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Parasympathetic nervous system and cancer
at 30.12.2021Kevin Tracey, a well-known American neurosurgeon and inventor who was deeply affected by his mother's illness and early death as a child, deduced from this experience that "the brain and nerves are responsible for our health." He would later learn that there was a link between inflammation in the brain and inflammation in the body. It was previously assumed that there is no interference between immune system specialized cells, blood flow, and nervous system electrical connections. Instead, Tracey discovers that the two systems are intricately intertwined.
As a result, the nervous system plays a critical role in the emergence and progression of cancer [1]. The interdependence of nerves and cancer cells has been well established in many cancers, including pancreatic, prostate, breast, head and neck, and cholangiocarcinoma. Several research teams have attempted to answer essential questions based on this discovery, such as the influence of neoactive molecules on cancers, the role of different nerves in the appearance and development of cancer, and how the interdependence between cancers and nerves occurs. In addition, technological advances in nerve imaging have resulted in a greater understanding of the molecular mechanisms underlying the interaction of various types of cancer and nerves.
When a patient learns that he has cancer, he typically exhibits a complex psychological response, characterized by a great deal of negative stress, which aggravates his condition. Concerns about possible death and other negative consequences, such as job loss, loss of income, and loss of independence, cause stress and anxiety [17], which leads to sympathetic hyperactivation and vagal tone reduction, complicating the therapeutic process. In addition, there is now disease-specific pain and cachexia. Thornton et al., for example, discovered a link between plasma levels of epinephrine, norepinephrine, and cortisol, on the one hand, and pain, depression, and fatigue measures in women with breast cancer, on the other hand [18]. Furthermore, patients with metastatic cancer have significantly higher plasma cortisol levels than non-metastatic patients [19]. Malnutrition patients have elevated epinephrine, norepinephrine, and cortisol levels in their urine [20]. A meta-analysis published recently by Kim et al. suggests that psychological stress reduces heart rate variability [21]. Furthermore, health self-assessment reports, which reflect mental and physical health, show lower heart rate variability, which is also associated with poorer health [22]. As a result, heart rate variability reflects the body's overall state, and this marker allows us to assess the current balance of the autonomic nervous system. Furthermore, as previously stated, the parasympathetic and sympathetic nervous systems influence each other. As a result, because so many factors influence the heart rate variability, its changes cannot be used as an accurate indicator of the progression of the oncological disease.
On the other hand, the role of the parasympathetic nervous system, which is responsible for digestion, relaxation, and healing, in the emergence and progression of cancer is less clear. Its precise role in various cancers is still unknown. However, the available data suggest that the parasympathetic nervous system influences tumor progression both locally and systemically. Depending on the type of cancer and the receptors expressed in the cancer microenvironment, parasympathetic nerve fibers' local and systemic effects may potentiate or inhibit cancer progression. Furthermore, the results of experiments involving sub-diaphragmatic vagotomy must be carefully interpreted because, after this surgery, the sympathetic system is activated, which leads to cancer progression.
According to some research, as measured by heart rate variability, vagus nerve activity may play a prognostic role in cancer. Several authors have reported that in a large sample of patients with various types of cancer, patients with low heart rate variability had shorter survival times [23] [24]. As a result, some authors believe that vagal nerve stimulation positively affects tumor progression via an anti-inflammatory effect [25] [26]. As a result, based on Tracey et al.'s anti-inflammatory pathway, it is assumed that the decrease in the level of the inflammatory marker is due to increased vagal nerve activity, increasing the chances of survival.
However, if one assumes that changing heart rate variability reflects tumor progression, this concept may be incorrect. In several types of tumors, serum levels of pro-inflammatory cytokines have been shown to correlate with the disease stage. IL-6 levels, in particular, are associated with patient survival [27] [28] [29], as long as service IL-6 levels rise with tumor stage. In addition, many epidemiological studies currently suggest a negative relationship between plasma IL-6 and HRV in various clinical conditions [30] [31] [32].
