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Journal of Neuroimmunology 180 (2006) 104 – 116

www.elsevier.com/locate/jneuroim

Point of view
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 A plethora of evidence, accumulated mainly during the


first half of the 20th century, indicates that the endocrine and
The central nervous system (CNS) provides a precise nervous systems integrate and regulate different body
coordination of all body functions utilizing the signals from functions. In addition, many studies demonstrate that
internal environments (Ádám, 1998). To aid such coordination immune mechanisms may also be influenced by these sys-
in organisms, highly differentiated systems of visceral receptors tems (Besedovsky and del Rey, 1996). Lastly, rich inter-
have been developed. Visceral receptors are able to monitor a connections take place between neural, endocrine, and
wide range of biological parameters (e.g. concentration of immune systems (Andersson, 2005; Blalock, 2002; Downing
chemical compounds in plasma, osmotic pressure, mechanical and Miyan, 2000),which may constitute a neural–endocrine–
pressure, etc.). Therefore, visceral receptors are important immune functional complex (Kvetnoy, 2002). The hypothal-
components of internal conveying systems that participate in amus with its paraventricular nucleus represents an important
the maintenance of homeostasis (Berthoud, 2004). anatomical link in this complex, which integrates the acti-
vities of all three systems (Turnbull and Rivier, 1999).
The nervous and immune systems can bi-directionally
⁎ Corresponding author. Institute of Pathophysiology, Faculty of Medicine,
communicate by using a common chemical language
Comenius University, Sasinkova 4, 811 08 Bratislava, Slovak Republic.
Tel.: +421 2 59357613; fax: +421 2 59357601. employing neurotransmitters, neurohormones, hormones,
E-mail address: ueenmrav@savba.sk (B. Mravec). cytokines and the common respective receptors (Savino and
0165-5728/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jneuroim.2006.07.003
B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116 105

Dardenne, 1995; Blalock, 2005). The immune system may Mantovani, 2001). Tumorigenesis evokes both humoral and
work as a complex of sensors informing the nervous system cellular responses of the immune system (Chiplunkar,
about changes in the immune function of organism and 2001).
about internal threats (Blalock, 1984). The genesis and In this review, an attempt was done to extend and sum-
progression of tumors are intimately interconnected with the marize the recent data supporting the hypothesis that the
immune system. The cells and molecules of the immune central nervous system can monitor and modulate tumori-
system are highly involved in tumorigenesis, on one hand genesis, beyond the role of the vagus nerve alone (Gidron et
playing an important role in eliminating and annihilating a al., 2005). This assumption was based on a complex of
wide scale of pathogens and transformed cells (Chaplin, anatomical and functional interrelationships between ner-
2003; Delves and Roitt, 2000a,b; Parkin and Cohen, 2001) vous, endocrine and immune systems, which in the future
and on the other hand in some cases facilitating tumorigen- might open new avenues in cancer research with a possible
esis at various stages (Pikarsky et al., 2004; Balkwill and 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.
106 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116

2. Messages conveying pathways from the immune cules such as prostaglandins, seem crucial for humoral im-
system to the brain mune-to-brain communication.
Circumventricular organs play a critical role as transdu-
The CNS can monitor activities of the immune system cers of information between the blood, neurons, and cerebral
mainly via two pathways: humoral and neural (Fig. 1; spinal fluid. They permit both the release and sensing of
Dantzer et al., 2000; Elmquist et al., 1997; Goehler et al., chemical compounds without disrupting the BBB. Therefore
2000; Pavlov et al., 2003). While the humoral pathways are they play an essential role in the regulation of diverse physio-
relatively slow and less informative regarding the location or logical functions (e.g. control of the cardiovascular function,
source of the immune signals, the neural pathways, on the body fluid regulation, feeding behavior, and reproduction).
