Putative role of non‐invasive vagus nerve stimulation in cancer pathology and immunotherapy: Can this be a hidden treasure, especially for the elderly?

Abstract Cancer is globally a disease of significant public health concern owing to its prevalence, and association with morbidity and mortality. Thus, cost‐effective treatments for cancer are important to help reduce its significant morbidity and mortality. However, the current therapeutic options for cancer such as chemotherapy, radiotherapy, and surgery may produce serious adverse events such as nausea, vomiting, fatigue, and peripheral neuropathy, especially in the long term. In addition, these therapeutic options may not be well tolerated by the elderly especially those who are frail. The current article is aimed at discussing an alternative therapeutic option, non‐invasive vagus nerve stimulation (VNS), and the roles it plays in cancer pathology and immunotherapy. The VNS does this by reducing oxidative stress via silent information regulator 1 (SIRT1); inhibiting inflammation via both hypothalamic–pituitary–axis (HPA) and the release of corticosteroid from the adrenal gland, and cholinergic anti‐inflammatory pathway (CAP), and increasing vagal activity which helps in the regulation of cell proliferation, differentiation, apoptosis, and metabolism, and increase chance of survival. Furthermore, it helps with reducing complications due to cancer or its treatments such as postoperative ileus and severity of peripheral neuropathy induced by chemotherapy, and improves cancer‐related fatigue, lymphopenia, and quality of life. These suggest that the importance of non‐invasive VNS in cancer pathology and immunotherapy cannot be overemphasized. Therefore, considering the safety of non‐invasive VNS and its cost‐effectiveness, it is a therapeutic option worth trying for these patients, especially in combination with other therapies.


| INTRODUCTION
][3] The alteration can be caused by many factors.One of the factors is the error in protein synthesis and DNA duplication, which results in metabolic waste accumulation over a long period of time. 4,50][11][12][13][14][15][16] Furthermore, reversible alterations in gene expression called 'epigenetic changes' can also cause neoplasm, which may lead to the development of cancer. 17,18ccording to global cancer statistics, as of the year 2020, there were about 19 million new cases of cancers globally; out of which, nine million cases resulted in death. 19In addition, although, there are many types of cancers, there are 10 types of cancers that are recognized as major types of cancers. 20These include breast invasive carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, bladder urothelial carcinoma, rectum adenocarcinoma, kidney renal clear cell carcinoma, lung squamous cell carcinoma, uterine corpus endometroid carcinoma, colon adenocarcinoma, and ovarian serous cystadeno carcinoma. 20owever, despite the number and different types of cancers, they share several pathological processes. 21,22he pathological processes they share are the capacity to convey information for cell growth and increase in its number for a long time; avoid genes that forcibly put an end to cell development and growth; resist cell death, enable unlimited replication of cells; and form new blood vessels and invade and migrate to other cells and tissues of the body. 23][26][27][28] Thus, some of the therapeutic targets for cancer are oxidative stress, inflammation, and sympathetic nerve activity.3][34] In particular, for the treatment of cancer in the elderly, the kind of therapies that should be given deserve special consideration. 35This is because, the risk of developing cancer and death thereof, increases with age. 36The reason for this, is the accumulation of mutation over the years. 373]38 In addition, the types of treatment given may be associated with more adverse events.For instance, elderly people, especially those who are frail have an increased risk of mortality, morbidity, and complication due to surgery, 39 and surgery is one of the interventions used for people living with cancers. 40n addition, since many people in the world are suffering from one or more cancers, and that the disease incidence increases with age, and it has high potential for morbidity and mortality, finding any therapeutic solutions especially those that are cost-effective, will be welcomed with an open arm.One such therapeutic option that is nowadays being considered, is the vagus nerve stimulation (VNS).

| VAGUS NERVE STIMULATION
6][47] It performs both motor and sensory functions, as it is comprised of 80% afferent (sensory) fibers that carry information from the body to the brain, and 20% efferent fibers that carry information from the brain to the body. 41,48,49hus, the nerve serves a two-way means of carrying information from the body to the brain and vice-versa, by meandering from the brainstem to the proximal two-thirds of colon, giving off many branches to various organs and parts of the body such as the tongue, pharynx, heart, and gastrointestinal system in order to help maintain homeostasis. 49This wide distribution of the nerve throughout the body, makes it to have many important clinical correlations 46 ; and as such, VNS is carried out to subserve the aforementioned roles and more.
Stimulation of the vagus nerve can be carried out directly via surgically implanted electrodes connected to it (invasive VNS); or indirectly via electrodes applied over the distribution of its peripheral branches in the skin, manual touch of its branch in the neck, and respiratory stimulation of its diaphragmatic branch (non-invasive VNS). 42,50][52][53] Thus, considering non-invasive VNS in the treatment of cancer, may be a long-awaited hidden treasure.][56] In addition, as noted earlier, some of the methods of administering non-invasive VNS include electrical, manual touch, respiratory stimulation of the peripheral branches of the vagus nerve, and mindfulness meditation. 41,42,579][60] However, the concha and inner tragus of the external ear are regarded as the most suitable stimulation areas for non-invasive VNS. 49For the VNS using manual touch, the peripheral branch of the vagus nerve in the neck around the position of the carotid sheath is pressed or electrically stimulated. 41,61,62This is because, after the vagus nerve exited the brainstem, it coursed through the neck, around the carotid sheath area. 63For the respiratory stimulation of the vagus nerve, slow-deep breathing is used to stimulate the diaphragmatic branch of the vagus nerve. 64For the mindfulness meditation, it is a stress-coping technique that promotes relaxation and elevates heart rate variability (HRV), an indicator of stimulation of the activity of the vagus nerve. 576][67][68][69] The aim of this article is to present the putative role of non-invasive VNS in cancer pathology and immunotherapy.