The ambiguity of the findings regarding the effect of the parasympathetic nervous system on the onset and progression of cancer is most likely due to interactions between the sympathetic and parasympathetic nervous systems. The impact of the sympathetic and parasympathetic nervous systems on innervated tissues is hugely complex. These effects are based on the anatomical and functional characteristics of these divisions of the autonomic nervous system:
1. Some tissues are innervated by both the parasympathetic and sympathetic nervous systems, while others are only innervated by the sympathetic nerves.
2. Activation of the parasympathetic nerves induces the opposite effects as sympathetic nerve activation.
3. Activation of the parasympathetic nerves potentiates the effects of the sympathetic nerves.
4. Epinephrine and norepinephrine released from the adrenal medulla may also affect tissues not innervated by the autonomic nerves.
Thus, a better understanding of the autonomic nervous system's functioning can provide appropriate treatment for cancer prevention and therapy, identifying patients at risk for life-threatening complications, such as those with changes in the cardiovascular reflex or some paraneoplastic manifestations, contributing to the improvement of patients' care and, as a result, their quality of life.
[1] https ://doi.org/10.1158/2159-8290.CD-18-1398
[2] https://doi.org/10.1007/s12094-020-02465-w
[3]https ://doi.org/10.1016/j.psyne uen.2007.02.013
[4] https://www.nature.com/articles/ncomms2413
[5] https://link.springer.com/article/10.1007%2Fs10549-010-0822-2
[6] https://www.sciencedirect.com/science/article/abs/pii/S0889159116304044?via%3Dihub
[7]https://www.frontiersin.org/articles/10.3389/fimmu.2018.00164/full
[8]https://www.sciencedirect.com/science/article/abs/pii/S0889159108003899?via%3Dihub
[9] https://link.springer.com/article/10.1007%2Fs00432-016-2278-1
[10]https://www.jbc.org/article/S0021-9258(20)63710-3/fulltext
[11]https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.25589
[12] https://www.oncotarget.com/article/17267/text/
[13] https://www.nature.com/articles/ncomms10634
[14]https://cancerres.aacrjournals.org/content/66/21/10357
[15]https://clincancerres.aacrjournals.org/content/12/2/369
[16]https://cancerres.aacrjournals.org/content/70/18/7042
[17] https://academic.oup.com/biomedgerontology/article/58/1/M82/582413
[18]https://doi.apa.org/doiLanding?doi=10.1037%2Fa0018836
[19]https://link.springer.com/article/10.1007%2FBF00964585
[20]https://journals.lww.com/annalsofsurgery/Abstract/1988/11000/Increased_Urinary_Excretion_of_Cortisol_and.17.aspx
[21]https://www.psychiatryinvestigation.org/journal/view.php?doi=10.30773/pi.2017.08.17
[22]https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117196
[23] https://www.sciencedirect.com/science/article/abs/pii/S0022399916303701?via%3Dihub
[24]https://www.frontiersin.org/articles/10.3389/fphys.2018.00623/full
[25]https://www.sciencedirect.com/science/article/abs/pii/S0165247818301937?via%3Dihub
[26] https://www.hindawi.com/journals/jo/2018/1236787/
[27] https://www.advances.umed.wroc.pl/en/article/2017/26/3/421/
[28]https://www.tandfonline.com/doi/full/10.1080/2162402X.2015.1093722
[29] Nakashima J, Tachibana M, Horiguchi Y, Oya M, Ohigashi T, Asakura H, et al. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res. 2000;6(7):2702–6.
[30]https://www.sciencedirect.com/science/article/abs/pii/S0306453008002126?via%3Dihub
[31]https://journals.lww.com/psychosomaticmedicine/Abstract/2007/10000/Stimulated_Production_of_Proinflammatory_Cytokines.1.aspx
[32] https://journals.physiology.org/doi/full/10.1152/ajpgi.90488.2008
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