contrary, are fast and location specific. Moreover, CVOs are significantly involved in the central
immune responses (Buller, 2001; Cottrell and Ferguson,
2.1. Humoral pathways 2004; Ferguson and Bains, 1996; Ganong, 2000). There are
two main arguments that support the emergence of CVOs as
Cytokines are key messengers involved in the transmis- important CNS structures in the immune regulations: a) all
sion of signals from the immune to the nervous system sensory CVOs (the subfornical organ, the organum vasculo-
(Mantovani, 1999; Sternberg, 1997). They can exert their sum of the lamina terminals and the area postrema) possess
effect on the nervous system utilizing different routes. Recep- receptors for cytokines, i.e. IL-1β, IL-6; TNF that provide a
tors for cytokines are present in many peripheral structures as basis for transmission of immune signals to the brain
well as in the CNS (Rothwell and Hopkins, 1995). Inter- (Ericsson et al., 1995; Nadeau and Rivest, 1999; Roth et
actions with autonomic nerves (especially the vagus nerve) al., 2004; Turrin and Rivest, 2004) and b) cells of the CVOs
and with peripheral somatic nerves are discussed bellow. show physiologically relevant morphological and electro-
Another route for signal transmissions is represented by an physiological changes during the early phase of the immune
indirect interaction of circulating cytokines with the brain response (Cottrell and Ferguson, 2004). Thus, the humoral
(Licinio and Wong, 1997). The brain is informed about pathways may convey immune information in certain
cytokines that circulate in the blood and reach the brain physiological contexts.
circulation at least by three different pathways that may
convey information from the immune system to the CNS: a) 2.2. Neuronal pathways
cytokines can pass the blood–brain barrier (BBB) at the level
of circumventricular organs (CVOs) and bind to receptors on Information from the immune system may also reach the
macrophages (Buller, 2001); b) circulating cytokines may CNS via peripheral nerves. Cytokines play a pivotal role in
activate the cerebral endothelial cells, which in turn transmit the transmission of signals from the immune system to
signals to perivascular macrophages that activate the mi- peripheral nerves. However, other peptides/proteins are also
croglia within the brain parenchyma (Elmquist et al., 1997; involved in the interaction between the immune and peri-
Perry, 2004); and c) cytokines may be actively transported by pheral nervous system. Immune cells are capable of synthe-
the endothelium across the BBB (Quan and Herkenham, sizing many peptide hormones and neurotransmitters, e.g.
2002; Turrin and Rivest, 2004). It is important to note that corticotrophin releasing hormone (CRH), adrenocorticotro-
cytokines binding to receptors on macrophages, endothelial pic hormone (ACTH), endorphins, thyroid stimulating hor-
cells, or astrocytes induce the production of soluble mole- mone, growth hormone, prolactin, substance P, vasopressin,
cules (e.g. prostaglandins, nitric oxide) that convey the signal oxytocin, somatostatin, and neuropeptide Y (Savino and
from the circulation to the CNS (Konsman et al., 2002; Dardenne, 1995; Petrovsky, 2001; Shepherd et al., 2005).
Nadeau and Rivest, 1999; Szelenyi, 2001; Turrin and Rivest, These compounds do not act only in a paracrine manner. For
2004; Watkins et al., 1995). It has been suggested that example, immune cell-derived β-endorphins might act on
prostaglandins may also be crucial messengers that constitute opioid receptors on the peripheral terminals of sensory
links between circulatory cytokines and the CNS (Quan and neurons (Blalock, 1994).
Herkenham, 2002; Rivest, 2001; Turnbull and Rivier, 1999). Peripheral nerves could receive information directly from
In addition, the presence of receptors for cytokines in the non- specialized immune cells or from sentinel cells, e.g. dendritic
tanycytic portions of the ependymal lining, the choroid ple- cells and subpopulations of tissue fibroblasts. Sentinel cells
xus and vascular endothelium, suggests that the endothelial process information about the immune status of surrounding
cells might participate in the transmission of immune signals tissue and may consequently transmit these signals to the
to the CNS (Ericsson et al., 1995; Harre et al., 2002; Turrin peripheral nervous system via production of cytokines
and Rivest, 2004; Vallieres and Rivest, 1997). Circulating IL- (Buckley et al., 2001; Kaufman et al., 2001; Smith et al.,
1α has direct access to cortical brain cells located behind the 1997). It is suggested that sentinel cells might represent an
BBB through a saturable transport system that provides a analogy to taste cells. Both, the sentinel and taste cells are in
pathway by which the brain and immune systems interact the first line of contact with the chemical stimulus, and res-
(Banks et al., 1993). Thus, activation of endothelial cells in pond by generating a second signal capable of activating
the BBB followed by secretion of specific messenger mole- neural elements (Goehler et al., 2000).
B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116 107

One of the most important visceral sensors is represented leprosies is responsible for the loss of anti-inflammatory
by the vagus nerve. It innervates the thorax and abdomen with immune–nervous system communicative and modulatory
fibers containing a variety of sensory receptors (Paintal, circuits (Rook et al., 2002).
