Chronic stress, via activation of the HPA axis, results in the release of various mediators that can suppress some of the non-specific and specific parts of the immune response including NK-cell activity, phagocytosis, production of inflammatory cytokines (e.g. IL-2, interferon, TNF by Th1 cells) and activity of cytotoxic T cells, all of which are important components of the cancer surveillance and the immune response against cancer [68, 99]. Psychological stress also reduces the ability of cells to initiate genetically programmed cancer cell death [116].

Chemical messengers secreted by nerve cells, endocrine organs or immune cells mediate the communication between the central nervous system (CNS) and the immune system, and psychological stress can down-regulate various parts of the cellular immune response, disrupting these communication networks between the CNS and immune system [99]. Bio-behavioural oncology research has found that stress can not only down-regulate the cellular immune response (mediated largely by adrenergic and glucocorticoid signalling) but that it can also affect tumor angiogenesis, invasion and anoikis, stromal cells in the tumor microenvironment and inflammation, all pathways involved in cancer [68].

Interventions that reduce psychological distress have been found to create changes at the cellular level, for example, significantly increasing the percentage of large granular lymphocytes and increasing NK cytotoxic activity in patients with malignant melanoma [31].

There is strong evidence that chronic inflammation precedes tumorigenesis [59] and that the stress response and inflammation play an important role in the pathogenesis of cancer metastasis [68, 91]. Chronic stress can lead to inflammation through the production of cytokines, including interleukins [68, 99]. People with major depression have been found to have increased production of pro-inflammatory cytokines interleukin 1, interleukin 6, soluble interleukin 2 and interleukin 6 receptors, suggesting that concentrations of pro-inflammatory cytokines correlate with HPA activity and disease severity [99]. Stress increases the level of cytokines such as Vascular Endothelial Growth Factor (VEGF), a cytokine which mediates angiogenesis and cancer patients with high levels of VEGF have a poorer prognosis [45]. Cytokines can also stimulate tumor growth [45].

Stress and depression can alter the functioning of the endocrine system, leading to increased insulin secretion from the pancreas, increased cortisol, growth hormone and prolactin, which can contribute to increased tumor growth [56]. Neuroendocrine stress hormones, released via the brain, sympathetic nervous system and/or HPA axis, in the tumor microenvironment assert a systemic influence on tumor growth [68]. High cortisol levels (and a tendency towards flatter diurnal cortisol rhythms) have been found to be associated with greater disease severity in women with metastatic breast cancer [1]. Other research in women with early metastatic breast cancer found that women who repressed emotions and those who were highly anxious had a significantly flatter diurnal cortisol slope than self-assured and non-extreme groups, though there was no difference in mean cortisol levels [36].

In patients with depression, cortisol was found to be increased in those who were chronically stressed, suggesting that depression is associated with sensitisation of the HPA axis to chronic stress [110]. As previously stated, depression affects a significant proportion of cancer patients [22, 46 and 64].

Corticotropin-releasing factor (CRF) is a hypothalamic neuropeptide that is involved in the control of the stress response. It is also expressed in organs and peripheral tissues [6]. In the tumor microenvironment, it may be produced by innervating sympathetic neurons, immune cells and endothelial cells [5, 6]. CRF has been found in breast cancer cells and tissue and can affect breast cancer cells in an autocrine or paracrine manner [5]. Research has found that CRF stimulates cell motility and invasiveness of breast cancer cells, and that the likely mechanism is via induction of Focal Adhesion Kinase (FAK) phosphorylation and the reorganisation of actin filaments and the production of prostaglandins: CRF induces the production of prostaglandins and expression of Cox-1 in breast cancer cells, which are factors that can promote invasiveness and metastasis [5]. In vitro, research has found that CRF can induce the expression of genes involved in breast cancer proliferation and metastases. In vivo, research has also demonstrated that peripheral CRF at least partly mediates the tumor-promoting effects of stress (including neoangiogenesis and tumor growth) [6].

Stress can lead to DNA damage, accumulation of somatic mutations, impaired genetic mutation repair and inhibition of apoptosis [39, 50, 99]. In human studies, perceived psychological stress and perception of inability to alleviate stress have both been found to be associated with increased levels of 8-hydroxydeoxyguanosine (8-OH-dG), a biomarker of cancer-related oxidative DNA damage, in females but interestingly not in males [50]. In healthy workers, the levels of 8-OH-dG were higher in females with poor stress-coping behaviours and in males with a self-blame coping strategy [51].

