. Beta-adrenergic receptors mediate the biological effects of NE and EP, and numerous studies have shown that stimulation of these receptors by a synthetic beta agonist stimulates proliferation and migration of cancer cells ^[10]. Interestingly, COPD, chronic brochnitis, emphysema and asthma are documented risk factors for certain types of lung cancers, yet little attention appears to be devoted to the observation that the leading therapeutic for these conditions are agents that stimulate beta-adrenergic receptors ^[11]. Further, a number of retrospective studies have found that chronic use of beta blocking drugs is associated with lower recurrence and mortality of breast cancer, malignant melanoma, and reduced cancer generally. A potential mechanism behind this is that suppression of SNS functioning can result in increased levels of peripheral natural killer cells and macrophages, as well as elevated levels of anti-inflammatory cytokines ^[11-14].

A discussion of stress in cancer patients cannot exclude a discussion of depression in cancer patients, and both share similar physiological states. Both stress and depression are associated with elevated levels of IL-6, MMP-9, EP and NE, and down regulation of the immune system ^[15]. Depression is the most frequently found psychological symptom among individuals with cancer, and severe depression is correlated with prolonged hospital stays, poorer quality of life and shorter survival. A study of socially isolated ovarian cancer patients showed higher intratumoral levels of NE than those that reported a high level of social support ^[16]. One study reported that the combination of severe stress and low social support was related to a 9-fold increase in breast cancer incidence ^[17]. Depression may be under diagnosed and under treated in the cancer population as many of the symptoms of cancer can mimic that of depression, such as fatigue, insomnia and decreased appetite ^[15]. Therefore, screening for this condition should also be part of routine cancer care.

STRATEGIES FOR STRESS MANAGEMENT

CHAMOMILE

The use of chamomile extract as an herbal remedy dates back to ancient times, mainly for its calming effect. It is a highly effective herb, and also has a high safety profile. In a recent study on the effects of using chamomile extract in anxious individuals, often with co-morbid depressive disorder, results showed statistically significant reduction of symptoms ^[18]. While this study did in fact look at DSM-IV diagnosed generalized anxiety disorder (GAD), and not just stress per se, many of the diagnostic criteria required for GAD arguably are symptoms experienced by chronically stressed individuals. Another reason chamomile should be considered for use for stress reduction is its effect on modulating NE and reducing stress induced increases in HPA activity ^[19]. It also acts as an anti-inflammatory and anti-oxidant ^[20].

ACUPUNCTURE

Acupuncture is a widely used complementary medicine tool, and those reporting increased levels of anxiety, depression and stress are more likely to utilize this therapy due to dissatisfaction with usual care ^[21]. A study of 102 patients exhibiting psychological stress in a primary care setting were treated with acupuncture weekly for 8 weeks, and compared to conventional treatment. Patients treated with acupuncture reported less distress than the control group, and these results were maintained at 6 month follow up ^[22]. Similar results have been reported among cancer patients, in that acupuncture helped to alleviate distress and helped improve quality of life ^[23]. In addition to its stress reduction qualities, a fascinating body of research exists with respect to the effects that acupuncture has on the immune system. A recent pilot study reported that after the application of needles to 5 acupuncture points, there was a statistically significant increase in a number of white blood cell subtypes, and a decrease in cancer related fatigue ^[24]. Many other studies have replicated this work, showing increased white blood cells and natural killer cells after weekly acupuncture treatments ^[25].

WITHANIA SOMNIFERA

Withania somnifera (WS), or more commonly known as Ashwaghanda, is an ayurvedic herb that is receiving a lot of attention with respect to its role in anxiety disorders, cancer and neurodegenerative disorders. It is classified as an anti-oxidant and anti-inflammatory. A recent systematic review reported on 5 human trials looking at anxiety and stress symptoms before and after treatment with an extract of WS. Scores on several scales, such as the Beck Anxiety Inventory and Perceived Stress Scale, improved, and the improvement was as much as 44% in one trial ^[26]. WS also contains compounds that possess anti-cancer properties, and while a discussion on its mechanisms is too vast a subject for the purposes of this article, it deserves mention that it contributes to apoptotis, interferes with the cell cycle, and modulates genes involved in the survival and death of cancer cells.

EXERCISE

There are hundreds, if not thousands, of research articles published on the benefits of exercise for stress reduction, and improvements in mood with respect to anxiety and depression. In addition to its effects on stress reduction, there are anti-cancer benefits as well. A recent regression study interviewed 2863 cancer survivors and found that those who participated in resistance training had a 33% lower risk of all cause mortality ^[27]. There are also hundreds of studies supporting the fact that exercise improves quality of life in cancer patients, as well as reduced cancer related symptoms. Potential biological mechanisms related to this are reductions in body mass, lowered circulating hormone levels, and increases in anti-tumour immunity.

CONCLUSION

The stress response, like cancer, is extremely complex. It cannot with any certainty be stated that inhibiting the stress response and lowering stress related hormones will prevent cancer, or treat it on its own. However, there is growing thought that cancer should be considered a chronic disease. Stress reduction is routinely prescribed for other chronic diseases, such as cardiovascular disease, and given the evidence discussed, there should be no reason why it shouldn’t be a routine part of an integrative cancer treatment plan.