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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. Neuro-endocrine–immune interactions as a base for neurobiology of peripheral diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

2. Nervous system and tumorigenesis (tumor progression): facts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
2.1. Clinical and experimental data supporting the assumption that the brain monitors and modulates tumorigenesis . . . . . . . . . . . . . 151
2.2. The impact of psychosocial factors on cancer incidence and progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
3. Nervous system and tumorigenesis: questions, assumptions, and hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
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. . . . . . . . . . 154
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? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.2.1. Indirect transmission of information about cancer to the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
3.2.2. Direct transmission of information about cancer to the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
3.3. How are brain functions influenced by cancer? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
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? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
3.5. Mechanisms potentially enabling the brain to modulate tumorigenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
3.5.1. Indirect modulation of cancer by the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
3.5.2. Direct modulation of cancer by the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
3.6. Could the cholinergic anti-inflammatory pathway take part in the modulation of tumor growth? . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
3.7. Is there a role for axon reflexes in modulation of tumorigenesis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

∗ 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: ueenmrav@savba.sk (B. Mravec).

1044-579X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.semcancer.2007.12.002
 Author's personal copy

B. Mravec et al. / Seminars in Cancer Biology 18 (2008) 150–163 151

3.8. Could a disrupted neural mechanism mean an increased risk for accelerated tumorigenesis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
3.9. Modulation of tumorigenesis by the brain as a new therapeutic approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
3.10. What is the role of the CNS and tumor interactions in alternative therapeutic approaches? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

1. Neuro-endocrine–immune interactions as a base for might constitute the basis for the formation of a new branch in
neurobiology of peripheral diseases oncology—the neurobiology of cancer.

Homeostasis within the body of every higher animal is reg- 2. Nervous system and tumorigenesis (tumor
ulated by three interwoven systems—the nervous, endocrine progression): facts
and immune systems. It is increasingly clear that the exchange
of information between these systems plays important roles in 2.1. Clinical and experimental data supporting the
various physiological as well as pathological processes [1]. assumption that the brain monitors and modulates
The data accumulated in the past decades show that the tumorigenesis
interactions between nervous, endocrine and immune systems
constitute the basis for the involvement of the central ner- Involvement of the nervous system in modulating cancer
vous system (CNS) in etiopathogenesis of some pathological development and its progression is indicated by various clinical
states and diseases, in which the role of CNS was previously and experimental data.
either not recognized or neglected (e.g. arthritis, atherosclero- The interruption of interconnection between the brain and
sis, diabetes mellitus, hemorrhagic shock, ischemia-reperfusion, organs, namely that of vagal pathways, might cause aggrava-
ileus, pancreatitis, sepsis; [2–4]). However, it is necessary to tion or acceleration of tumor growth [22]. Several retrospective
note that even when knowledge about the nervous system studies of patients who have undergone vagotomy suggest an
functions are increasing exponentially, our understanding of increased risk of cancer development [23–26]. However, some
the brain’s role in the pathogenesis of various diseases of controversial results were obtained from human and experimen-
peripheral tissues is probably still at its beginnings and not tal studies in animals [27–31]. Conflicting results on the risk of
precise. cancer following vagotomy may be due to other factors such
The development of cancer is a highly complex process, in as hypochlorhydria, Helicobacter pylori, bile reflux and smok-
which many known and unknown factors are involved, which we ing, which might also play a role in the increased incidence of
cannot now precisely quantify [5]. Close interactions between tumorigenesis in these patients [25,26,32,33].
the nervous and immune systems, and the important role of the Involvement of the sensory neurons of the vagus nerve in
immune system in the development and progression of cancer modulating the tumorigenesis is indicated by experiments in
[6,7] evoke the question whether the brain might monitor and which mice were chemically vagotomized by capsaicin. Erin
modulate the tumorigenesis (tumor growth; [8–12]). et al. [22] found out that chemical vagotomy increases metas-
The role of the immune system in tumorigenesis is of rele- tasis of breast-cancer cells. Furthermore, when the tumor cells
vance to the CNS since the nervous and immune systems can were administered long after capsaicin challenge, hence allow-
bi-directionally communicate by using a common chemical lan- ing nerve regeneration, animals given capsaicin had no more
guage employing peptide and non-peptide neurotransmitters, metastases when compared with placebo-treated mice. It is sug-
hormones, cytokines and common receptors [13–15]. Through gested that inactivation of sensory neurons with high dose of
the sharing of ligands and receptors, the immune system could capsaicin enhanced metastases by promoting the growth of more
serve as the “sixth sense” to detect signals that the body cannot aggressive cells. Moreover, it is hypothesized that loss of sensory
otherwise hear, see, smell, taste or touch. Pathogens, aller- nerve mediators (e.g. substance P (SP), calcitonin gene-related
gens as well as tumors may be detected with great sensitivity peptide (CGRP)) might have led to the loss of activators for
and specificity by the immune system. As the sixth sense, the certain genes involved in inhibition of cancer growth [34].
immune system may have the capacity to signal information In a series of studies, Hodgson and coworkers [35,36] found
about changes of these types of mutative challenges to the brain that administration of IL-1␤ in the cerebral ventricles led to
[16,17]. greater tumor retention in the lung in an animal model of ade-
In recent years, it has become certain that also neuroimmune nocarcinoma. Their data suggests that observed exaggeration
mechanisms play a role in the defense against cancer as well of tumorigenesis was mediated by possible immunosuppressive
as in its progression [18–20]. However, these interactions are effects of increased activity of the sympathetic nervous system
highly complex, and many variations are possible according to (SNS) and hypothalamic–pituitary–adrenal (HPA) axis [36]. It
the nature of the neoplasm involved [21]. This article depicts appears that effects of intracerebroventricularly administered
the findings that strongly indicate the involvement of the brain IL-1␤ on peripheral cancer is mediated in the brain via central
in cancer monitoring and modulating. We anticipate that focus- prostaglandins and in the periphery via ␤-adrenergic receptors
ing on the study of interactions between the brain and cancer [37].
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152 B. Mravec et al. / Seminars in Cancer Biology 18 (2008) 150–163
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]. Sym-
pathectomy might influence the tumorigenesis by modulating
the activity of the immune system in two ways—by reduc-
ing the modulatory influences of catecholamines on immune
cells as well as by increasing the secretion of glucocorti-
coids. However, it was found that chemical sympathectomy
induced by 6-hydroxydopamine was connected with protec-
tive 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 recep-
tors 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 meth-
ods 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 signifi-
cant 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 asso-
ciated 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 homeo-
static 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 differ-
ences 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 sug-
gested 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 treat-
ments (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 behav-
ioral 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 depres-
sion [53]. A hyperactive HPA axis and sympathoadrenal system,
due to stress and possible depression, might influence cancer
progression by stimulating the tumor growth or immunosup-
pression (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 nore-
pinephrine 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 men-
tioned above, the activation of ␤-adrenergic receptors on tumor
cells may promote the tumor growth [40,56]. Another possi-
ble 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 progres-
sion [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 dis-
ruption 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 produc-
tion of abnormal cells is the major trigger of tumors. Stress
was found to reduce levels of methyltransferase, an impor-
tant 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 fac-
tors and DNA-damage in humans [63]. Given the central
role of DNA-damage in the onset of cancer and in the alter-
ations of established tumor antigens, psychological factors
may influence the tumorigenesis and progression via affecting
DNA-integrity.
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B. Mravec et al. / Seminars in Cancer Biology 18 (2008) 150–163 153