1973). The role of the vagus nerve in the transmission of
information about peripheral inflammatory processes is well 3. Messages conveying pathways from the brain to the
recognized. The data indicate that capsaicin-sensitive afferent immune system
fibers of the hepatic vagus nerve constitute necessary com-
ponents of the afferent mechanism of the first febrile phase The CNS has the capacity to deliver neurotransmitters and
(Romanovsky et al., 2000). This is supported by data neuropeptides to all tissues in the body. For a long time, the
showing that vagal sensory neurons themselves express immune system was considered an exception to this rule.
mRNA for IL-1 receptors, suggesting a direct reaction of However, it is now clear that the thymus, spleen, and other
afferent vagal fibers to IL-1 (Ek et al., 1998). Therefore, lymphoid organs are also innervated by the nervous system.
cytokines might activate the sensory afferents of the vagus Therefore the nervous system, including the brain and the
nerve, which transmit signals from the immune system to the peripheral nervous system, can stimulate or inhibit activities of
CNS, particularly to the nucleus of the solitary tract (Maier et the innate and adaptive immune systems via two ways, neural
al., 1998; Perry, 2004). While the role of the vagus in and humoral (Fig. 2; Berczi, 2001; Brogden et al., 2005).
immune-to-brain communication is quite established (Ek et
al., 1998; Goehler et al., 1998), this may be limited to low 3.1. Humoral pathways
concentrations of peripheral pro-inflammatory cytokines
(Hansen et al., 2000). This role may be pertinent to low The main messengers of humoral communication between
concentrations of inflammation that can promote tumorigen- the brain and the immune system are hormones released from
esis, as described below. Another group of important visceral adenohypophysis (Berczi, 2001). It was shown that after
sensors are paraganglia, which represent structures support- parturition, the function of the bone marrow, the thymus and
ing transmission of information from the immune system to the maintenance of immunocompetence, all became depen-
the brain via the vagus nerve (Watkins et al., 1995). Para- dent on the pituitary prolactin (PRL) and growth hormone
ganglia, innervated by the vagus nerve, contain cells that (GH). Thyroid stimulating hormone modulates immune
express IL-1 receptors. This arrangement represents an functions both by the stimulation of thyroid hormones and
important link between the immune and nervous systems by its action on the lymphoid cells (Berczi, 1997, 1994;
(Goehler et al., 1997, 1999). IL-1 receptors appear to be Fabris et al., 1995).
located on dendritic-like cells as well, interdigitating the The proopiomelanocortin derived peptides – ACTH,
vagus nerve parenchyma (Licinio and Wong, 1997). In the α-melanocyte stimulating hormone (α-MSH) and β-endor-
paraganglia, immune cells are activated during inflammation phin (β-END) – act antagonistically to GH and PRL and
and consequently may stimulate the vagus nerve endings. suppress adaptive immune responses by acting on the nervous,
Therefore, immune cells of paraganglia are responsible for endocrine and immune systems (Berczi, 2001; Vamvakopou-
the indirect activation of the vagus nerve (Goehler et al., los and Chrousos, 1994). It has been shown that α-MSH
2000). Interestingly, some data suggest, that the carotid body suppresses nuclear factor-κB (NF-κB) activated by various
(paraganglion involved in the monitoring of blood oxygen- inflammatory agents and that this mechanism probably
ation), also expresses cytokine receptors for the monitoring of contributes to α-MSH induced anti-inflammatory effects
immune signals (Wang et al., 2002a). The vagus nerve does (Manna and Aggarwal, 1998). The influence of ACTH on
not innervate all visceral organs. Therefore it can be hy- immune status is mediated mainly via glucocorticoids, re-
pothesized that sympathetic sensory (afferent) fibers might leased from the adrenal gland, which affect immune responses
also transmit certain immune-related information from the via glucocorticoid receptors expressed by immune cells.