| PUTATIVE ROLE OF NON-INVASIVE VAGUS NERVE STIMULATION IN CANCER PATHOLOGY AND IMMUNOTHERAPY
Roles of non-invasive VNS in cancer pathology and immunotherapy are emerging.In particular, several important mechanisms have been identified: oxidative stress reduction; inhibition of inflammatory response by targeting two inflammation pathways (the hypothalamic-pituitaryadrenal axis (HPA) and the cholinergic anti-inflammatory pathway) and inhibition of sympathetic activity. 48,70,71See Table 1 for the summary of the potential VNS parameters The stimulation started 24 h prior to the operation and continued till the 4th postoperative day for patients with cancer [72][73][74][75] ; and Figure 1 for the schematic representation of its mechanisms.

| Oxidative stress reduction
Oxidative stress is a pathological process that results from an imbalance between the production and accumulation of reactive oxygen species such as superoxide radicals, hydrogen peroxide, hydroxyl radicals, and singlet oxygen in the cells and the ability of the body system to detoxify them. 76,77Vagus nerve stimulation (VNS) reduces oxidative stress via silent information regulator 1 (SIRT1), which is a histone of deacetylase of nicotinamide adenine dinucleotide (NAD + ) that helps in the regulation of cell proliferation, differentiation, apoptosis, and metabolism. 71,78

| Anti-inflammatory effect
Inflammation characterizes cancer pathology. 16,79It is defined as the cellular, tissue, organ, or system's response or defense against a foreign body such as pathogens, chemical compounds, and radiation. 80It results in cancer when it fails to resolve over a long period of time. 1,81]82 The pathological process through which inflammation results in cancer generally starts from the recognition of the foreign body by the cell surface pattern receptors, which is then followed successively by the activation of inflammatory pathways, release of inflammatory markers, and recruitment of inflammatory cells. 835][86] Activation of these pathways in turn results in the activation of proinflammatory cells such as the macrophages, and the release of inflammatory biomarkers such as the interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis alpha (TNF-α), and other inflammatory proteins and enzymes that eventually cause abnormal growth of the cells, damage, and death. 83Thus, arresting these pathological processes can be an important immunotherapeutic target.
Vagus nerve stimulation (VNS) is known to reduce systemic inflammatory response. 87This is because, through the use of its afferent and efferent pathways, the vagus nerve brings about an anti-inflammatory effect that inhibits inflammation. 41,70For that to occur, the afferent pathways will activate or regulate the hypothalamic-pituitary-axis (HPA) and release of corticosteroid by the adrenal gland. 70Similarly, the efferent pathways will regulate the cholinergic antiinflammatory pathway (CAP). 41 3.2 This is made possible because, the afferent fibers of the vagus nerve are endowed with interleukin-1β (IL-1β) receptors in the paraganglia which transmit sensory information to nucleus tractus solitarius (NTS), where neurons located in the A2 noradrenergic group are activated and then project information to the parvo-cellular zone of paraventricular nucleus of the hypothalamus (PVH) around corticotrophin-releasing factor (CRF)-containing neurons.90 These CRF neurons then activate the release F I G U R E 1 Mechanisms of treatment of cancer using VNS.Keywords: HRV, heart rate variability; VNS, vagus nerve stimulation.
of adreno-corticotrophin hormone by the hypophysis that will finally stimulate the release of glucocorticoids by the adrenal glands to decrease peripheral inflammation. 90onsequently, the HPA is the physiological basis for the use of hormonal treatments for cancer malignancies and, it is considered cytostatic because it restricts tumor development by limiting the hormonal growth factors acting through the direction of HPA, hormone receptor blockage, and limiting adrenal steroid synthesis. 70nterestingly, VNS also acts on the same pathway to maintain homeostasis. 70For instance, it has been shown that VNS resulted in the downregulation of the insulin catabolic process, which may reduce circulating blood glucose that is pro-inflammatory. 91-933.2.2| The cholinergic anti-inflammatory pathway (CAP) The cholinergic anti-inflammatory pathway (CAP) is a neural mechanism of inhibiting inflammation via the parasympathetic nervous system activity that influences the level of circulating tumor necrosis α (TNF-α) and other inflammatory biomarkers such as the interleukins, and endotoxins. 94The VNS can activate the CAP by stimulating the activation of vagal afferent which inhibits inflammation by reducing or suppressing the production and release of pro-inflammatory cytokines and biomarkers such as the tumor necrosis α (TNF-α) and interleukin-6 (IL-6). 41,45,95,96In particular, VNS may delay tumorigenesis through its action on acetylcholine (ACh) and the acetylcholine receptor, α7nAChR, since they are widely expressed in many types of immune cells. 97In addition, the sympathetic nervous system and the vagus nerve act in synergy, through the splenic nerve, to inhibit the release of tumor necrosis factor-alpha (TNFα) by macrophages of the peripheral tissues and the spleen. 48urthermore, VNS helps to suppress the activation of other inflammatory pathways such as the activation of NF-κB. 98Consequently, non-invasive VNS has been reported to surge CAP to suppress 1, 2-dimethyhydrazine (DMH) induced colon cancinogenesis. 99This role is similar to that of the drug, Roflumilast, a selective phosphodiesterase-4 inhibitor (PDE4). 100Furthermore, non-invasive VNS stimulates tumor-infiltrating lymphocytes. 72The tumor-infiltrating lymphocytes are types of immune cells that help attenuate acute inflammatory response and kill cancer cells. 72,73