The gut microbiome is now understood to play a critical role in the functioning of the immune system, thereby influencing inflammation, as well as the nervous system [93]. The gut microbiome plays a key role in regulating intestinal permeability and maintaining the intestinal barrier function and deficits in intestinal permeability may be a causal factor in the chronic low-grade inflammation observed in depression [54]. A U.S. study found that major depression is accompanied by activation of the inflammatory response system and that pro-inflammatory cytokines and lipopolysaccharide (LPS) may induce depressive symptoms—a significant increase in level of antibodies against LPS in the blood was found in those with major depression [71]. LPS, the major component of the outer membrane of certain bacteria, is able to enter the bloodstream only if the normally tight junctions in the cells lining the intestine are compromised and the intestine lining becomes permeable or ‘leaky’ [93]. It can then fuel inflammation. Inflammation is a key component of many chronic diseases including cancer.

The gut microbiome has been found to affect neural, immunological and endocrine systems, with the microbiome-gut-brain axis modulating emotions and moods. Stress is able to modulate the microbiota and the microbiota is able to alter the set point for stress sensitivity [106]. The gut microbiota generates several neurotransmitters including gamma-aminobutyric acid (GABA), acetylcholine, dopamine, norepinephrine and serotonin [42]. Neurotransmitter imbalances or deficiencies are known to cause psychiatric problems such as depression [42]; altered GABA receptor expression is implicated in the pathogenesis of anxiety and depression (both of which are associated with functional bowel problems) [15]. Depression has been found to be associated with dysregulation of the gut microbiota composition [106].

Animal research demonstrates clear links between the gut microbiome and stress/anxiety/depression as well as changes in the brain. This includes findings that the gut microbiota can modulate the blood-brain barrier [54]. How translatable such findings are to humans in understanding brain-gut relationships and disorders is not yet known [72, 73]. Some key findings from pre-clinical (animal) research are set out in Table 2.3.

The relationship between the gut microbiome and emotions and stress is an important and complex one. However, there is increasing evidence that the gut microbiome and brain, immune and endocrine systems are all in constant communication, and the gut microbiome is a key player in the stress response. And the storage of emotions and stress is closely linked to the pathogenesis of cancer.

Disturbances of the anatomical barriers between the host and microbes can also promote inflammation and diseases including cancer. The relationship is bidirectional: barrier failure can trigger inflammation, and inflammation and carcinogenesis can promote barrier failure [105]. These are but a few of the potential pathways of involvement of the microbiota; the mechanisms involved in carcinogenesis are complex. The reader is referred to other sources for a more complete explanation.

Obesity, a major modifiable risk factor for the development of many types of cancer, is associated with microbiotal dysbiosis which may result in several physiological changes that could contribute to the link between obesity and cancer. These include altered microbial metabolism that can contribute to the generation of pro-carcinogenic toxic metabolites, induction of subclinical inflammation that could initiate tumor formation, and/or increased extraction of energy and nutrient availability causing metabolic dysregulation, thereby contributing to tumor growth [101].

The gut microbiome, of course, undergoes quite a beating during chemotherapy, with a severe compositional and functional imbalance in the gut microbiome associated with chemotherapy-induced mucositis [77]. Research has established that over the course of chemotherapy, there is a significant decrease in oral and intestinal microbial diversity and an increase in specific microorganisms known to cause infection [4]. A patient’s microbial diversity, even prior to cancer treatment, can be linked to increased risk of infection during induction chemotherapy. Thus researchers have suggested that microbiome sampling could be used to predict the chance of infections during chemotherapy, and that monitoring a patient’s microbiome during induction chemotherapy could be used to predict risk of microbial-related illness during subsequent treatments [4]. A depleted gut microbiome following chemotherapy leaves the patient with a greater risk of future illness.

Suffice to say, the gut microbiome is an important player in the pathogenesis of cancer. Given its role in influencing the immune, nervous and endocrine systems, including its role in depression which often coexists in cancer sufferers, addressing any imbalance in the gut will be important.

The good news is that research indicates that social support can positively influence cancer survival, discussed in the later sections of this chapter.

