Stress and cancer

Author: Federica Boglione
Date: 13/06/2012



Stress can be defined as an intense emotional reaction to a series of external stimuli that mobilize physiological and psychological responses of adaptive nature. The body responds to stressful stimuli with a defensive reaction.The defensive reaction provides an alarm phase with biochemical changes, by a phase of resistance in which the body is organized and by a stage of exhaustion. Once you reach this stage, defenses and the ability to adapt again collapse. Stress is part of life, but in excess can alter the homeostasis of the organism.
Definition of stress, site of clinical psychiatry and dynamic psychotherapy 2008

Reaction to stress

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What happens in our bodies when we are subjected to stress is an alteration of biochemical and muscle.
The sympathetic nervous system sends impulses to the adrenal medulla, which in turn secretes epinephrine and norepinephrine in the bloodstream.
The pituitary produces the hormone ACTH, which in turn reaches the adrenal cortex and stimulates the production of cortisol.
These hormones spread throughout the body cause a series of reactions. The heart rate accelerates, the cardiac output increases, in response to the stressful situation. The supply of blood to muscles and brain increases so that in those districts arrive more oxygen and glucose. The breathing rate increases to provide the necessary oxygen to the heart, brain and muscles.
Sweating increases to eliminate toxic substances produced by the body and this process lowers the body temperature. Digestive secretions are drastically reduced, since the digestive activity tract is not essential to counteract stress. The concentration of sugar in the blood increases as the liver releases its reserve of glucose in the bloodstream.

What happens when we are subjected to a stress!

The neuroendocrine system

The adaptations to stress may be due to the activity of the neuroendocrine system (SNE). The main structure of the SNE is the hypothalamus that receives information from various brain areas and the periphery. The hypothalamus, in turn, projects numerous efferents, particularly to the pituitary gland, of which it controls the secretory activity and biological rhythms, and to the limbic areas. These are responsible for behavioral responses induced by stress.
The hypothalamic-pituitary-adrenal axis is the most important structure of the SNE. The SNE responds to stress by increasing the secretion of CFR, epinephrine, serotonin, GABA and glutamic acid. The CRF activates noradrenergic neurons and stimulates the secretion of pituitary ACTH.
The increase in blood levels of adrenaline and cortisol is very important because it involves a series of metabolic responses that serve to reduce the effects of stress. Ceased stress, hypercortisolism, through a mechanism of negative feedback on the hypothalamus and adenohypophysis, restores the balance. The activation of this cascade also influences several aspects of the behavior such as attention, memory, alertness, emotional tone. The hypothalamic pituitary adrenal axis has a circadian rhythm which is affected by changes induced by stress.
Even the immune system responds to stress by increasing the release of leukocytes,of several mediators, including cytokines. We cite in particular the interleukins (IL) 1,2 and 6, which regulate the immuneresponse and stimulate the synthesis of CRF and norepinephrine. The resulting increase of cortisol level in blood , however, in turn inhibits the gene expression of leukocyte interleukins.
Then in the acute response to stress, there is the stimulation of the immune system with increase of leukocytes, cytokines and other mediators of inflammation. In chronic stress, however, prolonged exposure to high levels of cortisol reduces the activity of lymphocytes T and B. Cortisol causes division of the suppressor cells. This rapid cell division increas the number of t suppressor cells while at the same time t helper cell are supressed. This reduces immune protection and leaves the body vulnerable to deseas.

The stress, trough the cortisol, induces transient TDO (tryptophan 2,3-dioxygenase). This enzyme mediates the catabolism of the tryptophan and the formation of kynurenine, that is immunosuppressive and simultaneously may induce mood alteration.
The kynurenine induces the synthesis of cytokines that have a final effect of immunosuppression.

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As well as neuropeptides, cytokines can influence the body temperature, sleep-wake cycle, the sexual behavior , mood, eating behavior and psychomotor performance.

Molecules and choice, neuropeptides 2006

Stress (physiologhy)wikipedia

Psychological Stress-Induced, IDO1-Dependent Tryptophan Catabolism: Implications on Immunosuppression in Mice and Humans,2010

