Seminars in Cancer Biology 18 (2008) 150–163

Review

Neurobiology of cancer: Interactions between nervous, endocrine and immune systems as a base for monitoring and modulating the tumorigenesis by the brain Boris Mravec a,b,∗ , Yori Gidron c , Ivan Hulin a a

Institute of Pathophysiology, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovak Republic b Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06 Bratislava, Slovak Republic c Department of Psychology and Health, University of Tilburg, 5000 LE Tilburg, The Netherlands

Abstract The interactions between the nervous, endocrine and immune systems are studied intensively. The communication between immune and cancer cells, and multilevel and bi-directional interactions between the nervous and immune systems constitute the basis for a hypothesis assuming that the brain might monitor and modulate the processes associated with the genesis and progression of cancer. The aim of this article is to describe the data supporting this hypothesis. © 2007 Elsevier Ltd. All rights reserved. Keywords: Cholinergic anti-inflammatory pathway; Neurobiology of cancer; Neurotransmitters; Innervation of the tumors; Vagus nerve

Contents 1. 2.

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Neuro-endocrine–immune interactions as a base for neurobiology of peripheral diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nervous system and tumorigenesis (tumor progression): facts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Clinical and experimental data supporting the assumption that the brain monitors and modulates tumorigenesis . . . . . . . . . . . . . 2.2. The impact of psychosocial factors on cancer incidence and progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nervous system and tumorigenesis: questions, assumptions, and hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. The tight interconnection between the immune and nervous systems elicits a question as to whether the brain might monitor and modulate the process of tumorigenesis, and if yes, at which level of the nervous system is it involved. . . . . . . . . . 3.2. If we assume that the brain can modulate the tumorigenesis then the brain must be informed about cancer. How is this information transmitted to the brain? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Indirect transmission of information about cancer to the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Direct transmission of information about cancer to the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. How are brain functions influenced by cancer? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. The monitoring of tumorigenesis by the brain as a new diagnostic approach. Could any of the functional imaging techniques (e.g. fMRI, PET) be able to detect an altered response in certain brain areas in cancer patients, especially after exposing them to experimental stimuli? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Mechanisms potentially enabling the brain to modulate tumorigenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1. Indirect modulation of cancer by the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.2. Direct modulation of cancer by the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Could the cholinergic anti-inflammatory pathway take part in the modulation of tumor growth? . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Is there a role for axon reflexes in modulation of tumorigenesis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗

Corresponding author at: Institute of Pathophysiology, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovak Republic. Tel.: +421 2 59357389; fax: +421 2 59357601. E-mail address: [email protected] (B. Mravec). 1044-579X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcancer.2007.12.002

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3.8. Could a disrupted neural mechanism mean an increased risk for accelerated tumorigenesis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Modulation of tumorigenesis by the brain as a new therapeutic approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. What is the role of the CNS and tumor interactions in alternative therapeutic approaches? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Neuro-endocrine–immune interactions as a base for neurobiology of peripheral diseases

might constitute the basis for the formation of a new branch in oncology—the neurobiology of cancer.

Homeostasis within the body of every higher animal is regulated by three interwoven systems—the nervous, endocrine and immune systems. It is increasingly clear that the exchange of information between these systems plays important roles in various physiological as well as pathological processes [1]. The data accumulated in the past decades show that the interactions between nervous, endocrine and immune systems constitute the basis for the involvement of the central nervous system (CNS) in etiopathogenesis of some pathological states and diseases, in which the role of CNS was previously either not recognized or neglected (e.g. arthritis, atherosclerosis, diabetes mellitus, hemorrhagic shock, ischemia-reperfusion, ileus, pancreatitis, sepsis; [2–4]). However, it is necessary to note that even when knowledge about the nervous system functions are increasing exponentially, our understanding of the brain’s role in the pathogenesis of various diseases of peripheral tissues is probably still at its beginnings and not precise. The development of cancer is a highly complex process, in which many known and unknown factors are involved, which we cannot now precisely quantify [5]. Close interactions between the nervous and immune systems, and the important role of the immune system in the development and progression of cancer [6,7] evoke the question whether the brain might monitor and modulate the tumorigenesis (tumor growth; [8–12]). The role of the immune system in tumorigenesis is of relevance to the CNS since the nervous and immune systems can bi-directionally communicate by using a common chemical language employing peptide and non-peptide neurotransmitters, hormones, cytokines and common receptors [13–15]. Through the sharing of ligands and receptors, the immune system could serve as the “sixth sense” to detect signals that the body cannot otherwise hear, see, smell, taste or touch. Pathogens, allergens as well as tumors may be detected with great sensitivity and specificity by the immune system. As the sixth sense, the immune system may have the capacity to signal information about changes of these types of mutative challenges to the brain [16,17]. In recent years, it has become certain that also neuroimmune mechanisms play a role in the defense against cancer as well as in its progression [18–20]. However, these interactions are highly complex, and many variations are possible according to the nature of the neoplasm involved [21]. This article depicts the findings that strongly indicate the involvement of the brain in cancer monitoring and modulating. We anticipate that focusing on the study of interactions between the brain and cancer

