Stress receptor spreads breast cancer - Review

Stress is known to cause the production of neuropeptides in the brain and microbiome, stimulating hormones that turn on Cox-2 pathways and increase metastasis; research shows neurotransmitters also directly stimulate growth and migration of cancer cells in women with breast cancer; a short review of the ways stress may drive cancer.

Stress - known to alter metabolic function

Stress is well known to induce hyperglycemia in the body (1). This increase in blood sugar levels can prompt insulin resistance, lowered insulin production and even lead to diabetes. Higher blood sugar damages the immune system - as one expert described it, 'putting it into a state of shock'. Higher blood sugar levels promote inflammation throughout the body via the Cox-2 pathway. This can increase the risk of autoimmune diseases (2). Stress thus promotes metabolic syndrome.

Stress alters the gut microbiome

It is well known that high blood sugar levels can alter the composition of the gut microbiome and that there is a gut/brain axis. At the 2016 Neurobiology of Stress Workshop in Newport Beach, CA, a group of experts presented the symposium "The Microbiome: Development, Stress, and Disease". 

Members of the gut microbiota can synthesize neurotransmitters, e.g., Lactobacilli and Bifidobacteria produce GABA; Escherichia coli produce serotonin and dopamine; Lactobacilli produce acetylcholine. They signal the brain via the vagus nerve. And the majority of neurotransmitters can be found in the GI tract. It's a two way process. Stress lowers the pH of the gut (i.e. increases acidity) and stress, especially in early life, can damage the microbiome affecting overall health (3)

Stress can cause and spread cancer

So, stress is known to damage the microbiome by altering the pH and decreasing the growth and replication of commensal bacteria. Stress is also no known to increase blood sugar levels. And several studies have now shown how stress turns on the production of neuropeptides which not only cause inflammation in the body through the Cox-2 pathway, they can actually stimulate cancer cells. Stress has also been shown to reduce white cell levels.

Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line

Published online in the International Journal of Cancer, research from scientists at The University of Western Ontario (4) in 2011 showed that stress neurotransmitters could stimulate the growth and progression of breast cancer cells.

Studying a branch of the nervous system called the sympathetic nervous system, which talks to cells in various organs throughout the body, they found that when the sympathetic nervous system is activated during times of stress, it communicates with receptors on cells through the release of neurotransmitters called Norepinephrine and Neuropeptide Y or NPY. This is a normal response that prepares the body for fight or flight. In this case, Dwayne Jackson of the Departments of Medical Biophysics and Biomedical Engineering and the team showed that the neurotransmitter directly stimulated cancer cell growth and migration in breast cancer.

"Since there is a very dense supply of sympathetic nerves in the female breast, it would be reasonable to suspect that NPY may be released in greater amounts in the breasts of those at risk for breast cancer. Thus, we postulated if cancer cells are present and they respond to NPY, then this neuropeptide and its receptors would form a functional link between stress and breast cancer progression.

Once we had established that breast cancer cells express the receptors for NPY, then we went through a set of experiments that looked at the functional consequences of activating them. We found NPY greatly accelerates cell growth as well as cell migration and these are two important steps in primary tumour growth, as well as in metastasis," concluded the researchers.

Psychological stress link to breast cancer

A systematic review of studies between 1966 and 2016, revealed that there was a total of 1813 studies on stress and breast cancer occurrence! From this, 52 studies were eligible for the review and these covered 29,000 women. This was not a meta-analysis but did show an association between stress and cancer, especially regarding stressful life events (5).

Stress can reawaken dormant cancer cells

2019 research (6) showed that Catecholamines, which are released by sympathetic nerves under the influence of stress can activate receptors present on nearly every cell type, including cancer suppressor cells. In mice, this caused dormant cancer cells to reawaken.  The study also showed that stress hormones can increase the number of pro-tumor immune cells in tumors. That could mean that stress not only wakes up dormant tumor cells but also provides the right environment for them to grow.

But there may be other ways stress prompts dormant cells to reawaken. A 2020 study (7) showed that stress hormones can cause a rapid release of proinflammatory S100 proteins by neutrophils. Neutrophils are normally an essential part of your innate immune system.  However, under the effects of stress, S100 can then cause activation of myeloperoxidase, resulting in accumulation of oxidized lipids in dormant lung and ovarian cells. This then reawakens the dormant cells and can cause early reccurence..

Chris Woollams, former Oxford University Biochemist and founder of CANCERactive added, "You can go back to John Vane, who won a Nobel Prize and a knighthood in 1982 for his work on eicosanoids and prostaglandins - he showed clearly back then that both insulin and stress hormones like cortisol, turned on the production of inflammatory enzymes via the Cox-2 system; and this inflammation helped cancer to spread. The issue now is if stress can make my cancer worse, can a positive mindset also heal me?"

Go to: CANCERactive Stress Management Section - Stress Management aids cancer survival

******
References

1. Stress-Induced Hyperglycemia: Consequences and Management; Deepanjali Vedantam et al; Cureus. 2022 Jul; 14(7): e26714.
2. The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming; Sophia M. Hochrein et al;  Cell Metabolism, 2022; DOI: 10.1016/j.cmet.2022.02.015
3. Stress gets into the belly: Early life stress and the gut microbiome; Liisa Hantsoo; Babette S Zemel; Behav Brain Res. 2021 Sep 24;414:113474.
4. Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line. Philip J. Medeiros, Baraa K. Al-Khazraji, Nicole M. Novielli, Lynne M. Postovit, Ann F. Chambers, Dwayne N. Jackson; Cancer Cell Biology, 05 August, 2011
5. Psychological stress and breast cancer incidence: a systematic review; VALENTINA-FINETA CHIRIAC, ADRIANA BABAN, and DAN L. DUMITRASCU; Clujul Med. 2018; 91(1): 18–26.
6. β2 adrenergic receptor–mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells; Hemn Mohammadpour,  Cameron R. MacDonald et al; J Clin Invest. 2019 Dec 2; 129(12): 5537–5552.
7. Reactivation of dormant tumor cells by modified lipids derived from stress-activated neutrophils; Michela Perego et al; ci Transl Med, 2020 Dec 2;12(572):