Neural–endocrine–immune Complex In The Central Modulation Of Tumorigenesis Facts, Assumptions, And Hypotheses

Journal of Neuroimmunology 180 (2006) 104 – 116 www.elsevier.com/locate/jneuroim

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Neural–endocrine–immune complex in the central modulation of tumorigenesis: Facts, assumptions, and hypotheses Boris Mravec a,b,⁎, Yori Gidron c , Barbara Kukanova b , Jozef Bizik d , Alexander Kiss b , Ivan Hulin a a

Laboratory of Neurophysiology, Institute of Pathophysiology, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovak Republic b Laboratory of Functional Neuromorphology, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06 Bratislava, Slovak Republic c University of Tilburg, 5000 LE, Tilburg, The Netherlands d Cancer Research Institute, Slovak Academy of Sciences, Vlarska 6, 833 06 Bratislava, Slovak Republic Received 22 June 2006; received in revised form 7 July 2006; accepted 7 July 2006

Abstract For the precise coordination of systemic functions, the nervous system uses a variety of peripherally and centrally localized receptors, which transmit information from internal and external environments to the central nervous system. Tight interconnections between the immune, nervous, and endocrine systems provide a base for monitoring and consequent modulation of immune system functions by the brain and vice versa. The immune system plays an important role in tumorigenesis. On the basis of rich interconnections between the immune, nervous and endocrine systems, the possibility that the brain may be informed about tumorigenesis is discussed in this review article. Moreover, the eventual modulation of tumorigenesis by central nervous system is also considered. Prospective consequences of the interactions between tumor and brain for diagnosis and therapy of cancer are emphasized. © 2006 Elsevier B.V. All rights reserved. Keywords: Autonomic nervous system; Brain; Cytokines; Tumorigenesis; Vagus nerve

1. Introduction The central nervous system (CNS) provides a precise coordination of all body functions utilizing the signals from internal environments (Ádám, 1998). To aid such coordination in organisms, highly differentiated systems of visceral receptors have been developed. Visceral receptors are able to monitor a wide range of biological parameters (e.g. concentration of chemical compounds in plasma, osmotic pressure, mechanical pressure, etc.). Therefore, visceral receptors are important components of internal conveying systems that participate in the maintenance of homeostasis (Berthoud, 2004). ⁎ Corresponding author. Institute of Pathophysiology, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovak Republic. Tel.: +421 2 59357613; fax: +421 2 59357601. E-mail address: [email protected] (B. Mravec). 0165-5728/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2006.07.003

A plethora of evidence, accumulated mainly during the first half of the 20th century, indicates that the endocrine and nervous systems integrate and regulate different body functions. In addition, many studies demonstrate that immune mechanisms may also be influenced by these systems (Besedovsky and del Rey, 1996). Lastly, rich interconnections take place between neural, endocrine, and immune systems (Andersson, 2005; Blalock, 2002; Downing and Miyan, 2000),which may constitute a neural–endocrine– immune functional complex (Kvetnoy, 2002). The hypothalamus with its paraventricular nucleus represents an important anatomical link in this complex, which integrates the activities of all three systems (Turnbull and Rivier, 1999). The nervous and immune systems can bi-directionally communicate by using a common chemical language employing neurotransmitters, neurohormones, hormones, cytokines and the common respective receptors (Savino and

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Dardenne, 1995; Blalock, 2005). The immune system may work as a complex of sensors informing the nervous system about changes in the immune function of organism and about internal threats (Blalock, 1984). The genesis and progression of tumors are intimately interconnected with the immune system. The cells and molecules of the immune system are highly involved in tumorigenesis, on one hand playing an important role in eliminating and annihilating a wide scale of pathogens and transformed cells (Chaplin, 2003; Delves and Roitt, 2000a,b; Parkin and Cohen, 2001) and on the other hand in some cases facilitating tumorigenesis at various stages (Pikarsky et al., 2004; Balkwill and

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Mantovani, 2001). Tumorigenesis evokes both humoral and cellular responses of the immune system (Chiplunkar, 2001). In this review, an attempt was done to extend and summarize the recent data supporting the hypothesis that the central nervous system can monitor and modulate tumorigenesis, beyond the role of the vagus nerve alone (Gidron et al., 2005). This assumption was based on a complex of anatomical and functional interrelationships between nervous, endocrine and immune systems, which in the future might open new avenues in cancer research with a possible impact on prevention, diagnosis and therapy of cancer.