2. Nervous system and tumorigenesis (tumor progression): facts 2.1. Clinical and experimental data supporting the assumption that the brain monitors and modulates tumorigenesis Involvement of the nervous system in modulating cancer development and its progression is indicated by various clinical and experimental data. The interruption of interconnection between the brain and organs, namely that of vagal pathways, might cause aggravation or acceleration of tumor growth [22]. Several retrospective studies of patients who have undergone vagotomy suggest an increased risk of cancer development [23–26]. However, some controversial results were obtained from human and experimental studies in animals [27–31]. Conflicting results on the risk of cancer following vagotomy may be due to other factors such as hypochlorhydria, Helicobacter pylori, bile reflux and smoking, which might also play a role in the increased incidence of tumorigenesis in these patients [25,26,32,33]. Involvement of the sensory neurons of the vagus nerve in modulating the tumorigenesis is indicated by experiments in which mice were chemically vagotomized by capsaicin. Erin et al. [22] found out that chemical vagotomy increases metastasis of breast-cancer cells. Furthermore, when the tumor cells were administered long after capsaicin challenge, hence allowing nerve regeneration, animals given capsaicin had no more metastases when compared with placebo-treated mice. It is suggested that inactivation of sensory neurons with high dose of capsaicin enhanced metastases by promoting the growth of more aggressive cells. Moreover, it is hypothesized that loss of sensory nerve mediators (e.g. substance P (SP), calcitonin gene-related peptide (CGRP)) might have led to the loss of activators for certain genes involved in inhibition of cancer growth [34]. In a series of studies, Hodgson and coworkers [35,36] found that administration of IL-1␤ in the cerebral ventricles led to greater tumor retention in the lung in an animal model of adenocarcinoma. Their data suggests that observed exaggeration of tumorigenesis was mediated by possible immunosuppressive effects of increased activity of the sympathetic nervous system (SNS) and hypothalamic–pituitary–adrenal (HPA) axis [36]. It appears that effects of intracerebroventricularly administered IL-1␤ on peripheral cancer is mediated in the brain via central prostaglandins and in the periphery via ␤-adrenergic receptors [37].

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It has been found that sympathectomy might influence tumorigenesis. The published data suggest that sympathectomy might suppress immune functions. Chemical sympathectomy in mice is followed by an increase in both hypothalamic Fos expression and levels of circulating corticosterone [38]. Sympathectomy might influence the tumorigenesis by modulating the activity of the immune system in two ways—by reducing the modulatory influences of catecholamines on immune cells as well as by increasing the secretion of glucocorticoids. However, it was found that chemical sympathectomy induced by 6-hydroxydopamine was connected with protective effects against colon carcinogenesis [39]. The role of the sympathetic system in tumorigenesis is further complicated by studies demonstrating that its neuroendocrine substances promote the tumor progression. Norepinephrine can promote certain tumors’ invasion angiogenesis via ␤-adrenergic receptors on various types of tumor cells (ovarian, nasopharyngeal), by increasing levels of vascular endothelial growth factor and matrix-metalloproteins [40,41]. Experiments in which were used stimulatory and lesion methods showed that specific immune functions are modulated by discrete brain areas [42]. Interestingly, lesion methods showed also links between tumorigenesis and the brain. Lesions of the median hypothalamus were found to result in a significant rise in the proliferation rate of Yoshida ascites tumor in rats and Erlich’s tumors and L1210 ascites tumor in mice, and a significant increase in cell multiplication in inoculated ascitic and solid tumors in mice and rats. Pinealectomy is associated with an increased incidence of induced breast cancer in rats, and this can by reversed by melatonin administration [43]. These studies suggest the tumor-modulatory role of certain CNS regions, particularly those involved in important homeostatic and neuroendocrine functions (e.g. hypothalamus, pineal gland). Surprisingly, there is only scattered data describing the changes in neuronal activity in CNS in animals with tumors. Immunohistochemical investigation of CNS in tumor-bearing rats showed an increased activity of spinal cord and forebrain neurons [44,45]. Recently we have found that the advanced stage of tumorigenesis is accompanied by an increased activity of brainstem and hypothalamic neurons (unpublished results). It is well known that these neurons are also activated by various immune challenges [46]. Therefore, our data might support the assumption that CNS receives signals related to tumorigenesis. Finally, some studies in humans have found interesting differences between cancer patients and control patients in the activity of various brain regions. Tashiro et al. [47,48] found a reduced prefrontal activation in cancer patients versus controls, and suggested that the brain’s response to a tumor resembles that of depressive states. This is important considering the prognostic role of depression in some cancers [49]. However, these studies need to be viewed with caution since it is difficult to distinguish the effects of the cancer per-se from the effects of cancer treatments (radiation, chemotherapy), that the patients underwent. In addition, the patients knew they had cancer, thus it is difficult to conclude whether these findings reflect any relationship between