The neuroendocrine system and the immune system in communication

A relationship exists between cortisol and immune system. The communication between the immune and neuroendocrine system has a double direction as the two systems influence each other; both are essential for their development and their functionality.
The removal of the thymus in a newborn mouse involves the development of various endocrine abnormalities of the apparatus. Similarly, a study shows that elevated levels of cortisol circulating conduct to rapid atrophy of the thymus. Several studies underline the importance of the neuroendocrine system in the induction of immune response.
Immune cells communicate with the SNE through several neuropeptides and neurohormones, such as CRF, ACTH , GH, TRH, prolactin, the B-endorphin; immune cells also possess specific membrane receptors, for these mediators and for the neurotransmitters such as adrenaline, serotonin, histamine, the gaba.
There is definitely a communication between the neuroendocrine system and the immune system, which allows the whole body to respond to external stimuli.
This works fine until the continuation of the external stimulus does not bring to light the negative aspects of this relationship.
Pathogenic action of chronic stress also plays an important role in the reduction of activity of the GABA receptor complex, whose function is to reduce the release of excitatory neurotransmitters noradrenaline, dopamine, serotonin, and glutamic acid. A reduction of GABA receptor function amplifies the responses of central excitatory systems to chronic stress.
When the body is subject to a state of chronic stress, its ability to respond and adapt fails. At some point, these conditions weaken his immune response.
The body becomes more vulnerable to infection, disease and development of diseases autoimmuni. Even if you need to consider that each of us reacts to these situations according to features and constitutional predisposition. Various experiments have brought to light the correlation between stress and reduced immune response.

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Pathophysiological relationship between the immune system and stress

The influence of the psyche and the brain on immunity and disease susceptibility:a critical review 1979

Cortisol, noradrenaline and VEGF in the ovarian cancer

A study has highlighted the effect of norepinephrine and cortisol levels on the VEGF. The study has considered the ovarian cancer. The results have pointed out that noradrenaline and cortisol can increase the levels of VEGF thus favoring the progression of the tumor.
This has been demonstrated by an experiment in which the ovarian tumor cells were stimulated by epinephrine and cortisol. What has been actually observed is that the values ​​of VEGF increased. Then it is assumed that the stimulation of the production of VEGF was mediated by beta-adrenergic receptors. Then was used a blocker of these receptors. Actually the values ​​of VEGF after stimulation did not grow more, unlike what happened instead previously.
VEGF expression was also analyzed in brown adipocytes. The adrenergic stimulation of VEGF expression in brown adipocytes is exclusively mediated by a β-adrenoreceptor/cAMP/PKA signaling pathway. The β-adrenoreceptor-induced increase in cAMP activates PKA, which in turn activates the Src tyrosine kinase-Erk1/2 MAP kinase signaling cascade. Src further mediates the signal to stimulate VEGF expression, independently of downstream mediation via Erk1/2.

Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines, 2003

Cancer research, the expression of the vascular endothelial growth factor 2006

Norepinephrine Induces Vascular Endothelial Growth Factor Gene Expression in Brown Adipocytes through a β-Adrenoreceptor/cAMP/Protein Kinase A Pathway Involving Src,2000

Stress and tumor of the skin

Now we go to tackle a study carried out to assess the relationship between stress and cancer, in this case a tumor of the skin.
In the study were examined two mice, one subjected to stressful stimuli, the other not subjected to these stimuli. The mice were then either exposed to ultraviolet light. The study would examine the onset and progression of skin cancer in both animals.
First of all, it was observed that in the stressed mice the developed tumors were very aggressive, while in the other group the tumors were less aggressive. The study was to analyze the development of hyperplasia, papilloma or invasive carcinomas.
In the second place it went to see any alterations of the molecules and cytokines with a protective role about tumor and of the molecules with a promoter role about the tumor. Have been investigated as protective molecules ccl27, IL- 12 and interferon gamma.
It was found that in mice subjected to stress, the levels of these cytokines were lower than the other group studied. On the contrary as regards instead the tumor-promoting molecules (CCL22, IL-10 and IL-4), which were higher in the first group (ie stressed mice).
After that, the study observed the immune cell infiltration in the tumor, considering the t helper lymphocytes and the cells T- reg , that control negatively the immune response . The tumors of the first group showed a low level of t-helper cells and a greater number of cells t-reg.
The tumors of the second group, instead, showed a greater number of T helper cells. This demonstrates that the immune response of two mice is different, poor in mice defined stressed, good in the others.
The study was then to investigate the relationship between the response to stress and the axis hypothalamus- pituitary- adrenal, measuring cortisol levels in the blood.
In the first group of mice, the levels were very high. But it was shown that not only the basal levels were higher but also the response to stressful events was excessive compared to the stimulus. Finally, it was also examined the VEGF, vascular endothelial growth factor which was found to be higher in the first studied group compared to the second group.

High-anxious individulas show increas chronic stress, burden, decreased protective immunity and increased cancer progression in a mouse model of squamos cell carcinoma 2012

About stress and cancer

Implications for stress-related enhancement of tumor progression,2009


In conclusion we can say that a state of chronic stress can affect the emergence of cancer, but especially its development, its growth and its spread.This is because stress reduces the ability of the immune system to defend the body against disease.
The relationship between stress and immune system exists, but it shall be evaluated within the context of individual, as each of us reacts differently to external events. It is clear that stress can promote tumor development more likely in people who already have a predisposition to it and may possibly affect its performance in different situations.

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