vagus innervation-free visceral regions of the body. While the Whereas it was initially thought that glucocorticoids mediate
vagus nerve mediation of immune signals from the visceral immunosuppression, more recent studies indicate that they
regions is well characterized, the role of the cutaneous suppress Th1 and activate Th2 cytokines (Almawi et al.,
sensory nerves in transmission of immune signals is less 1999). Thus, ACTH-induced changes of immune system
clear. However, experiments using bacterial lipopolysaccha- activity are not always immunosuppressive, but rather immu-
ride-induced inflammation and local anesthesia indicate that nomodulatory (Sternberg, 1997). It is necessary to take into
cutaneous sensory nerves can modestly participate in the consideration that immune cells also possess a capacity to
transmission of inflammatory information to the CNS (Roth produce some hormones, e.g. PRL, GH (Savino and
and De Souza, 2001). Tactile hypersensitivity during Dardenne, 1995). Another humoral “effector” of immunity is
inflammatory diseases and observations in patients with oxytocin, a hormone synthesized in the hypothalamus and
leprosies also suggest a possible role of cutaneous sensory secreted from the pituitary gland. Oxytocin has immunomod-
afferent fibers in transmission of signals from the immune ulatory roles (e.g., Yang et al., 1997) and is relevant to
system to the CNS (Hermann et al., 2005). It is presumed, that tumorigenesis since it may have a role in suppressing tumor
disruption of sensory C-fibers and sympathetic innervation in cell proliferation (Cassoni et al., 2004).
108 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116

Therefore, the interplay between hormones released from The immune system is regulated, to a great extent, by the
the CNS and immune cells might participate in the modu- sympathetic nervous system (SNS), which innervates the
lation of immune functions. majority of lymphoid organs (Basu and Dasgupta, 2000;
Weigent and Blalock, 1987; Denes et al., 2005). For example,
3.2. Neuronal pathways the spleen has exclusively only sympathetic innervation
(Stevens-Felten and Bellinger, 1997). It is well documented
Both the sympathetic and parasympathetic parts of the that catecholamines released from sympathetic nerve endings
autonomic nervous system may modulate immune processes modulate the function of many components of the immune
in the organism. All lymphoid organs receive autonomic system via adrenergic and purinergic receptors on immune
innervation and cells located in the lymphoid tissues possess cells (Elenkov et al., 1995, 2000; Hasko and Szabo, 1998;
receptors for transmitters released from autonomic nerves Tracey, 2002; Vizi et al., 1995). Recent findings also show
(Czura and Tracey, 2005; Dardenne and Savino, 1994; that the SNS is important in the regulation of the egress of
Elenkov et al., 2000). 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.
B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116 109

2006). Moreover, the SNS may modulate immune functions and Steinke, 2003; Hopkins and Rothwell, 1995; Mitra et al.,
also by direct regulation of blood flow (Vizi, 1998). Experi- 2003, Strieter, 2001; Wang et al., 1998). Natural killer (NK)
mental data show that interruption of the SNS in animals has cells are a type of lymphocytes that posses a variety of
produced enhancement or suppression of inflammation, effector mechanisms enabling them to mount a potent anti-
depending on the stage of development at which the system tumor response (Wallace and Smyth, 2005). The function of
is ablated, and whether the system is interrupted at a local or NK cells is regulated by a balance between signals trans-
systemic level (Sternberg, 1997). mitted by activating receptors, which recognize ligands on
It is well established that afferent neural pathways in the tumor cells and inhibitory receptors specific for major histo-
vagus nerve participate in the brain-mediated responses to compatibility complex class I (MHC-I) molecules (Cerwenka
inflammation (Sternberg, 1997). In addition to this sensory and Lanier, 2001). Tumor cells frequently lack the co-
function of the vagus nerve, an efferent or motor vagus nerve stimulatory molecules that drive the development of T-cells
mechanism has also been described by which acetylcholine, to killer cells (cytotoxic T-cells), and tumors also express less
the principal vagus nerve neurotransmitter, inhibits cytokine MHC-I (Bubenik, 2004), making MHC-dependent anti-
release from resident tissue macrophages (Borovikova et al., tumor immunity more challenging. Dendritic cells (DC)
2000b). The findings show that both pharmacological and help to solve this problem, because they help activate
electrical stimulation of the vagus nerve can attenuate the cytotoxic T-cells. DC in the periphery act as antigen-presen-
systemic inflammatory response via cholinergic anti-inflam- ting cells, and capture and process tumor antigens, express
matory pathways (Bernik et al., 2002). co-stimulatory molecules, and secrete cytokines to initiate
It is necessary to point out that lymphocytes of the various cellular immune responses against tumor cells. Therefore DC
immunological compartments were found to be equipped have a crucial role in the activation of the immune response
with the key enzymes for the synthesis of both acetylcholine against tumors, especially by activation of NK cells and
and catecholamines (Rinner et al., 1998; Kawashima and cytotoxic T-cells (Banchereau and Steinman, 1998).