brain activity and cancer or reflect an anxiety accompanying the diagnosis of cancer. 2.2. The impact of psychosocial factors on cancer incidence and progression Several lines of evidence suggest that psychological or behavioral factors can influence the progression of cancer [50,51], though some reviews challenge these conclusions [52]. Cancer is associated with many circumstances, e.g. fear of death, side effects of treatment, cancer pain, disruption of social activities and social isolation. Approximately half of all cancer patients suffer from psychiatric disorders usually associated with depression [53]. A hyperactive HPA axis and sympathoadrenal system, due to stress and possible depression, might influence cancer progression by stimulating the tumor growth or immunosuppression (mainly via modulating activity of natural-killer cells) [53–56]. Stimulation of tumor growth by hypercortisolemia can be explained by a possible stimulation of angiogenesis, direct stimulation of tumor growth in hormone-sensitive tumors, and altered gluconeogenesis. The latter involves different responses of tumor cells to glucocorticoid signals compared to normal cells leading to a selective deprivation of normal cells of metabolic resources and facilitation of tumor cell growth instead [54]. Stress is associated with enhanced secretion of norepinephrine that may alter the NK cells availability and their function [50]. Ben-Eliyahu et al. [57] showed that the effects of stress on tumor growth were mediated by suppression of NK cell activity caused by catecholamines. Furthermore, as mentioned above, the activation of ␤-adrenergic receptors on tumor cells may promote the tumor growth [40,56]. Another possible mechanism of linking the stress with cancer progression is that intermediated by pro-inflammatory cytokines. Cerebral IL-1 may mediate the effects of helplessness [58] and cerebral administration of IL-1 can enhance peripheral tumor progression [35]. Since the peripheral IL-1 plays pivotal roles in tumor angiogenesis and metastasis [59], IL-1 may mediate the effects of helplessness on tumor progression [60]. Psychosocial factors may also influence the disease by disruption of neuroendocrine and immune circadian rhythms. The disruption of circadian systems was found in advanced cancer, and this is explained by the possible disruption of immune cell trafficking and cell proliferation cycles, as well as by altered hormone levels affecting the tumor versus host metabolism [61]. The damage of cellular DNA and consequent production of abnormal cells is the major trigger of tumors. Stress was found to reduce levels of methyltransferase, an important DNA repair enzyme induced in response to carcinogens [62]. A recent review also points at the quite consistent effects of stress on DNA-integrity in animal studies and points at significant associations between psychological factors and DNA-damage in humans [63]. Given the central role of DNA-damage in the onset of cancer and in the alterations of established tumor antigens, psychological factors may influence the tumorigenesis and progression via affecting DNA-integrity.

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Fig. 1. Pathways, which might provide base for monitoring of tumorigenesis by the brain. Direct effect on the nervous system: molecules released actively from tumor cells (e.g. growth factors, CEA, PSA, CA125 [186]) or molecules released during necrosis of tumor cells (e.g. HMGB1, DNA fragments) might reach the brain via humoral pathway (A). Tumor cells might also influence vagal paraganglia (B), somatic afferents (C) or spinal visceral afferent nerves (D). Indirect effect mediated by immune system: Circulating cytokines (e.g. IL-1, IL-6, TNF) produced by tumor-activated immune cells might influence brain activity via circumventricular organs (e.g. subfornical organ, SFO, organum vasculosum laminae terminalis, OVLT, area postrema, AP) or via interaction with brain endothelial cells (A). Binding of cytokines (e.g. IL-1) to receptors on vagal paraganglion dendritic cells (grayish cell with protrusions) or directly to receptors of the vagus nerve activate the vagus nerve afferents that transmit information to the nucleus of the solitary tract (NTS) (B). Endorphins (␤-END) might bind to the endings of somatic afferents and produce an analgesic effect (C). Whether spinal visceral nerve afferents are influenced by some compound (?) released from immune cells remains to be investigated (D). As the vagus nerve innervates only limited visceral areas, it is possible that the immune signals are also carried via the spinal visceral afferents. The scheme omits sentinel cells (e.g. tissue fibroblasts) which may also play an important role in modulating the inflammatory processes and tumorigenesis [187,188] and might process and transmit signals from the immune system and tumor cells to the nervous system.

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3. Nervous system and tumorigenesis: questions, assumptions, and hypotheses 3.1. The tight interconnection between the immune and nervous systems elicits a question as to whether the brain might monitor and modulate the process of tumorigenesis, and if yes, at which level of the nervous system is it involved. It has been suggested that the immune system might realize sensory functions that can in addition to infectious agents monitor tumor cells [14]. While Blalock has only indirectly approached the problem of interconnections between tumor cells, the immune system, and the brain, others have delineated this relationship more clearly [9,11,12]. 3.2. If we assume that the brain can modulate the tumorigenesis then the brain must be informed about cancer. How is this information transmitted to the brain? Information about cancer might reach brain indirectly, using the immune system as a transducer. Moreover, we hypothesize that some molecules released from tumor cells might represent messengers that might directly “inform” the brain about tumorigenesis (Fig. 1). 3.2.1. Indirect transmission of information about cancer to the brain The immune system might inform the brain about tumorigenesis via two pathways: humoral and neural [64–66]. The humoral pathways are relatively slow and less informative regarding the location or source of the immune signals. The neural pathways are fast and location-specific (Fig. 1). 3.2.1.1. Humoral pathways. Cytokines transmit signals from the immune to the nervous system, utilizing different routes [67,68]. Receptors for cytokines are present in peripheral nervous structures as well as in CNS [69]. The brain is informed about cytokines that circulate in the blood at least by three different pathways: (a) cytokines may be actively transported by the endothelium across the blood–brain barrier (BBB); (b) cytokines pass to the brain tissue at the level of circumventricular organs (CVOs) and activates CNS targets in the vicinity of CVOs; (c) cytokines induce the production of cytokines from cells of BBB, which then secrete cytokines into the brain parenchyma [70,71]. It is important to note that cytokines binding to receptors on macrophages, endothelial cells, or astrocytes induce the production of soluble molecules (prostaglandins, nitric oxide) that convey the signal from the circulation to CNS [71–75]. Therefore, prostaglandins may represent crucial messengers that constitute the links between circulatory cytokines and CNS [70,76,77]. 3.2.1.2. Neuronal pathways. Information from the immune system may reach the CNS also via peripheral nerves. Cytokines play a pivotal role in the transmission of signals from the immune system to peripheral nerves. However, other signaling molecules are also involved in the interaction between the immune and