| Inhibition of sympathetic activity
2][103][104][105][106][107] This is because high vagal activity inhibits sympathetic nervous system activity, which is associated with decreased plasma level of TNF-α. 108In contrast, the absence of vagal nerve activity promotes tumor growth and reduces cell survival due to increased levels of TNF-α, which in turn promotes invasion and migration of cancer cells, one of the hallmarks of cancer pathology. 23,109,110

NON-INVASIVE VNS IN CANCER
Other ways through which non-invasive VNS play a role in patients with cancer are also many.For instance, postoperative ileus was reported to reduce following low-intensity non-invasive VNS (25 Hz, 50 mA) that was given for 20 min prior to anesthesia in patients who had laparoscopic radical resection of colorectal cancer. 111,112imilarly, it was also reported to help reduce the severity of peripheral neuropathy induced by chemotherapy. 32In addition, it helps improve cancer-related fatigue, lymphopenia, and quality of life. 113Thus, the importance of noninvasive VNS cannot be overemphasized.
6][117] This is because VNS is used in the management of depression, which by implication helps improve a symptom associated with cancer and reduce the risk of developing it. 118,119Similarly, cardiovascular diseases and cancer share many common risk factors such as smoking, metabolic syndrome, age, environmental toxins, and air pollution. 120Moreover, heart rate variability (HRV), which is the fluctuation in the time intervals between adjacent heartbeats serves as a measure of vagal tone that is used to indicate the overall level of vagal activity. 121,122Thus, since HRV is a measure of cardiovascular health and an indicator of vagal activity, improving cardiovascular health with the use of VNS may help with positive outcomes during treatment of cancer. 57,123-125

| IMPLICATION FOR RESEARCH AND PRACTICE
Acute inflammatory response is an essential and protective response in injured tissues, and it can at times restore the tissues to their preinjury state. 126In addition, cancer cells as well as surrounding stromal and inflammatory cells may engage in well-orchestrated reciprocal interactions to form an inflammatory tumor microenvironment that is highly plastic. 15Thus, the use of non-invasive VNS for cancer treatment should take advantage of the early stage of the disease and the plastic nature of the tumor microenvironment.
Another way non-invasive VNS can be used for cancer treatment is by combining it with other therapies such as radiotherapy.This is because, such a combination has helped stimulate tumor-infiltrating lymphocytes, types of immune cells that kill cancer cells. 72In addition, very often, immunotherapy is utilized as a part of a combinatory therapy along with other treatments like radiation, chemotherapy, remission surgery and so on. 127lthough, the role of VNS in cancer pathology and immunotherapy is still ambiguous and requires further investigation 128 ; however, its role may just be similar to that of the corticotrophic releasing hormone (CRH), which has an anti-inflammatory effect when released from the brain, but pro-inflammatory effect when released by the nerve endings at the site of the inflammation. 129This analogy was made because the vagus nerve consists of 80% afferent (sensory) fibers that carry information from the body to the brain. 41,48,49That way, it can sense peripheral inflammation and transmit action potentials from the periphery to the brain stem. 23,130Thus, a proper understanding of the vagus nerve is required for understanding its pathophysiology and its potential roles in the treatment of diseases such as cancer. 131THOR CONTRIBUTIONS Auwal Abdullahi: Conceptualization (equal); data curation (equal); funding acquisition (supporting); resources (equal); software (equal); writing -original draft (lead); writing -review and editing (equal).Thomson W. L. Wong: Conceptualization (equal); data curation (equal); funding acquisition (supporting); resources (equal); software (equal); writing -original draft (equal); writing -review and editing (equal).Shamay S. M. Ng: Conceptualization (equal); data curation (equal); funding acquisition (lead); resources (equal); software (equal); writing -original draft (equal); writing -review and editing (equal).
Potential parameters for the treatment of cancer using vagus nerve stimulation (VNS).