Fujii, 2003; Qiu et al., 2004). Therefore effect of acetylcho- Powerful regulators of normal cell behavior are cytokines
line and catecholamines released by immune cells in para- which play an important role in the host immune response
crine manner might co-operate/interfere with effect of against cancer (Mitra et al., 2003). Cytokines modulate tumor
neurotransmitters released by autonomic nerves within behavior by three important mechanisms including regula-
immunological compartments. tion of tumor-associated angiogenesis, activation of a host
tumor-specific immunological response, and direct stimula-
4. The nervous system and tumorigenesis tion of tumor cell proliferation in an autocrine fashion (Arya
et al., 2003; Frederick and Clayman, 2001; Strieter, 2001;
4.1. Factors modulating tumorigenesis Wang et al., 1998). However, certain pro-inflammatory
cytokines such as IL-1 may also promote tumorigenesis by
Cancer progression is modulated by tumor-related factors enhancing escape from apoptosis, angiogenesis, and metas-
and also by characteristics of the host. Tumor-related factors tasis (e.g. Voronov et al., 2003). Thus, while certain arms of
include the aggressiveness of a tumor that is determined by the immune response act against tumor development, others
the source tissue, the degree of dedifferentiation, the func- promote tumorigenesis (Balkwill and Mantovani, 2001).
tionality of apoptosis, DNA repair mechanisms, loss of
contact inhibition, and ability to induce a vascular supply and 4.3. The impact of psychosocial factors on cancer incidence
to metastasize. Resistance of the host depends on immune and progression
competence and neuroendocrine regulation, which are
subjected to the influence of the brain and behavior (Sephton Several lines of evidence suggest that psychological or
and Spiegel, 2003). Furthermore, tumors can shift a hosts' behavioral factors can influence mainly the progression of
immune response from immune surveillance to immune cancer (Kiecolt-Glaser and Glaser, 1999; Spiegel and Kato,
tolerance (Pardoll, 2003). 1996), though some reviews challenge these conclusions
(Petticrew et al., 2002). Cancer is associated with many cir-
4.2. The immune system and tumorigenesis cumstances e.g. fear of death, the side effects of treatment,
cancer pain, the disruption of social activities and social
An important role of the immune system is to survey the isolation. Comorbidity of cancer with depression and hope-
body for the development of malignancy and to eliminate lessness is also a common problem. It has been estimated that
tumors as they arise (Chiplunkar, 2001). Given the fact that half of all cancer patients suffer from psychiatric disorders
thousands of studies dealt with various aspects of the immune usually associated with depression (Spiegel, 1996). Because of
surveillance of cancer, this review presents only a very misattribution of depressive symptoms to cancer or its treat-
succinct and by no means comprehensive account of the ment, depression remains often unrecognized and therefore
complex issue. Cell-mediated immune mechanisms together untreated. Reduced activity of natural killer cell and hyper-
with humoral mechanism (both mediated by cytokines) are activity of the hypothalamic–pituitary–adrenal (HPA) axis,
involved in the modulation of tumor tissue growth (Borish which have been observed in major depression (Zorrilla et al.,
110 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116

2001), may also promote the disease progression (Spiegel, cancer and in the alterations of established tumors' antigens,
1996). A hyperactive HPA axis, due to stress and possible psychological factors may influence tumorigenesis and
depression in cancer patients, might influence a disease pro- progression via affecting DNA-integrity.
gression by two main mechanisms: stimulation of tumor There is evidence that psychosocial treatment affects not
growth and immunosuppression (Spiegel, 1999). Stimulation only the quality of life in cancer patients, but also patient's
of tumor growth by hypercortisolemia can be explained by survival (Fawzy et al., 1990; Spiegel, 1995; Spiegel and Kato,
some theories, which include possible stimulation of angio- 1996; Spiegel and Moore, 1997). Various psychotherapies
genesis, direct stimulation of tumor growth in hormone- improve the course of the disease by reducing depression,
sensitive tumors, and altered gluconeogenesis. The latter in- anxiety, fatigue, pain, chemotherapy-induced nausea, vomit-
volves different responses of tumor cells to glucocorticoid ing and improving coping skills (Spiegel, 1995, 1996; Spiegel
signals compared to normal cells. This consequently leads to a and Kato, 1996). The impact of psychosocial treatment on
selective deprivation of normal cells of metabolic resources survival as well as on the quality of life, may be mediated by
and facilitation of tumor cell growth instead (Spiegel, 1999). diverse factors including diet, exercise, sleep or compliance to
In addition, stress is associated with enhanced secretion of medical treatment. On the other hand, psychosocial treatment
norepinephrine that may alter NK cell availability and their may influence disease progression by acting on the immune,
function by influencing presence of cell adhesion molecules endocrine, and nervous systems (Spiegel and Kato, 1996;
on lymphocytes (Spiegel and Kato, 1996). Ben-Eliyahu et al. Spiegel, 1999).