peripheral nervous systems. Immune cells are capable of synthesizing many peptide hormones and neurotransmitters, e.g. corticotrophin releasing hormone, adrenocorticotropic hormone (ACTH), endorphins, thyroid stimulating hormone, growth hormone, prolactin, substance P, vasopressin, oxytocin, somatostatin, and neuropeptide Y [78–80]. These compounds do not act only in a paracrine manner. For example, immune cell-derived ␤-endorphins might act on opioid receptors on the peripheral terminals of sensory neurons [81]. Peripheral nerves could receive information directly from specialized immune cells or from sentinel cells, e.g. dendritic cells and subpopulations of tissue fibroblasts. Sentinel cells process information about the immune status of surrounding tissue and may consequently transmit these signals to the peripheral nervous system via production of cytokines [82–84]. It is suggested that sentinel cells might represent an analogy to taste cells. Both, the sentinel and taste cells are in the first line of contact with the chemical stimulus, and respond by generating a second signal capable of activating neural elements [65]. One of the most important visceral sensors is represented by the vagus nerve. It innervates the thorax and abdomen with fibers containing a variety of sensory receptors [85]. The role of the vagus nerve in the transmission of information about peripheral inflammatory processes is well recognized. The data indicates that capsaicin-sensitive afferent fibers of the hepatic vagus nerve constitute necessary components of the afferent mechanism of the first febrile phase [86]. This is supported by data showing that vagal sensory neurons themselves express mRNA for IL-1 receptors, suggesting a direct reaction of afferent vagal fibers to peripheral IL-1 [87]. Therefore, cytokines might activate the vagus nerve sensory afferents that transmit signals from the immune system to CNS, particularly to the nucleus of the solitary tract [88,89]. While the role of the vagus in immune-to-brain communication is quite established [87,90], this may be important especially in a situation when concentrations of peripheral pro-inflammatory cytokines are low [91]. This role may be pertinent to low concentrations of inflammation that can promote tumorigenesis, as described below. Another group of important visceral sensors are paraganglia, which represent structures supporting the transmission of information from the immune system to the brain via the vagus nerve [72]. Paraganglia, innervated by the vagus nerve, contain cells that express IL-1 receptors. IL-1 receptors appear to be located on dendritic-like cells as well as on cells interdigitating the vagus nerve parenchyma [92]. This arrangement constitutes an important link between the immune and nervous systems [93,94]. The vagus nerve does not innervate all visceral organs. Therefore, it can be hypothesized that spinal visceral afferent fibers and cutaneous sensory fibers might also transmit certain immune-related information from the vagus innervationfree visceral regions of the body. Experiments using bacterial lipopolysaccharide-induced inflammation and local anesthesia indicate that cutaneous sensory nerves can modestly participate in the transmission of inflammatory information to CNS [95]. Tactile hypersensitivity during inflammatory diseases and observations in patients with leprosies also suggest a possible role of cutaneous sensory afferent fibers in the transmission of

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signals from the immune system to CNS [96]. It is presumed, that disruption of sensory C-fibers and sympathetic innervation in leprosies are responsible for the loss of anti-inflammatory immune–nervous system communicative and modulatory circuits [97]. 3.2.2. Direct transmission of information about cancer to the brain As it is hypothesized that interactions between the nervous and immune systems might constitute the basis for monitoring the tumorigenesis, a question arises as to whether the brain is able to distinguish between inflammation and tumorigenesis? Presumably, the spectrum of cytokines and other chemical compounds emerging during tumorigenesis might provide a sufficient source of information necessary for the brain to “detect” the presence of tumor cells in organisms. Molecules released from tumor cells (CEA, PSA, CA125) or during their necrosis (HMGB1, DNA fragments; [98]) might represent another kind of messengers that might inform the brain about peripheral tumorigenesis (Fig. 1). Other, but unspecific signals might represent stimulation of tissue mechanoreceptors by tumor growth. Thus, although we cannot answer this question adequately, we propose that a pattern of signals, specific to tumorigenesis, may signal this process to the brain. 3.3. How are brain functions influenced by cancer? Anorexia–cachexia syndrome is observed in 80% of patients in advanced stages of cancer. The findings suggest that cancer anorexia–cachexia syndrome results from multifactorial processes involving various mediators, including cytokines, hormones and neuropeptides. It is likely that the hypothalamus can provide the basis for close interactions among these mediators given its role in feeding behavior [99]. Tumors might induce anorexia by modifying the brain function via two pathways, humoral and nervous. It was found, that the vagus nerve represents an important structure involved in processes associated with tumor-induced anorexia. Animals given a peripheral carcinogen, and subsequently undergoing chemical or surgical vagotomy, did not develop reduced food intake [100]. Depression represents another example of altered brain function common in patients with cancer. Even minimal peripheral inflammation can lead to negative moods in healthy humans [101]. It is suggested that depression (and also anorexia) in patients with cancer is caused by upregulation of production of inflammatory cytokines as a consequence of the immunological response to tumors [102]. As the brain activity may be altered by tumorigenesis, it can by hypothesized, that a modification of transmission of information from cancer cells to the brain, which is responsible for the induction of anorexia and depression, might represent a new potential method of restricting the negative consequence of cancer on the organism. On the other hand it can be hypothesized that the information related to tumorigenesis may induce the negative-feedback anti-inflammatory response by HPA axis or directly by the descending vagus, which may slow down the tumorigenesis. If this assumption is correct then the benefi-

