Impact of Stress on the Progression and Recurrence of Cancer

Cancer consists of a large number of diseases where cells from a specific part of the body grow and reproduce uncontrollably, which end up infiltrating and destroying normal body tissue (MayoClinic, 2020). This uncontrollable growth and reproduction occur as a result of interference of the normal genetic process involved with cell growth and reproduction (Conquer Cancer: ASCO, 2020).

Each individual gene contains DNA which, in turn, contains a set of instructions on the functions of growth and reproduction of the cell. Errors in the instructions within the DNA can cause cells to stop its normal function and as a result, the cells start to divide and grow uncontrollably forming a mass called a tumour (MayoClinic, 2020). These genetic mutations can either instruct the cell to divide more rapidly than necessary; stop the cell from knowing when to stop growing and thus, grow rapidly; or make mistakes when fixing DNA errors, thus causing it to become cancerous (MayoClinic, 2020).

The cause of cancer is attributed to an interaction between genetic, environmental, and constitutional characteristics around an individual (Stanford Health Care, 2020). These characteristics tend to be ‘activated’ due to repeated exposure to risk factors, which may not necessarily cause the cancer, but increase the chances of getting cancer (Conquer Cancer: ASCO, 2020). Some of these include genetics, age, lifestyle choices, existing medical conditions, and exposure to certain carcinogens in one’s environment (Stanford Health Care, 2020). While some risk factors such as genetics and age are uncontrollable, others such as lifestyle choices and exposure to carcinogens can be manipulated to reduce as much risk as possible.

Cancer is classified into different types based on the origin of the growth: carcinoma, sarcoma, mylenoma, leukemia, and lymphoma. Carcinomas begin in the skin or tissues that line the internal organs, and account for 80 to 90 percent of all cancer cases (National Cancer Institute, n.d.). Sarcomas develop in the supportive and connective tissues such bones, cartilage, fat, muscle or other connective tissues (Conquer Cancer: ASCO, 2020). Mylenoma begins in the plasma cells of bone marrow (National Cancer Institute, n.d.). Leukemia begins in the blood and bone marrow. Lymphomas start in the lymphatic system (Conquer Cancer: ASCO, 2020).

Cancer is a major public health issue around the world. GLOBOCAN statistics show that in 2018, there were an estimated 18.1 million new cancer cases (17 million excluding skin cancer non-melanoma) and 9.6 million cancer deaths (9.5 million excluding skin cancer non-melanoma) worldwide (Ferlay et al., 2018). The most prevalent cancers worldwide include (in order) lung cancer, female breast cancer, prostate cancer, colorectal cancer, stomach cancer, and liver cancer (Bray et al., 2018).

This essay aims to provide an overview of the effect of chronic stress and surgical-related acute stress on the progression and recurrence of cancer by critically exploring the evidence proposing the implications for cancer management.

This shall be done by drawing upon a small amount of literature investigating the link between chronic and surgical-related stress and progression and recurrence of cancer and providing a deeper understanding of the significant role stress plays in the development and recurrence of the disease and suggest ways in which cancer induced stress can be managed.

Stress and Allostatic Load

Stress can be defined as “a threat, real or implied, to the psychological or physiological integrity of an individual” (McEwen, 2000). It is a common aspect in life and significantly impacts the development and maintenance of health conditions and diseases (Kudielka & Kirschbaum, 2001). There are two types of stress: acute stress which tends to be short-lived and/or chronic stress which occurs over an extended time period (Segerstrom & Miller, 2004). Under chronic stress conditions, the body remains in a constant state of ‘overdrive’, with detrimental effects on regulation of stress response systems, as well as many organ systems (Moreno-Smith et al., 2010).

While the current literature contains many different definitions of stress and theories and frameworks attached to the concept of stress, this paper will focus on the work on Hans Selye (1907–1983) who is credited for bringing the concept of stress into medical discussions.

Selye’s general adaptation syndrome entails of an enlargement of the adrenal gland; atrophy of the thymus, spleen and other lymphoid tissue; and gastric ulcerations (Neylan, 1998). It proposes a three-stage pattern of response to stress: the alarm stage, the resistance stage, and the exhaustion stage (McEwen, 2005). During the alarm reaction stage, the adrenal medulla releases epinephrine and the adrenal cortex produces glucocorticoids, thus starting to restore homeostasis (Selye, 1950). This stage is characterized by a significant increase of the hypothalamic-pituitary-adrenal (HPA) axis activity (Ganzel et al., 2010). Restoration of biological responses to the stressor, i.e., homeostasis leads to the resistance stage where defense and adaptation are sustained, overt symptoms of stress decrease, or disappear, and body function is optimal (Ganzel et al., 2010), (Selye, 1950). The exhaustion stage only follows if the stressor persists and physiological defenses are exhausted whereby the overt symptoms will reappear (Ganzel et al., 2020). If there is no relief from the exhaustion stage, the consequences are illness and death (Selye, 1950).