(2000) showed that the effects of stress on tumor growth were Besides providing social support, psychotherapy for
mediated by suppression of NK cell activity caused by cancer patients consists of emotional expression, cognitive
catecholamines. Furthermore, activation of β-adrenergic interventions, imagery techniques and hypnosis (Spiegel,
receptors on tumor cells may promote tumor growth (Antoni 1995; Spiegel and Moore, 1997). There is evidence that the
et al., 2006). Another pathway linking psychological factors coping style and the emotional expression affect survival time
with cancer progression is by influencing levels of pro- in cancer patients (Spiegel and Kato, 1996). The term
inflammatory cytokines. For example, cerebral IL-1 may “fighting spirit” is used to describe assertive patients, who
mediate the effects of helplessness (Maier and Watkins, 1995) ventilate their emotions directly, including dysphoric affect or
and cerebral IL-1 can enhance peripheral tumor progression realistic optimism. These patients tend to live longer in
(Hodgson et al., 1998). Thus, IL-1 may mediate the effects of comparison to patients who are more conforming and sub-
helplessness on tumor progression (Argaman et al., 2005). missive (Spiegel and Kato, 1996; Spiegel, 1999). Hypnosis
Recent studies have indicated that psychosocial factors has been found as a psychotherapeutic approach used mainly
(e.g. stress) may influence the disease by disruption of to control cancer pain. It is known that such pain can produce
neuroendocrine and immune circadian rhythms. Circadian or exacerbate depression, being a common problem in cancer
rhythm disturbance has also been suggested to be associated patients (Spiegel, 1996). It has been shown that the hypnotic
with both cancer incidence and cancer progression. The analgesia is more efficacious than acupuncture analgesia in
effects of circadian system alterations on tumor tissue and in hypnotizable patients (Spiegel and Moore, 1997).
tumor-bearing animals support this idea. Greater disruption
of circadian systems has also been seen in more advanced 5. Nervous system and tumorigenesis: questions,
cases of cancer patients. It is hypothesized that circadian assumptions, and hypotheses
disruption may facilitate tumor growth by several mechan-
isms including abnormalities of immune cell trafficking and 5.1. The tight interconnection between immune and nervous
cell proliferation cycles. Another possible pathway includes systems elicits a question whether the brain might modulate
direct effects of altered hormone levels on tumor cells and the process of tumorigenesis and if yes, at which level of the
effects on tumor versus host metabolism (Sephton and nervous system and in which stage of the tumorigenesis
Spiegel, 2003).
The studies, which focus on molecular biology and on the The following hypotheses have emerged regarding this
effects of stress on cellular processes, represent another issue. It has been suggested that the immune system might
possible mechanism by which psychosocial factors may realize sensory functions that can monitor besides infectious
influence process of cancer. Damage of cellular DNA and agents also tumor cells (Blalock, 2005). While Blalock has
consequent production of abnormal cells is involved in etio- only indirectly approached the problem of interconnections
pathogenesis of tumors. It was shown in animals that stress between tumor cells, immune system, and the brain, Gidron
exposure was related to lower levels of methyltransferase, an et al. (2005) have delineated this relationship more clearly.