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cial effect can by induced by the activation of selected brain structures. 3.4. The monitoring of tumorigenesis by the brain as a new diagnostic approach. Could any of the functional imaging techniques (e.g. fMRI, PET) be able to detect an altered response in certain brain areas in cancer patients, especially after exposing them to experimental stimuli? In general, the tumorigenesis is a long-lasting process, and it may induce changes in the activity of some brain regions. Can these changes modulate the tumorigenesis and thus affect the prognosis of cancer disease? The nucleus of the solitary tract (NTS), which relays visceral information, might be modulated from peripheral tumors by receiving tumor-related inflammatory signals via the vagus nerve [9,12]. Other regions may represent the hypothalamic paraventricular (PVN) and suprachiasmatic (SCN) nuclei. The PVN is a coordinating center of autonomic, endocrine, and immune systems. Given the major roles of these systems in tumor development mentioned above, the PVN could potentially influence the tumorigenesis as well. The SCN is one of the key regulators of the circadian rhythm. The activation of SCN neurons by light induces complex neuroendocrine changes which can modulate the immune activity [103]. Therefore, it is not surprising that it is suggested that the disruption of the circadian rhythm might also participate in tumorigenesis [61,104]. For example, melatonin, a hormone of importance in circadian rhythms, influences the growth of spontaneous and induced tumors in animals. While the data in humans are conflicting, the majority of reports point toward protective actions of melatonin [43,105]. Whether the potential alteration of NTS neurons activity influences also the processing of gustatory information, and thus the change in quality or quantity of food intake in patients with cancer, is unclear. Similarly, a possible interference between cancer therapy and processing of the information in the abovementioned and other brain regions needs further investigation. Future studies need to examine whether the sensitivity and responses of such brain regions to tumor-related inflammatory signals may play a role in the early and later stages of cancer progression. To the best of our knowledge, only Tashiro et al. [47,48] have examined brain activity in cancer patients and found reduced pro-frontal activity, resembling the depressive symptoms (see above). 3.5. Mechanisms potentially enabling the brain to modulate tumorigenesis We suggest that the brain might modulate the course of tumorigenesis indirectly by modulating the immune functions as well as directly by released neurotransmitters that might locally influence the activity of cancer cells (Fig. 2). 3.5.1. Indirect modulation of cancer by the brain The nervous system can stimulate or inhibit activities of the innate and adaptive immune systems via neural and humoral pathways (Fig. 2) [106,107]. Due to the role of immune fac-

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Fig. 2. Pathways, which might provide base for modulation of tumorigenesis by the brain. Tumorigenesis might be modulated directly by compounds released by the brain (e.g. melatonin; (A)) and by neurotransmitters released by vagal (acetylcholine; (B)) or sympathetic (norepinephrine, neuropeptide Y; (C)) postganglionic neurons. Moreover, the activation of sensory endings via axonal reflex (F) might induce the release of neuropeptides (e.g. substance P, calcitonin gene-related peptide) that might potentially modulate the tumorigenesis. The progression of cancer might be influenced by the brain also indirectly via modifying the immune cells activity. Hormones released from the pituitary gland (e.g. ACTH, prolactin, GH) might modulate the immune function (A). Acetylcholine released from postganglionic vagal neurons (VNpo) binds to the nicotine receptors of immune cells and produces an anti-inflammatory effect (B). Norepinephrine and neuropeptide Y released from postganglionic sympathetic neurons (SNpo) and epinephrine/norepinephrine released from adrenal medulla might influence immune functions after binding to adrenergic receptors on the immune cells (C and D). Glucocorticoids released from adrenal cortex have complex effects on the immune system (E). The scheme omits the modulation of immune cells by somatic afferent sensory fibers that after being activated by inflammatory processes release neuropeptides via axonal reflex manner. Similarly, the release of norepinephrine from sympathetic nerve endings might be modulated by cytokines released from neighboring immune cells [189]. However, these mechanisms are the primary consequence of local peripheral processes that are not initiated by the activity of the central nervous system. Abbreviations: CGRP, calcitonin gene-related peptide; SNpr, preganglionic sympathetic neurons; SP, substance P; VNpr, preganglionic vagal neurons.