The language the clinician uses is most important. At the very outset, it is important to remember this is a person with cancer you are talking to, and the cancer is part of them, it originated due to imbalance within them, and it is a reflection of what is happening within them as a person. The cancer is not a separate, external entity and therefore ‘it’ cannot be ‘aggressive’ (as compared with an external infectious organism which could be described as aggressive). In the world of oncology, cancer is treated almost like a separate, external entity to be removed, poisoned or irradiated. This type of thinking may have evolved from the world of infectious diseases where microbes were the infectious agent, the enemy to be gotten rid of. The language that has evolved around this still positions cancer as something separate and unfortunately, the focus of many oncologists is on the disease, the tumor, the cells and not the human being.

To open up the conversation about stresses in the patient’s life, Professor Sali typically begins with handing the patient a diagram such as the one in Fig. 2.1 that sets out in diagram form the relationship between the mind/stress/depression and the immune system, the endocrine system and the gut microbiome. He explains the different components involved in the stress response, including the link between the mind and storage of emotions and stress and the link between the mind/depression/nervous system and the immune system, endocrine system and the gut. Professor Sali elaborates on the concept of storage of emotions and stress, and how one can, by relieving some of the stresses in one’s life, positively influence health (via those afore-mentioned interdependent systems).

At this point, the clinician needs to sit back and listen, and simply prompt the patient to consider and talk about what difficulties they might be facing. This part of the consultation is critical, and in many ways facilitates a feeling, by the patient, of being heard and understood. Therefore, do not rush this part of the consultation—there is plenty of time for you to impart your knowledge. Listen carefully and you will be able to pick up important clues.

In discussing the link between mind/emotions and the body, it is important that the patient is not left feeling in some way guilty or anxious that they have somehow brought the cancer on themselves or ‘drawn’ cancer to them, for example, through negative thinking or actions. This is simply neither the case nor helpful to the patient. The power of the mind to positively impact on various pathophysiological pathways should be emphasised, as should how they can be proactive in changing the status quo—this is about empowering positive change through the power of the mind.

The discussion on storage of stress and emotions then leads onto a discussion on how the patient can help themselves by decreasing the storage of stress and emotions: by ‘unloading storage’.

Unloading of stress and emotions is important in the prevention of illness, including cancer, and as part of a therapeutic approach. Social support and its role in unloading are extremely important. The disadvantages of poor social support have been discussed in the previous section. Therefore, the clinician should probe whether the cancer patient has social avenues for unloading in their personal life. If not, then there are professional options including working with a psychologist, cancer support groups, and other therapists. And there are other ways to unload stress and emotions, discussed later in this chapter.

The conversation about stress is not a one-off conversation. It should be an ongoing dialogue over subsequent conversations, and an opportunity to check in with how the patient is doing.

Some things to look out for in consultations include symptoms and signs of:

During the initial and subsequent consultations, the clinician will need to be sensitive to the level of anxiety that the patient is likely to be experiencing, particularly on initial diagnosis but also at other time points. For example, following surgery, chemotherapy or radiation therapy, a patient will likely be extremely anxious about follow-up pathology results. Where results are not positive, or where the symptoms and signs associated with the cancer or cancer treatment are impacting physically on the patient, anxiety and depression can compound an already extremely difficult experience.

As we learned earlier, depression can also influence lifestyle factors that may negatively impact on health including smoking, consuming an excess of alcohol, lack of physical activity and excess weight [45]. So it is good to question the patient about their smoking status/habits, alcohol consumption and other lifestyle factors and gently probe to see if they are leaning on any of these as a crutch; lack of or a decrease in physical activity and increase in weight gain in someone who has previously indicated they were active may give some clues as to their current state of mind.

An integrative medicine approach will encourage the patient to explore various treatment options to help them with their anxiety and depression. For example, a timely referral to a psychologist or counsellor or a cancer support group may assist the patient work through and cope with anxiety and/or depression. At the very least, how the experience of cancer is impacting on the patient emotionally should be discussed with the patient at each consultation. The emotional aspects of what the patient with cancer and their loved ones are facing are critical to address, as the patient has much to gain if they can use their mind positively to impact their health. There is enough research to demonstrate how anxiety and depression can negatively impact on the body, creating in some ways a negative spiral.

As humans, we have many things in common. One is that most humans seek happiness. It is an important goal to pursue. The fourteenth Dalai Lama says:

Whether one believes in religion or not, whether one believes in this religion or that religion, the very purpose of our life is happiness, the very motion of our life is toward happiness (His Holiness the Dalai Lama and Cutler [21]).

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