Fig. 1. Pathways, which transmit information from the immune system to the brain (A–D). (A) Cytokines (e.g. IL-1,a IL-6, TNF) circulating in blood stream influence brain activity via circumventricular organs (e.g. subfornical organ—SFO, organum vascullosum lamine terminalis—OVLT, area postrema—AP) or via interaction with brain endothelial cells. (B) 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 vagus nerve afferents that transmit information to the NTS. (C) Endorphins (β-END) might bind to the endings of somatic afferents and produce an analgesic effect. (D) Whether sympathetic nerve afferents are influenced by some compound (?) released from immune cells remains to be investigated. Because the vagus nerve innervates only limited visceral areas, it is possible that information is carried via the sympathetic afferents.

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2. Messages conveying pathways from the immune system to the brain The CNS can monitor activities of the immune system mainly via two pathways: humoral and neural (Fig. 1; Dantzer et al., 2000; Elmquist et al., 1997; Goehler et al., 2000; Pavlov et al., 2003). While the humoral pathways are relatively slow and less informative regarding the location or source of the immune signals, the neural pathways, on the contrary, are fast and location specific. 2.1. Humoral pathways Cytokines are key messengers involved in the transmission of signals from the immune to the nervous system (Mantovani, 1999; Sternberg, 1997). They can exert their effect on the nervous system utilizing different routes. Receptors for cytokines are present in many peripheral structures as well as in the CNS (Rothwell and Hopkins, 1995). Interactions with autonomic nerves (especially the vagus nerve) and with peripheral somatic nerves are discussed bellow. Another route for signal transmissions is represented by an indirect interaction of circulating cytokines with the brain (Licinio and Wong, 1997). The brain is informed about cytokines that circulate in the blood and reach the brain circulation at least by three different pathways that may convey information from the immune system to the CNS: a) cytokines can pass the blood–brain barrier (BBB) at the level of circumventricular organs (CVOs) and bind to receptors on macrophages (Buller, 2001); b) circulating cytokines may activate the cerebral endothelial cells, which in turn transmit signals to perivascular macrophages that activate the microglia within the brain parenchyma (Elmquist et al., 1997; Perry, 2004); and c) cytokines may be actively transported by the endothelium across the BBB (Quan and Herkenham, 2002; Turrin and Rivest, 2004). It is important to note that cytokines binding to receptors on macrophages, endothelial cells, or astrocytes induce the production of soluble molecules (e.g. prostaglandins, nitric oxide) that convey the signal from the circulation to the CNS (Konsman et al., 2002; Nadeau and Rivest, 1999; Szelenyi, 2001; Turrin and Rivest, 2004; Watkins et al., 1995). It has been suggested that prostaglandins may also be crucial messengers that constitute links between circulatory cytokines and the CNS (Quan and Herkenham, 2002; Rivest, 2001; Turnbull and Rivier, 1999). In addition, the presence of receptors for cytokines in the nontanycytic portions of the ependymal lining, the choroid plexus and vascular endothelium, suggests that the endothelial cells might participate in the transmission of immune signals to the CNS (Ericsson et al., 1995; Harre et al., 2002; Turrin and Rivest, 2004; Vallieres and Rivest, 1997). Circulating IL1α has direct access to cortical brain cells located behind the BBB through a saturable transport system that provides a pathway by which the brain and immune systems interact (Banks et al., 1993). Thus, activation of endothelial cells in the BBB followed by secretion of specific messenger mole-

cules such as prostaglandins, seem crucial for humoral immune-to-brain communication. Circumventricular organs play a critical role as transducers of information between the blood, neurons, and cerebral spinal fluid. They permit both the release and sensing of chemical compounds without disrupting the BBB. Therefore they play an essential role in the regulation of diverse physiological functions (e.g. control of the cardiovascular function, body fluid regulation, feeding behavior, and reproduction). Moreover, CVOs are significantly involved in the central immune responses (Buller, 2001; Cottrell and Ferguson, 2004; Ferguson and Bains, 1996; Ganong, 2000). There are two main arguments that support the emergence of CVOs as important CNS structures in the immune regulations: a) all sensory CVOs (the subfornical organ, the organum vasculosum of the lamina terminals and the area postrema) possess receptors for cytokines, i.e. IL-1β, IL-6; TNF that provide a basis for transmission of immune signals to the brain (Ericsson et al., 1995; Nadeau and Rivest, 1999; Roth et al., 2004; Turrin and Rivest, 2004) and b) cells of the CVOs show physiologically relevant morphological and electrophysiological changes during the early phase of the immune response (Cottrell and Ferguson, 2004). Thus, the humoral pathways may convey immune information in certain physiological contexts. 2.2. Neuronal pathways Information from the immune system may also reach the CNS via peripheral nerves. Cytokines play a pivotal role in the transmission of signals from the immune system to peripheral nerves. However, other peptides/proteins are also involved in the interaction between the immune and peripheral nervous system. Immune cells are capable of synthesizing many peptide hormones and neurotransmitters, e.g. corticotrophin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), endorphins, thyroid stimulating hormone, growth hormone, prolactin, substance P, vasopressin, oxytocin, somatostatin, and neuropeptide Y (Savino and Dardenne, 1995; Petrovsky, 2001; Shepherd et al., 2005). These compounds do not act only in a paracrine manner. For example, immune cell-derived β-endorphins might act on opioid receptors on the peripheral terminals of sensory neurons (Blalock, 1994). 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 (Buckley et al., 2001; Kaufman et al., 2001; Smith et al., 1997). 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 (Goehler et al., 2000).