tors in enhancing and inhibiting the tumorigenesis and given effects of the brain on immunity, CNS could potentially influence the tumorigenesis. In the regulation of immune functions, the innervation of the bone marrow by autonomic nerves plays important roles as well [108,109], possibly influencing the estab-

lishment of new immune cells and influencing the bone marrow microenvironment. 3.5.1.1. Humoral pathways. The main messengers of humoral communication between the brain and the immune system are

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hormones released from the adenohypophysis [106]. It was shown that after parturition, the function of the bone marrow, the thymus and the maintenance of immunocompetence became all dependent on pituitary prolactin (PRL) and growth hormone (GH). Thyroid stimulating hormone modulates immune functions both by stimulation of thyroid hormones and by its action on the lymphoid cells [110–112]. The pro-opiomelanocortin derived peptides (ACTH, ␣melanocyte-stimulating hormone (␣-MSH) and ␤-endorphin (␤-END)) act antagonistically with GH and PRL and suppress the adaptive immune responses by acting on the nervous, endocrine and immune systems [106,113]. It has been shown that ␣-MSH suppresses the nuclear factor-␬B (NF-␬B) activated by various inflammatory agents and that this mechanism probably contributes to ␣-MSH-induced anti-inflammatory effects [114,115]. The influence of ACTH on immune status is mediated mainly via glucocorticoids, released from the adrenal gland, which affect the immune responses via glucocorticoid receptors expressed by immune cells. Whereas it was initially thought that glucocorticoids mediate immunosuppression, more recent studies indicate that they suppress Th1 and activate Th2 lymphocytes [116]. Thus, ACTH-induced changes of the immune system activity are not always immunosuppressive, but rather immunomodulatory [67]. It is necessary to take into consideration that immune cells also possess a capacity to produce some hormones, e.g. PRL, GH [78]. Another humoral “effector” of immunity is oxytocin, a hormone synthesized in the hypothalamus and secreted from the pituitary gland. Oxytocin has immunomodulatory roles [117] and is relevant to tumorigenesis since it may have a role in suppressing the tumor cell proliferation [118]. As immune cells might synthesize some neurotransmitters, the interplay between hormones released from CNS and immune cells might participate in the modulation of immune functions. Neurohormones may suppress the activity of natural-killer cells or cytotoxic T-cells, thus facilitating the tumors’ escape from immune surveillance [57,119]. Furthermore, the effects of adrenal hormones on eliciting the Th2 immune profile may influence the tumorigenesis since this profile has a prognostic value in certain cancers [120]. 3.5.1.2. Neuronal pathways. Both the sympathetic and parasympathetic parts of the autonomic nervous system may modulate immune processes in the organism. All lymphoid organs receive autonomic innervation, and cells located in the lymphoid tissues possess receptors for transmitters released from autonomic nerves [121–124]. The immune system is regulated, to a great extent, by the SNS, which innervates the majority of lymphoid organs [125–128]. It is well documented that catecholamines released from sympathetic nerve endings modulate the function of many components of the immune system via adrenergic and purinergic receptors on immune cells [122,129–132]. Recent findings also show that SNS plays an important role in the regulation of the egress of hematopoietic cells from bone marrow [133]. Moreover, SNS may modulate immune functions also by direct regulation of blood flow via immune tissues [134]. Experimental data shows

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that an interruption of SNS in animals produces either enhancement or suppression of inflammation, depending on the stage of development, at which the system is ablated, and whether the system is interrupted at a local or systemic level [67]. It is well established that afferent neural pathways in the vagus nerve participate in the brain-mediated responses to inflammation [67]. In addition to this sensory function of the vagus nerve, an efferent or motor vagus nerve mechanism has also been described, by which acetylcholine, the principal vagus nerve neurotransmitter, inhibits cytokine release from resident tissue macrophages [135]. The findings show that both pharmacological and electrical stimulations of the vagus nerve can attenuate the systemic inflammatory response via cholinergic anti-inflammatory pathways [136]. Given the role of inflammatory signals in early [137] and late [59] stages of tumorigenesis, this anti-inflammatory actions of the vagus nerve may have implications for tumorigenesis as well [9]. It is necessary to point out that lymphocytes of various immunological compartments were found to be equipped with the key enzymes for the synthesis of both acetylcholine and catecholamines [138–140]. Therefore, the effects of acetylcholine and catecholamines released by immune cells in a paracrine manner might co-operate/interfere with effect of neurotransmitters released by autonomic nerves within immunological compartments. 3.5.2. Direct modulation of cancer by the brain In analogy with the potential antimicrobial activity of neuropeptides (substance P, neuropeptide Y, adrenomedullin, ␣-MSH, proenkephalin A) [141,142], arises a question as to whether the nervous system might produce substances with potential tumor-modulating activity. Receptors for neurotransmitters are often expressed in many primary human cancers [143]. Therefore, it is likely that tumor cells are susceptible to the same signal substances of the nervous system, just like the normal cells of the tissue they descent from [20]. This assumption is supported by accumulating the evidence suggesting the involvement of specific neuropeptides with defined physiological action such as neurotransmitters, in the modulation of progression of cancer of various organs [144,145]. The data suggests that neurotransmitters might influence apoptosis, mitogenesis, angiogenesis, and migration of cells as well as the genesis of metastasis [19,20,146,147]. Therefore, it is not surprising that some researchers propose the use of compounds affecting of the neurotransmitters receptors as a novel and promising approach for treating patients with cancer [10]. The migration of breast, prostate and colon cancer cells is enhanced by the stress-related neurotransmitter norepinephrine in vitro, and this effect can be inhibited by ␤-blocker propranolol [148]. Serotonin is able to significantly increase the apoptosis of cells of Burkitt lymphoma. It is speculated that serotonergic innervation might modulate the dynamics of this disease [149]. Another compound released from nerve endings that might regulate the apoptosis is the gaseous transmitter NO [150]. Also substance P is associated with various processes connected with tumorigenesis. SP might promote mitogenesis, angiogenesis, and genesis of metastasis [10]. It is suggested that SP released in