important DNA repair enzyme induced in response to a car- Gidron et al. have hypothesized that the brain is informed
cinogen (Heffner et al., 2003). A recent review also points at about the process of tumorigenesis and responds by modu-
the quite consistent effects of stress on DNA-integrity in lating processes associated with cancer. They focused on the
animal studies and points at significant associations between connections between inflammatory signals in tumorigenesis
various psychological factors and DNA-damage (Gidron et al., and consequent on interactions between immune signals and
2005). Given the central role of DNA-damage in onset of the brain. Recent data show that the brain can induce anti-
B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116 111

inflammatory processes in the immune system directly via vagotomy in later cancer development may indicate that the
acetylcholine (released from cholinergic pathways of the vagus nerve might represent only one route responsible for
efferent vagus) through α-7-nicotinic receptors on macro- the active interactions between the brain and cancer. We
phages (Bernik et al., 2002; Borovikova et al., 2000b; Czura hypothesize that the SNS, somatic and humoral routes might
and Tracey, 2005; Pavlov et al., 2003; Wang et al., 2002b). also be potentially involved in both monitoring and in
Moreover, it has been proven that electrical stimulation of modulating tumorigenesis (Fig. 3; Erin et al., 2004). More-
efferent vagal fibers blunted nuclear NF-κB activation, over, regulation of tumor blood supply by the autonomic
decreased the mRNA for TNF, and reduced the circulating nervous system (Vizi, 1998) might represent an important
levels of the cytokine (Guarini et al., 2003). It has also been factor in modulating tumor growth.
shown that nuclear NF-κB represents a link between
inflammation and tumorigenesis (Balkwill and Coussens, 5.2. Could any anti-inflammatory neural pathway take part
2004). Finally, TNF derived from neighboring macrophages in the inhibition of tumor growth?
play a pivotal role in the early stages of tumorigenesis
(Pikarsky et al., 2004) and pro-inflammatory cytokines pro- In recent years it was observed that guanylhydrazone
mote many aspects of late stages in cancer progression (e.g., CNI-1493 has anti-inflammatory effects that may take place
Vronov et al., 2003). Based on these facts, it has been through the vagus nerve (Borovikova et al., 2000a). CNI-
hypothesized that the vagus nerve might play an important 1493 was already studied in the phase I trial in melanoma
role in informing the brain about tumorigenesis. Moreover, and renal cancer patients showing evidence of pharmaco-
the vagus nerve may conduct brain-derived defense processes logical activity as an inhibitor of TNF production (Atkins et
against tumors (Gidron et al., 2005). al., 2001). In the case of melanoma, the interpretation of
However, is the brain able to distinguish between these findings in relation to the vagus nerve needs to be taken
inflammation and tumorigenesis? Presumably, the spectrum with caution since this nerve does not innervate the skin.
of cytokines and other chemical compounds emerging du- Though CNI-1493 activates the efferent vagus fibers, it is
ring tumorigenesis might provide a sufficient source of possible that by the effects of the vagus on the HPA-axis, a
information necessary for the brain to “detect” the presence systemic suppression of circulating cytokines may have
of tumor cells in organisms. Compounds released from aided in treating melanoma. Recent data indicate, that anti-
tumor cells during their necrosis might represent another inflammatory pathways of the vagus nerve might be acti-
kind of messengers that might inform the brain about vated also by occupation of central melanocortin receptors
tumorigenesis. Gidron et al. (2005) primarily focused on the (e.g. by ACTH, α-melanocyte-stimulating hormone; Guarini
role of the vagus nerve in the proposed mechanisms of the et al., 2004). It thus is possible that therapeutic modulation of
brain sensing tumorigenesis. Gidron paid more attention to cancer progression via vagomimetic drugs might act at the
studies which described findings, that patients with vagot- level of the CNS and “stimulate” a defense reaction against
omy, as a therapy for gastric ulcers, had a greater risk of lung tumor cells.
and colorectal cancers (Caygill et al., 1991, 1988; Ekbom et Accumulating data suggest that non-steroidal anti-inflam-
al., 1998; Watt et al., 1984). While data suggest an increased matory drugs (NSAIDs), especially aspirin, prevent cancer
risk of cancer progression in patients undergoing vagotomy, development (Shiff et al., 2003). Interestingly, it was proven,
it is necessary to take into consideration that other factors that NSAIDs modulate peripheral inflammation not only in
might also play a role in the increased incidence of tumori- regions of inflammation, but also by affecting the CNS
genesis in these patients (for details see Caygill et al., 1991; (Catania et al., 1991). Therefore preventive effects of NSAIDs
Ekbom et al., 1998) such as changes in life-style (resumption on cancer development might be potentially mediated also by
of smoking). Moreover, some controversial results are its action via the CNS.
obtained from human and experimental studies in animals
(Bayon et al., 2001; Caygill et al., 1993; Fisher et al., 1994; 5.3. Could a disrupted neural mechanism mean an
Lundegardh et al., 1994; Nelson et al., 1992). However, increased risk for accelerated tumorigenesis?