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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 (Paintal, 1973). The role of the vagus nerve in the transmission of information about peripheral inflammatory processes is well recognized. The data indicate that capsaicin-sensitive afferent fibers of the hepatic vagus nerve constitute necessary components of the afferent mechanism of the first febrile phase (Romanovsky et al., 2000). 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 IL-1 (Ek et al., 1998). Therefore, cytokines might activate the sensory afferents of the vagus nerve, which transmit signals from the immune system to the CNS, particularly to the nucleus of the solitary tract (Maier et al., 1998; Perry, 2004). While the role of the vagus in immune-to-brain communication is quite established (Ek et al., 1998; Goehler et al., 1998), this may be limited to low concentrations of peripheral pro-inflammatory cytokines (Hansen et al., 2000). 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 transmission of information from the immune system to the brain via the vagus nerve (Watkins et al., 1995). Paraganglia, innervated by the vagus nerve, contain cells that express IL-1 receptors. This arrangement represents an important link between the immune and nervous systems (Goehler et al., 1997, 1999). IL-1 receptors appear to be located on dendritic-like cells as well, interdigitating the vagus nerve parenchyma (Licinio and Wong, 1997). In the paraganglia, immune cells are activated during inflammation and consequently may stimulate the vagus nerve endings. Therefore, immune cells of paraganglia are responsible for the indirect activation of the vagus nerve (Goehler et al., 2000). Interestingly, some data suggest, that the carotid body (paraganglion involved in the monitoring of blood oxygenation), also expresses cytokine receptors for the monitoring of immune signals (Wang et al., 2002a). The vagus nerve does not innervate all visceral organs. Therefore it can be hypothesized that sympathetic sensory (afferent) fibers might also transmit certain immune-related information from the vagus innervation-free visceral regions of the body. While the vagus nerve mediation of immune signals from the visceral regions is well characterized, the role of the cutaneous sensory nerves in transmission of immune signals is less clear. However, experiments using bacterial lipopolysaccharide-induced inflammation and local anesthesia indicate that cutaneous sensory nerves can modestly participate in the transmission of inflammatory information to the CNS (Roth and De Souza, 2001). Tactile hypersensitivity during inflammatory diseases and observations in patients with leprosies also suggest a possible role of cutaneous sensory afferent fibers in transmission of signals from the immune system to the CNS (Hermann et al., 2005). It is presumed, that disruption of sensory C-fibers and sympathetic innervation in

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leprosies is responsible for the loss of anti-inflammatory immune–nervous system communicative and modulatory circuits (Rook et al., 2002). 3. Messages conveying pathways from the brain to the immune system The CNS has the capacity to deliver neurotransmitters and neuropeptides to all tissues in the body. For a long time, the immune system was considered an exception to this rule. However, it is now clear that the thymus, spleen, and other lymphoid organs are also innervated by the nervous system. Therefore the nervous system, including the brain and the peripheral nervous system, can stimulate or inhibit activities of the innate and adaptive immune systems via two ways, neural and humoral (Fig. 2; Berczi, 2001; Brogden et al., 2005). 3.1. Humoral pathways The main messengers of humoral communication between the brain and the immune system are hormones released from adenohypophysis (Berczi, 2001). It was shown that after parturition, the function of the bone marrow, the thymus and the maintenance of immunocompetence, all became dependent on the pituitary prolactin (PRL) and growth hormone (GH). Thyroid stimulating hormone modulates immune functions both by the stimulation of thyroid hormones and by its action on the lymphoid cells (Berczi, 1997, 1994; Fabris et al., 1995). The proopiomelanocortin derived peptides – ACTH, α-melanocyte stimulating hormone (α-MSH) and β-endorphin (β-END) – act antagonistically to GH and PRL and suppress adaptive immune responses by acting on the nervous, endocrine and immune systems (Berczi, 2001; Vamvakopoulos and Chrousos, 1994). It has been shown that α-MSH suppresses nuclear factor-κB (NF-κB) activated by various inflammatory agents and that this mechanism probably contributes to α-MSH induced anti-inflammatory effects (Manna and Aggarwal, 1998). The influence of ACTH on immune status is mediated mainly via glucocorticoids, released from the adrenal gland, which affect 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 cytokines (Almawi et al., 1999). Thus, ACTH-induced changes of immune system activity are not always immunosuppressive, but rather immunomodulatory (Sternberg, 1997). It is necessary to take into consideration that immune cells also possess a capacity to produce some hormones, e.g. PRL, GH (Savino and Dardenne, 1995). Another humoral “effector” of immunity is oxytocin, a hormone synthesized in the hypothalamus and secreted from the pituitary gland. Oxytocin has immunomodulatory roles (e.g., Yang et al., 1997) and is relevant to tumorigenesis since it may have a role in suppressing tumor cell proliferation (Cassoni et al., 2004).