More recent interpretations of Selye’s general adaptation syndrome have gone on to coin the term ‘allostatic state’ which occurs as a result of repeated exposure to stressors and, consequently, causes an imbalanced production of ‘stress hormones’ such as glucocorticoids and epinephrine (McEwen, 2005). Allostatic states can be prolonged for limited periods if food intake or stored energy such as fat can fuel the homeostatic mechanisms (McEwen & Wingfield, 2003). If the increased food intake continues, then symptoms of allostatic overload emerge (McEwen, 2005).

Allostatic load is defined as “the cost of chronic exposure to elevated or fluctuating endocrine or neural responses resulting from chronic or repeated challenges that the individual experiences as stressful” (Kudielka & Kirschbaum, 2001). Furthermore, if the additional load of stressors is ‘superimposed’, then allostatic load can increase significantly to become allostatic overload (McEwen, 2005). Simply put, allostatic load and allostatic overload, by extension, are the accumulative results of an allostatic state (McEwen, 2005).

Allostatic load and allostatic overload have negative effects to an individual’s predisposition to disease (McEwen, 2005). While the changes caused as a result of allostatic load and overload may be helpful in the short term, they have negative long-term consequences and/or costs for the individual, for example, prolonged high blood pressure causes wear and tear of the heart (Ganzel et al., 2010). In addition, allostatic load and overload could occur out of damage from the overproduction of the neurochemicals involved in the stress response, some of which are toxic, and through the enervation of stress response systems, as can occur in the immune system. This can bring about compromised immunocompetence in an individual, which is associated with higher levels of infection and vulnerability to cancer (Sapolsky & Donnelly, 1985). Increased load can also come through the inability to activate a particular stress response system, in which case other stress responses over-respond (McEwen, 1998).

Impact of Stress on the Progression of Cancer

Cancer progression is often collectively conceptualized and represented as a 'journey' in which a cell, with several possible intermediate steps along the way, evolves over time from a benign phenotype into an invasive or metastatic entity (Kumar & Weaver, 2009). The relationship between the cell's biophysical properties and the Extracellular Matrix (ECM) creates a complex mechanical reciprocity between the cell and the ECM in which the capacity of the cell to exert contractile stresses against the extracellular environment matches the ECM's elastic resistance to this deformation (Lelievre et al., 1998).

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A possible correlation between stress and cancer progression is dependent on a theoretical cancer biobehavioral model (Costanzo et al., 2011). Stress perception stimulates the HPA axis and SNS, which can modulate cellular immune responses that can interrupt tumor surveillance and containment physiological processes, which can in turn promote tumor progression or recurrence (Todd et al., 2014).

Cellular immune indices, including natural killer (NK) and cytotoxic T lymphocyte (CTL) function, and macrophage motility and phagocytosis have been documented to be suppressed by psychological stress (Neeman & Ben-Eliyahu, 2013). In animal models, stress hormones, specifically catecholamines, opioids and glucocorticoids, have been repeatedly demonstrated to cause metastatic progression through different immunological and non-immunological mechanisms (Benish et al., 2008). In fact, in animals, it has been shown that even a single exposure to stress or stress hormones could increase cancer mortality during a crucial period of tumor progression (Inbar et al., 2011).

In addition, preclinical experimental studies have shown that substantial surgical-related acute stress also promotes tumor incidence and progression by suppressing the activities of natural killer (NK) and T cells, impairing the presentation of antigen, and improving the presence of T regulatory cells (Ben-Eliyahu et al., 1999).

There is strong existing evidence in support for links between psychological factors such as stress, depression and social isolation and cancer progression (Moreno-Smith et al., 2010). In addition, several researchers have studied the relationships between stress and cancers, such as prostate, breast, gastric, lung, and skin cancer, and have found evidence that chronic stress can cause tumorigenesis and promote cancer growth (Dai et al., 2020).