more direct evidence for Gidron et al. (2005) hypothesis
came from a study demonstrating that animals given a peri- Czura and Tracey (2005) suggest that autonomic dys-
pheral carcinogen and subsequently undergoing chemical or function of the cholinergic anti-inflammatory pathways may
surgical vagotomy did not develop reduced food intake predispose some individuals to excessive inflammatory res-
(Bernstein, 1996). ponses. Whether dysfunction of the neuroendocrine and
While the above mentioned data seem to be ambiguous, immune interaction might predispose to cancer diseases
the convergence of evidence does support the assumption that needs to be investigated.
bi-directional interconnections between the nervous and Similarly, Shanks and Lightman (2001) focused on the
immune systems might constitute an important network for importance of the maternal–neonatal neuro–immune inter-
both sensing and modulation of tumorigenesis by the CNS as actions. Some environmental stimuli might alter develop-
originally predicted by Gidron et al. (2005). However, the ment of these interactions during the intrauterine period.
equivocal data from studies dealing with the effects of Shanks and Lightman (2001) suggest that an altered neuro–
112 B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116

immune developmental course might contribute to individual ment of these peptides in antimicrobial defense reactions is
vulnerability to stress-related diseases as well as inflamma- not known and needs further experimental supports. Whether
tion in adulthood. Whether intrauterine alterations of neuro– the nervous system might produce substances with potential
immune system interactions might potentially increase tumor-suppressive activity is unknown. However from this
vulnerability to cancer remains to be investigated. A rather point of view, an interesting molecule is melatonin, with its
simple manner for measuring such interactions is to test possible anti-tumor activity (Kajdaniuk et al., 1999).
relations between pro-inflammatory cytokines and heart-rate Similarly, as mentioned above, the role of brain-derived
variability (HRV), the latter reflecting descending vagal oxytocin in halting tumor progression also needs to be further
activity. Normally, an inverse relation exists between such examined.
parameters (Janszky et al., 2004). Future studies may wish to
test whether the magnitude of (inverse) relations between 5.5. Could any of the functional techniques (fMRI, PET) be
such parameters predicts risk of cancer. able to detect an altered response in certain important brain
areas (NTS, PVN, SCHN) in cancer patients, especially
5.4. Could the nervous system produce and release any after exposing them to experimental stimuli?
compound of tumor-suppressive significance within tumors?
The peripheral nerves may represent one of the most
Interestingly, several peptides (substance P, neuropeptide important routes for transmission of information about tu-
Y, adrenomedullin, α-MSH, proenkephalin A) with neural or morigenesis. In general, tumorigenesis is a long-lasting pro-
neuroendocrine signaling functions have been shown to have cess and it may potentially induce changes in the activity of
potent antimicrobial activity (Kowalska et al., 2002; Metz- some brain regions. For example, the nucleus of the solitary
Boutigue et al., 2003). This discovery suggests that the tract (NTS), which relays visceral information, might be
nervous system might use these peptides as anti-infective modulated from peripheral tumors. Other regions may be the
agents by delivering them rapidly and precisely to the target hypothalamic paraventricular (PVN) and suprachiasmatic
sites (Brogden et al., 2005). However, the extent of employ- (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.
B. Mravec et al. / Journal of Neuroimmunology 180 (2006) 104–116 113

of autonomic, endocrine, and immune systems. SCN is one of pothesis, that the brain might posses the capability to detect
the key regulators of the circadian rhythm. Disruption of the tumorigenesis and buttress defensive mechanisms against
circadian rhythm might also participate in tumorigenesis cancer progression (Gidron et al., 2005), there are not enough
(Filipski et al., 2002; Sephton and Spiegel, 2003). For data, at present time, to completely substantiate this hypo-
example, melatonin, a hormone of importance in circadian thesis. Therefore, further research is necessary to illuminate
rhythms, influences the growth of spontaneous and induced the possibility that the brain might “know” about tumorigen-
tumors in animals. While data in humans are conflicting, the esis in the body and modulate its progression, via several
majority of reports point toward protective actions of neuroendocrine routes.
melatonin (Brzezinski, 1997). Whether possible alteration
of NTS neuron activity influences also the processing of Acknowledgement
gustatory information and therefore the change in quality or
quantity of food intake in patients with cancer, is unclear. The authors thank MD. Peter Ujhazy, PhD for valuable
Similarly, possible interference between cancer therapy and contributions. This work was supported by Grant of
processing of information in the above-mentioned and other Comenius University UK/40/2006.
brain regions needs further investigation. Future studies need
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