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Therefore, the interplay between hormones released from the CNS and immune cells might participate in the modulation of immune functions. 3.2. 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 (Czura and Tracey, 2005; Dardenne and Savino, 1994; Elenkov et al., 2000).

The immune system is regulated, to a great extent, by the sympathetic nervous system (SNS), which innervates the majority of lymphoid organs (Basu and Dasgupta, 2000; Weigent and Blalock, 1987; Denes et al., 2005). For example, the spleen has exclusively only sympathetic innervation (Stevens-Felten and Bellinger, 1997). 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 (Elenkov et al., 1995, 2000; Hasko and Szabo, 1998; Tracey, 2002; Vizi et al., 1995). Recent findings also show that the SNS is important in the regulation of the egress of hematopoietic cells from bone marrow (Katayama et al.,

Fig. 2. Pathways, which transmit information from the brain to the immune system (A–E). (A) Hormones released from the pituitary gland (e.g. ACTH, prolactin, GH) might modulate immune function. (B) Acetylcholine released from postsganglionic vagal neurons (VNpo) bind to nicotine receptors of immune cells and produces an anti-inflammatory effect. (C, D) Norepinephrine 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. (E) Glucocorticoids released from adrenal cortex have complex effects on the immune system. The schema omits modulation of immune cells by somatic afferent sensory fibers that activated by inflammatory processes release neuropeptides via axonal reflex manner. Similarly, release of norepinephrine from sympathetic nerve ending might be modulated by cytokines released from neighboring immune cells (Straub et al., 1998). However, these mechanisms are primarily a consequence of local peripheral processes that are not initiated by activity of central nervous system. SNpr — preganglionic sympathetic neurons; VNpr — preganglionic vagal neurons.

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2006). Moreover, the SNS may modulate immune functions also by direct regulation of blood flow (Vizi, 1998). Experimental data show that interruption of the SNS in animals has produced 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 (Sternberg, 1997). It is well established that afferent neural pathways in the vagus nerve participate in the brain-mediated responses to inflammation (Sternberg, 1997). 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 (Borovikova et al., 2000b). The findings show that both pharmacological and electrical stimulation of the vagus nerve can attenuate the systemic inflammatory response via cholinergic anti-inflammatory pathways (Bernik et al., 2002). It is necessary to point out that lymphocytes of the various immunological compartments were found to be equipped with the key enzymes for the synthesis of both acetylcholine and catecholamines (Rinner et al., 1998; Kawashima and Fujii, 2003; Qiu et al., 2004). Therefore effect of acetylcholine and catecholamines released by immune cells in paracrine manner might co-operate/interfere with effect of neurotransmitters released by autonomic nerves within immunological compartments. 4. The nervous system and tumorigenesis 4.1. Factors modulating tumorigenesis Cancer progression is modulated by tumor-related factors and also by characteristics of the host. Tumor-related factors include the aggressiveness of a tumor that is determined by the source tissue, the degree of dedifferentiation, the functionality of apoptosis, DNA repair mechanisms, loss of contact inhibition, and ability to induce a vascular supply and to metastasize. Resistance of the host depends on immune competence and neuroendocrine regulation, which are subjected to the influence of the brain and behavior (Sephton and Spiegel, 2003). Furthermore, tumors can shift a hosts' immune response from immune surveillance to immune tolerance (Pardoll, 2003). 4.2. The immune system and tumorigenesis An important role of the immune system is to survey the body for the development of malignancy and to eliminate tumors as they arise (Chiplunkar, 2001). Given the fact that thousands of studies dealt with various aspects of the immune surveillance of cancer, this review presents only a very succinct and by no means comprehensive account of the complex issue. Cell-mediated immune mechanisms together with humoral mechanism (both mediated by cytokines) are involved in the modulation of tumor tissue growth (Borish