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the skin might participate in photocarcinogenesis [151]. While the majority of neurotransmitters have a stimulatory effect on cell migration, an endogenous substance amantadine and GABA exhibit an inhibitory effect [152,153]. The pineal gland and its principal hormone melatonin are known to influence the initiation and progression of cancer [154]. It is suggested that melatonin may have an anti-tumor activity [155]. Callaghan [43] hypothesized that melatonin is involved in the mechanism of psychological effects in the promotion of tumorigenesis. Data indicates that brain-derived oxytocin might participate in modulation of the tumor progression [118]. This hormone has recently been related to social support and synergistically interacts with its effects in reducing the stress-response [156]. Given that social support predicts a better prognosis in several cancers [157], the role of oxytocin in these effects also needs to be investigated. However, it is necessary to distinguish whether neurotransmitters that might influence tumorigenesis are released from the brain or nerve endings in tumor tissues, or whether they are synthesized by local non-neuronal (immune) cells and act in autocrine or paracrine manners [158]. Whereas the lack of innervation in tumors was a generally accepted fact [159] recent experimental data suggests that nerve cells infiltrate and innervate tumors [160,161]. Based on these facts, the concept of neuro-neoplastic synapse has emerged [162,163]. How is the process of tumor innervation regulated? Tumor cells are able to release neurotrophic factors. These factors may stimulate adjacent nerve cells to develop nerve axons into the tumor. These nerve cells might in turn release neurotransmitters, for which the tumor cells are susceptible. It is suggested that innervations of the tumor might provide additional support for a nerve-driven induction of metastasis development [20,164,165]. According to the concept of neuroneoplastic synapse a question arises as to whether this structure might represent a new target for cancer therapy [166]. 3.6. Could the cholinergic anti-inflammatory pathway take part in the modulation of tumor growth? The progression of several types of cancer is determined primarily by the severity of the inflammatory response, which may be regulated by NF-␬B [167]. Therefore, the NF-␬B pathway plays an important role in linking the chronic inflammation with cancer [168], since disruption of the NF-␬B pathway results in a strong reduction of cancer in models of colorectal and hepatocellular cancers [169]. Only recently it was discovered that there is a strong antiinflammatory effect induced by the stimulation of efferent vagus nerve axons (the cholinergic anti-inflammatory pathway) [132]. Even if some controversies regarding the anatomical and functional aspects of the cholinergic anti-inflammatory pathway remains [124], it was repeatedly confirmed that acetylcholine released from postganglionic neurons of the vagus nerve induces a profound inhibition of synthesis of pro-inflammatory cytokines in macrophages [4]. This anti-inflammatory effect is mediated by ␣7-nicotinic receptors. The occupation of this subtype of nicotinic receptors inhibits nuclear activity of NF-␬B [170]. Thus, the activation of cholinergic anti-inflammatory pathways might

inhibit chronic inflammation and perhaps modulate tumorigenesis. It was observed that guanylhydrazone CNI-1493 has antiinflammatory effects that may take place through the cholinergic anti-inflammatory pathway [171]. CNI-1493 was already studied in the phase I trial in melanoma and renal cancer patients, showing the evidence of pharmacological activity as an inhibitor of TNF production [172]. In the case of melanoma, the interpretation of these findings in relation to the vagus nerve need to be taken with caution since this nerve does not innervate the skin. Though CNI-1493 activates the efferent vagus fibers, it is possible that by the effects of the vagus on the HPA axis, a systemic suppression of circulating cytokines may aid in melanoma treatment. Furthermore, anti-inflammatory pathways of the vagus nerve might also be activated by the occupation of central melanocortin receptors (e.g. by ACTH, ␣-melanocyte-stimulating hormone) [115,173]. Thus it is possible that therapeutic modulation of cancer progression via vagus efferent pathway-activating drugs might act at the level of CNS, in addition to the tumor microenvironmental level, and “stimulate” a defensive reaction against tumor cells. Accumulated data suggests that non-steroidal antiinflammatory drugs (NSAIDs), especially aspirin, prevent cancer development [174]. Interestingly, it was shown that NSAIDs modulate peripheral inflammation not only in regions of inflammation, but also by affecting the CNS [175]. Therefore, the preventive effects of NSAIDs on cancer development might be potentially mediated also by their actions via the CNS. 3.7. Is there a role for axon reflexes in modulation of tumorigenesis? The main role of peripheral sensory nerve fibers is the transmission of information to the CNS allowing the host to sense and respond to peripheral stimuli. However, peripheral sensory nerve fibers are also capable of transmitting the signals antidromically via branches of the peripheral nerves to transmit signals in the reverse direction back to the peripheral innervated tissues. Via this so-called axon reflex, neuropeptides (e.g. SP, CGRP) are released from peripheral nerve endings into the tissues where they might modulate the immune and inflammatory reactions. Legat and Wolf [151] suggest that these interactions might constitute a link between cutaneous sensory nerves, photoaging and tumorigenesis. 3.8. Could a disrupted neural mechanism mean an increased risk for accelerated tumorigenesis? Czura and Tracey [123] suggest that autonomic dysfunction of cholinergic anti-inflammatory pathways may predispose some individuals to excessive inflammatory responses. Pro-inflammatory processes are clearly implicated in hypermetabolism and weight loss associated with cancer-associated cachexia. Moreover, the presence of systemic inflammation is now clearly linked with adverse prognosis in patients with cancer, the fact of which cannot be fully explained by the association