While the high prevalence of depression among cancer patients has been widely believed to be a reaction to the stress associated with a life-threatening diagnosis and cancer care (Spiegel & Giese-Davis, 2003), it has been hypothesized that inflammatory processes created secondary to treatment or tumor growth may contribute to depression pathogenesis, as well as fatigue and debilitation (Costanzo et al., 2011).

Inflammation, primarily known to confront and eliminate pathogens, is a protective response. It fulfils two corresponding functions, countering infection and promoting the growth of tissue, best evident in wound healing (Pribluda et al., 2013).

Notably, there is a relationship between inflammation and tumor progression which has been extended by recent data (Pribdula et al., 2013). There are many cancers that arise from infection sites, chronic irritation and inflammation. The tumor microenvironment, which is largely orchestrated by inflammatory cells, is now becoming apparent as an essential participant in the neoplastic process, promoting proliferation, survival and migration (Coussens & Werb, 2002).

The expression of stress-related pro-inflammatory genes in the circulating white blood cells can be increased by chronic stress and stress hormones, thus increasing the release of pro-inflammatory cells and the production of pro-inflammatory cytokines, and can activate the ageing-inflammatory response without triggering exogenous inflammation, leading to tumorigenesis promotion and metastasis (Bondar & Medzhitov, 2013).

While inflammation is emerging as one of the cancer characteristics (Hanahan and Weinberg, 2011), its role is not well understood in most tumors. Only a minority of solid tumors are associated with overt inflammation (Coussens & Werb, 2002), but long-term non-steroidal anti-inflammatory drugs (NSAID) treatment is remarkably effective in reducing mouse model intestinal tumorigenesis (Beazer-Barclay et al., 1996) and major human solid tumor-related mortality rates by up to 75% (Burn et al., 2011).

Impact of Stress on the Recurrence of Cancer

Stressor exposure has long been assumed to play a role in tumor activity recurrence. Psychological distress is an often-overlooked additional perioperative risk factor for cancer recurrence: starting with cancer diagnosis, patients experience anxiety, stress, and depression throughout and after surgical and adjuvant treatments, which translates, among other things, to activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis (Thornton et al., 2010) and thus resulting in the release of stress hormones.

Survivors frequently report recurrent physical health problems, including fatigue and pain, irrespective of the form of cancer. Physical side effects of cancer and/or its treatment collectively represent a psychosocial strain on survivors that may seriously affect the mental health of survivors (Hall et al., 2016).

Somatic symptoms can affect psychosocial stress through patient cognitive evaluations of stimuli related to cancer diagnosis, care, and survivorship, according to biopsychosocial models of cancer distress (Osborn et al., 2006). These cognitions include interpretations, judgments, and opinions about events or signs related to cancer. Fear of recurrence or development is topmost among these, with moderate to high levels present in 30–70% of cancer survivors (Savard & Ivers, 2013). A clinical study by Simard et al. (2010) examining whether fear of recurrence or progression is an intermediate between the intensity of somatic symptoms and perceived stress among survivors of heterogeneous cancer found that cancer survivors with moderate to high levels of fear of recurrence or progression reported elevated levels of stress.

Even though some researchers have suggested that exposure to psychological stressors plays a greater role in cancer recurrence than the incidence of cancer, Costanzo et al.’s (2011) review of literature found that there is insufficient evidence at this time to conclude that there is a causal association between stressor exposure and/or stress response and cancer recurrence. The review suggests that further study is needed before any final conclusions can be drawn. Furthermore, it recommends that, based on the possibility of a relationship between stress and recurrence, cancer survivors should be advised to maintain a reasonable level of tension in their lives and be encouraged to use evidence-based therapies to relieve psychological stress (Costanzo et al., 2011).

Conclusion

In summary, the current research body offers clear evidence that chronic stress and surgical-related acute stress, and mechanisms of stress response, are correlated with key elements involved in the growth and development of tumors, cancer progression and recurrence. However, this premise is based on empirical findings in animal studies, and on indirect evidence and argumentations based on findings from human studies. It is recommended that more findings around the relationship between stress (chronic stress and surgical-related acute stress) and the growth and development of tumors, cancer progression and recurrence be derived from more direct evidence from human studies.

Furthermore, current literature primarily contains information on the relationship between stress and cancer progression and recurrence for prostate, breast, gastric, lung, and skin cancers, but has inadequate information on other forms and types of cancers. Thus, in order to assess if there could be a proper association between stress and the type of cancer, treatment exposures, stressors, stress response, and recurrence, future research should concentrate on several more types of cancers.