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and Steinke, 2003; Hopkins and Rothwell, 1995; Mitra et al., 2003, Strieter, 2001; Wang et al., 1998). Natural killer (NK) cells are a type of lymphocytes that posses a variety of effector mechanisms enabling them to mount a potent antitumor response (Wallace and Smyth, 2005). The function of NK cells is regulated by a balance between signals transmitted by activating receptors, which recognize ligands on tumor cells and inhibitory receptors specific for major histocompatibility complex class I (MHC-I) molecules (Cerwenka and Lanier, 2001). Tumor cells frequently lack the costimulatory molecules that drive the development of T-cells to killer cells (cytotoxic T-cells), and tumors also express less MHC-I (Bubenik, 2004), making MHC-dependent antitumor immunity more challenging. Dendritic cells (DC) help to solve this problem, because they help activate cytotoxic T-cells. DC in the periphery act as antigen-presenting cells, and capture and process tumor antigens, express co-stimulatory molecules, and secrete cytokines to initiate cellular immune responses against tumor cells. Therefore DC have a crucial role in the activation of the immune response against tumors, especially by activation of NK cells and cytotoxic T-cells (Banchereau and Steinman, 1998). Powerful regulators of normal cell behavior are cytokines which play an important role in the host immune response against cancer (Mitra et al., 2003). Cytokines modulate tumor behavior by three important mechanisms including regulation of tumor-associated angiogenesis, activation of a host tumor-specific immunological response, and direct stimulation of tumor cell proliferation in an autocrine fashion (Arya et al., 2003; Frederick and Clayman, 2001; Strieter, 2001; Wang et al., 1998). However, certain pro-inflammatory cytokines such as IL-1 may also promote tumorigenesis by enhancing escape from apoptosis, angiogenesis, and metastasis (e.g. Voronov et al., 2003). Thus, while certain arms of the immune response act against tumor development, others promote tumorigenesis (Balkwill and Mantovani, 2001). 4.3. The impact of psychosocial factors on cancer incidence and progression Several lines of evidence suggest that psychological or behavioral factors can influence mainly the progression of cancer (Kiecolt-Glaser and Glaser, 1999; Spiegel and Kato, 1996), though some reviews challenge these conclusions (Petticrew et al., 2002). Cancer is associated with many circumstances e.g. fear of death, the side effects of treatment, cancer pain, the disruption of social activities and social isolation. Comorbidity of cancer with depression and hopelessness is also a common problem. It has been estimated that half of all cancer patients suffer from psychiatric disorders usually associated with depression (Spiegel, 1996). Because of misattribution of depressive symptoms to cancer or its treatment, depression remains often unrecognized and therefore untreated. Reduced activity of natural killer cell and hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis, which have been observed in major depression (Zorrilla et al.,

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2001), may also promote the disease progression (Spiegel, 1996). A hyperactive HPA axis, due to stress and possible depression in cancer patients, might influence a disease progression by two main mechanisms: stimulation of tumor growth and immunosuppression (Spiegel, 1999). Stimulation of tumor growth by hypercortisolemia can be explained by some theories, which include possible stimulation of angiogenesis, direct stimulation of tumor growth in hormonesensitive tumors, and altered gluconeogenesis. The latter involves different responses of tumor cells to glucocorticoid signals compared to normal cells. This consequently leads to a selective deprivation of normal cells of metabolic resources and facilitation of tumor cell growth instead (Spiegel, 1999). In addition, stress is associated with enhanced secretion of norepinephrine that may alter NK cell availability and their function by influencing presence of cell adhesion molecules on lymphocytes (Spiegel and Kato, 1996). Ben-Eliyahu et al. (2000) showed that the effects of stress on tumor growth were mediated by suppression of NK cell activity caused by catecholamines. Furthermore, activation of β-adrenergic receptors on tumor cells may promote tumor growth (Antoni et al., 2006). Another pathway linking psychological factors with cancer progression is by influencing levels of proinflammatory cytokines. For example, cerebral IL-1 may mediate the effects of helplessness (Maier and Watkins, 1995) and cerebral IL-1 can enhance peripheral tumor progression (Hodgson et al., 1998). Thus, IL-1 may mediate the effects of helplessness on tumor progression (Argaman et al., 2005). Recent studies have indicated that psychosocial factors (e.g. stress) may influence the disease by disruption of neuroendocrine and immune circadian rhythms. Circadian rhythm disturbance has also been suggested to be associated with both cancer incidence and cancer progression. The effects of circadian system alterations on tumor tissue and in tumor-bearing animals support this idea. Greater disruption of circadian systems has also been seen in more advanced cases of cancer patients. It is hypothesized that circadian disruption may facilitate tumor growth by several mechanisms including abnormalities of immune cell trafficking and cell proliferation cycles. Another possible pathway includes direct effects of altered hormone levels on tumor cells and effects on tumor versus host metabolism (Sephton and Spiegel, 2003). The studies, which focus on molecular biology and on the effects of stress on cellular processes, represent another possible mechanism by which psychosocial factors may influence process of cancer. Damage of cellular DNA and consequent production of abnormal cells is involved in etiopathogenesis of tumors. It was shown in animals that stress exposure was related to lower levels of methyltransferase, an important DNA repair enzyme induced in response to a carcinogen (Heffner et al., 2003). A recent review also points at the quite consistent effects of stress on DNA-integrity in animal studies and points at significant associations between various psychological factors and DNA-damage (Gidron et al., 2005). Given the central role of DNA-damage in onset of