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with weight loss alone. Therefore, it is suggested, that the systemic inflammation remains an important therapeutic target in combating the cachexia [176]. Whether the dysfunction of neuroendocrine and immune interactions (e.g. cholinergic antiinflammatory pathway) might predispose to cancer diseases and influence the progression of tumorigenesis needs to be investigated. Shanks and Lightman [177] focused on the importance of the maternal–neonatal neuroimmune interactions. Some environmental stimuli might alter the development of these interactions during the intrauterine period. Shanks and Lightman [177] suggest that an altered neuroimmune developmental course might contribute to individual vulnerability to stress-related diseases as well as inflammation in adulthood. Whether intrauterine alterations of neuroimmune system interactions might potentially increase the vulnerability to cancer remains to be investigated. A rather simple manner for measuring such interactions is to test relations between pro-inflammatory cytokines and heart-rate variability, the latter (primarily its high-frequency component) reflecting descending vagal activity. Normally, an inverse relation exists between such parameters [178]. Future studies may wish to test whether the magnitude of (inverse) relations between such parameters predicts a risk of cancer or cancer prognosis, reflecting poor neuroimmune modulation. 3.9. Modulation of tumorigenesis by the brain as a new therapeutic approach Various immunomodulatory methods for cancer therapy have been developed in recent years [179]. It is hypothesized that immunomodulation by the autonomic nervous system might represent a new therapeutic approach for cancer [180]. Tracey [4] proposed a hypothetical “immunological homunculus” which regulates various immune functions by selected brain areas. For example, elevated right-hemisphere activity is associated with reduced natural-killer activity [181], which could be relevant to eradicating tumor cells. We suggest that modifying the activity of specific brain structures involved in regulation of selected immune functions might represent one possible way of cancer therapy by immunomodulation. Finally, Gidron et al. [9] proposes to test the effects of vagal nerve stimulation on tumorigenesis. Such efforts are currently underway by our research team. 3.10. What is the role of the CNS and tumor interactions in alternative therapeutic approaches? Pavlov et al. [66] suggest a role of alternative therapeutic approaches (e.g. hypnosis, biofeedback, acupuncture, and even Pavlovian conditioning) in modulating the inflammatory diseases. On the basis of the data reviewed in this article, it can be suggested that all of these methods can potentially modulate the inflammatory processes connected with the progression of cancer via modulating the CNS–tumor interactions since these therapies influence the sympathoadrenal system and vagal activ-

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ity [182,183] as well as immune functioning in cancer patients [184,185]. 4. Conclusion The data accumulated in the past decades indicate that the brain is involved in etiopathogenesis of a much wider spectrum of diseases than previously expected. Various experimental and clinical data indicate that the brain might also be involved in etiopathogenesis of cancer. However, detection and modulation of tumorigenesis by the brain might represent a highly complex process with many unknown features. Known facts: • The transmission of information from the immune system to the central nervous system indicates that the brain might be involved in the monitoring of tumorigenesis or at least in monitoring of the tumor-associated inflammatory and other signals. • The transmission of signals from the brain to the immune system constitutes the basis for modulating the cancer growth by the brain. • The brain might also modulate tumorigenesis directly via neurotransmitters and hormones secreted from nerve endings and brain-associated endocrine organs. Unknown facts: • The hierarchical organization of neuroimmune processes involved in the detection of tumorigenesis. • The mode of operation of complex systems possibly responsible for regulating the cancer progression. • Nodal points “deciding” whether cancer will progress or regress. Action to be taken: • Define the manner of transmission of signals from cancer cells and the manner by which the brain might receive these signals. • Investigate the details of the role of the central nervous system in modulating the tumorigenesis. • Answer the question as to whether the differences in modulating the tumorigenesis by the brain (e.g. the density of vagal innervation; changes in cholinergic anti-inflammatory pathway activity) might predispose to the development of cancer. • Develop the methods of modulating the complex processes associated with tumorigenesis, from the level of cancer cells to the level of the brain. We expect that cancer research that focuses on the role of the brain in tumorigenesis might markedly extend our knowledge on the biology of cancer. We suggest that solely interdisciplinary and integrative oncological and neuroscientific approaches might effectively illuminate the possibility that the brain might “know” about tumorigenesis in the body and might modulate its progression. We suggest that creation of new scientific discipline, neurobiology of cancer, might open new avenues in cancer research with a possible impact on prevention, diagnosis and therapy of tumor diseases.

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