cancer and in the alterations of established tumors' antigens, psychological factors may influence tumorigenesis and progression via affecting DNA-integrity. There is evidence that psychosocial treatment affects not only the quality of life in cancer patients, but also patient's survival (Fawzy et al., 1990; Spiegel, 1995; Spiegel and Kato, 1996; Spiegel and Moore, 1997). Various psychotherapies improve the course of the disease by reducing depression, anxiety, fatigue, pain, chemotherapy-induced nausea, vomiting and improving coping skills (Spiegel, 1995, 1996; Spiegel and Kato, 1996). The impact of psychosocial treatment on survival as well as on the quality of life, may be mediated by diverse factors including diet, exercise, sleep or compliance to medical treatment. On the other hand, psychosocial treatment may influence disease progression by acting on the immune, endocrine, and nervous systems (Spiegel and Kato, 1996; Spiegel, 1999). Besides providing social support, psychotherapy for cancer patients consists of emotional expression, cognitive interventions, imagery techniques and hypnosis (Spiegel, 1995; Spiegel and Moore, 1997). There is evidence that the coping style and the emotional expression affect survival time in cancer patients (Spiegel and Kato, 1996). The term “fighting spirit” is used to describe assertive patients, who ventilate their emotions directly, including dysphoric affect or realistic optimism. These patients tend to live longer in comparison to patients who are more conforming and submissive (Spiegel and Kato, 1996; Spiegel, 1999). Hypnosis has been found as a psychotherapeutic approach used mainly to control cancer pain. It is known that such pain can produce or exacerbate depression, being a common problem in cancer patients (Spiegel, 1996). It has been shown that the hypnotic analgesia is more efficacious than acupuncture analgesia in hypnotizable patients (Spiegel and Moore, 1997). 5. Nervous system and tumorigenesis: questions, assumptions, and hypotheses 5.1. The tight interconnection between immune and nervous systems elicits a question whether the brain might modulate the process of tumorigenesis and if yes, at which level of the nervous system and in which stage of the tumorigenesis The following hypotheses have emerged regarding this issue. It has been suggested that the immune system might realize sensory functions that can monitor besides infectious agents also tumor cells (Blalock, 2005). While Blalock has only indirectly approached the problem of interconnections between tumor cells, immune system, and the brain, Gidron et al. (2005) have delineated this relationship more clearly. Gidron et al. have hypothesized that the brain is informed about the process of tumorigenesis and responds by modulating processes associated with cancer. They focused on the connections between inflammatory signals in tumorigenesis and consequent on interactions between immune signals and the brain. Recent data show that the brain can induce anti-

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inflammatory processes in the immune system directly via acetylcholine (released from cholinergic pathways of the efferent vagus) through α-7-nicotinic receptors on macrophages (Bernik et al., 2002; Borovikova et al., 2000b; Czura and Tracey, 2005; Pavlov et al., 2003; Wang et al., 2002b). Moreover, it has been proven that electrical stimulation of efferent vagal fibers blunted nuclear NF-κB activation, decreased the mRNA for TNF, and reduced the circulating levels of the cytokine (Guarini et al., 2003). It has also been shown that nuclear NF-κB represents a link between inflammation and tumorigenesis (Balkwill and Coussens, 2004). Finally, TNF derived from neighboring macrophages play a pivotal role in the early stages of tumorigenesis (Pikarsky et al., 2004) and pro-inflammatory cytokines promote many aspects of late stages in cancer progression (e.g., Vronov et al., 2003). Based on these facts, it has been hypothesized that the vagus nerve might play an important role in informing the brain about tumorigenesis. Moreover, the vagus nerve may conduct brain-derived defense processes against tumors (Gidron et al., 2005). However, is the brain 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. Compounds released from tumor cells during their necrosis might represent another kind of messengers that might inform the brain about tumorigenesis. Gidron et al. (2005) primarily focused on the role of the vagus nerve in the proposed mechanisms of the brain sensing tumorigenesis. Gidron paid more attention to studies which described findings, that patients with vagotomy, as a therapy for gastric ulcers, had a greater risk of lung and colorectal cancers (Caygill et al., 1991, 1988; Ekbom et al., 1998; Watt et al., 1984). While data suggest an increased risk of cancer progression in patients undergoing vagotomy, it is necessary to take into consideration that other factors might also play a role in the increased incidence of tumorigenesis in these patients (for details see Caygill et al., 1991; Ekbom et al., 1998) such as changes in life-style (resumption of smoking). Moreover, some controversial results are obtained from human and experimental studies in animals (Bayon et al., 2001; Caygill et al., 1993; Fisher et al., 1994; Lundegardh et al., 1994; Nelson et al., 1992). However, more direct evidence for Gidron et al. (2005) hypothesis came from a study demonstrating that animals given a peripheral carcinogen and subsequently undergoing chemical or surgical vagotomy did not develop reduced food intake (Bernstein, 1996). While the above mentioned data seem to be ambiguous, the convergence of evidence does support the assumption that bi-directional interconnections between the nervous and immune systems might constitute an important network for both sensing and modulation of tumorigenesis by the CNS as originally predicted by Gidron et al. (2005). However, the equivocal data from studies dealing with the effects of

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vagotomy in later cancer development may indicate that the vagus nerve might represent only one route responsible for the active interactions between the brain and cancer. We hypothesize that the SNS, somatic and humoral routes might also be potentially involved in both monitoring and in modulating tumorigenesis (Fig. 3; Erin et al., 2004). Moreover, regulation of tumor blood supply by the autonomic nervous system (Vizi, 1998) might represent an important factor in modulating tumor growth. 5.2. Could any anti-inflammatory neural pathway take part in the inhibition of tumor growth? In recent years it was observed that guanylhydrazone CNI-1493 has anti-inflammatory effects that may take place through the vagus nerve (Borovikova et al., 2000a). CNI1493 was already studied in the phase I trial in melanoma and renal cancer patients showing evidence of pharmacological activity as an inhibitor of TNF production (Atkins et al., 2001). In the case of melanoma, the interpretation of these findings in relation to the vagus nerve needs 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 have aided in treating melanoma. Recent data indicate, that antiinflammatory pathways of the vagus nerve might be activated also by occupation of central melanocortin receptors (e.g. by ACTH, α-melanocyte-stimulating hormone; Guarini et al., 2004). It thus is possible that therapeutic modulation of cancer progression via vagomimetic drugs might act at the level of the CNS and “stimulate” a defense reaction against tumor cells. Accumulating data suggest that non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, prevent cancer development (Shiff et al., 2003). Interestingly, it was proven, that NSAIDs modulate peripheral inflammation not only in regions of inflammation, but also by affecting the CNS (Catania et al., 1991). Therefore preventive effects of NSAIDs on cancer development might be potentially mediated also by its action via the CNS. 5.3. Could a disrupted neural mechanism mean an increased risk for accelerated tumorigenesis? Czura and Tracey (2005) suggest that autonomic dysfunction of the cholinergic anti-inflammatory pathways may predispose some individuals to excessive inflammatory responses. Whether dysfunction of the neuroendocrine and immune interaction might predispose to cancer diseases needs to be investigated. Similarly, Shanks and Lightman (2001) focused on the importance of the maternal–neonatal neuro–immune interactions. Some environmental stimuli might alter development of these interactions during the intrauterine period. Shanks and Lightman (2001) suggest that an altered neuro–

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immune developmental course might contribute to individual vulnerability to stress-related diseases as well as inflammation in adulthood. Whether intrauterine alterations of neuro– immune system interactions might potentially increase 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 (HRV), the latter reflecting descending vagal activity. Normally, an inverse relation exists between such parameters (Janszky et al., 2004). Future studies may wish to test whether the magnitude of (inverse) relations between such parameters predicts risk of cancer. 5.4. Could the nervous system produce and release any compound of tumor-suppressive significance within tumors? Interestingly, several peptides (substance P, neuropeptide Y, adrenomedullin, α-MSH, proenkephalin A) with neural or neuroendocrine signaling functions have been shown to have potent antimicrobial activity (Kowalska et al., 2002; MetzBoutigue et al., 2003). This discovery suggests that the nervous system might use these peptides as anti-infective agents by delivering them rapidly and precisely to the target sites (Brogden et al., 2005). However, the extent of employ-

ment of these peptides in antimicrobial defense reactions is not known and needs further experimental supports. Whether the nervous system might produce substances with potential tumor-suppressive activity is unknown. However from this point of view, an interesting molecule is melatonin, with its possible anti-tumor activity (Kajdaniuk et al., 1999). Similarly, as mentioned above, the role of brain-derived oxytocin in halting tumor progression also needs to be further examined. 5.5. Could any of the functional techniques (fMRI, PET) be able to detect an altered response in certain important brain areas (NTS, PVN, SCHN) in cancer patients, especially after exposing them to experimental stimuli? The peripheral nerves may represent one of the most important routes for transmission of information about tumorigenesis. In general, tumorigenesis is a long-lasting process and it may potentially induce changes in the activity of some brain regions. For example, the nucleus of the solitary tract (NTS), which relays visceral information, might be modulated from peripheral tumors. Other regions may be the hypothalamic paraventricular (PVN) and suprachiasmatic (SCHN) nuclei. The PVN represents the coordinating center

Fig. 3. Presumed interaction between nervous, endocrine, immune system, and tumor cells. Tumor cells release compounds (e.g. cytokines, growth factors) that might influence brain function. Whether the nervous system releases some compounds that might directly modulate tumor growth remains unclear. Bi-directional interconnections between tumor and immune cells and consequent interconnections between the nervous and immune systems might constitute a base for monitoring and modulation of tumorigenesis by brain. Sentinel cells (tissue fibroblasts) may also play an important role in modulating inflammatory processes and tumorigenesis (Silzle et al., 2004; Tlsty and Hein, 2001) and might process and transmit information from the immune system and tumor cells to the central nervous system. Tumor cells growth might be influenced by the endocrine system and vice versa. Therefore possible pathways for modulation of tumorigenesis might include bi-directional interconnections between the brain, endocrine system and tumor cells.

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of autonomic, endocrine, and immune systems. SCN is one of the key regulators of the circadian rhythm. Disruption of the circadian rhythm might also participate in tumorigenesis (Filipski et al., 2002; Sephton and Spiegel, 2003). For example, melatonin, a hormone of importance in circadian rhythms, influences the growth of spontaneous and induced tumors in animals. While data in humans are conflicting, the majority of reports point toward protective actions of melatonin (Brzezinski, 1997). Whether possible alteration of NTS neuron activity influences also the processing of gustatory information and therefore the change in quality or quantity of food intake in patients with cancer, is unclear. Similarly, possible interference between cancer therapy and processing of information in the above-mentioned 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. 5.6. What is the role of the CNS and tumor interactions in alternative therapeutic approaches? Pavlov et al. (2003) suggest a role of alternative therapeutic approaches (e.g. hypnosis, biofeedback, acupuncture, and even Pavlovian conditioning) in modulation of inflammatory diseases. On the basis of data reviewed in this article, it can be suggested that all of these methods can potentially modulate also inflammatory processes connected with progression of cancer via modulation of CNS–tumor interactions since these therapies influence the SNS and vagal activity (e.g., Infante et al., 2001; Bernardi et al., 2001). Focused experimental work is necessary to answer all these questions. The possibility that the brain is informed about tumors in the body is exciting and might open new research areas. Cancer research focuses in this new area might bring important data not only about etiopathogenesis, but also data that might improve diagnosis and therapy of cancer. 6. Conclusion In this review, an attempt was made to highlight certain facts indicating that deeper understanding of the immunoregulatory role of the brain and sensory functions of the immune system might dramatically modify our knowledge regarding the neural–endocrine–immune interactions relevant to the pathophysiology of tumorigenesis, with clinical implications for medicine. While the classical five senses inform us about the changes in the external world, it is under the speculation that the information detected by the vagal visceral receptors (Zagon, 2001) or the immune system (Andersson, 2005; Blalock, 2005; Ferencik and Stvrtinova, 1997) might form a “sixth sense”. Whether sensing of tumorigenesis might be a part of this “sixth sense” combining visceral perception by the vagus nerve with immune system signals, still remains unclear. Although, this article summarizes data supporting the hy-

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Further readings Bovbjerg, D.H., 1991. Psychoneuroimmunology. Implications for oncology? Cancer 67, 828–832. Molina, P.E., 2005. Neurobiology of the stress response: contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury. Shock 24, 3–10. Pert, C.B., Dreher, H.E., Ruff, M.R., 1998. The psychosomatic network: foundations of mind-body medicine. Altern. Ther. Health Med. 4, 30–41. Plata-Salaman, C.R., 1991. Immunoregulators in the nervous system. Neurosci. Biobehav. Rev. 15, 185–215. Tracey, K.J., Czura, C.J., Ivanova, S., 2001. Mind over immunity. FASEB J. 15, 1575–1576. Yabuuchi, K., Minami, M., Katsumata, S., Satoh, M., 1994. Localization of type I interleukin-1 receptor mRNA in the rat brain. Brain Res. Mol. Brain Res. 27, 27–36.