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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154 B. Mravec et al. / Seminars in Cancer Biology 18 (2008) 150–163
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 real-
ize 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 repre-
sent 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 tumorigen-
esis 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 ner-
vous structures as well as in CNS [69]. The brain is informed
about cytokines that circulate in the blood at least by three differ-
ent 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 recep-
tors 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 syn-
thesizing many peptide hormones and neurotransmitters, e.g.
corticotrophin releasing hormone, adrenocorticotropic hormone
(ACTH), endorphins, thyroid stimulating hormone, growth
hormone, prolactin, substance P, vasopressin, oxytocin, somato-
statin, 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 pro-
cess 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 sug-
gested 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 soli-
tary tract [88,89]. While the role of the vagus in immune-to-brain
communication is quite established [87,90], this may be impor-
tant especially in a situation when concentrations of peripheral
pro-inflammatory cytokines are low [91]. This role may be per-
tinent to low concentrations of inflammation that can promote
tumorigenesis, as described below. Another group of important
visceral sensors are paraganglia, which represent structures sup-
porting 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 affer-
ent fibers and cutaneous sensory fibers might also transmit
certain immune-related information from the vagus innervation-
free visceral regions of the body. Experiments using bacterial
lipopolysaccharide-induced inflammation and local anesthesia
indicate that cutaneous sensory nerves can modestly partici-
pate 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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B. Mravec et al. / Seminars in Cancer Biology 18 (2008) 150–163
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 cir-
cuits [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 suf-
ficient 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 necro-
sis (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 rep-
resent 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 can-
cer anorexia–cachexia syndrome results from multifactorial
processes involving various mediators, including cytokines, hor-
mones and neuropeptides. It is likely that the hypothalamus
can provide the basis for close interactions among these medi-
ators given its role in feeding behavior [99]. Tumors might
induce anorexia by modifying the brain function via two path-
ways, humoral and nervous. It was found, that the vagus nerve
represents an important structure involved in processes associ-
ated 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 func-
tion 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 infor-
mation 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 can-
cer 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-
155
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 circa-
dian rhythm might also participate in tumorigenesis [61,104].
For example, melatonin, a hormone of importance in circa-
dian 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 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 can-
cer 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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156 B. Mravec et al. / Seminars in Cancer Biology 18 (2008) 150–163

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 influ-
ence 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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B. Mravec et al. / Seminars in Cancer Biology 18 (2008) 150–163
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 func-
tions 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 sup-
press 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 prob-
ably contributes to ␣-MSH-induced anti-inflammatory effects
[114,115]. The influence of ACTH on immune status is medi-
ated 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 lym-
phocytes [116]. Thus, ACTH-induced changes of the immune
system activity are not always immunosuppressive, but rather
immunomodulatory [67]. It is necessary to take into consid-
eration that immune cells also possess a capacity to produce
some hormones, e.g. PRL, GH [78]. Another humoral “effec-
tor” 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 tumori-
genesis since it may have a role in suppressing the tumor cell
proliferation [118]. As immune cells might synthesize some neu-
rotransmitters, 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 sympa-
thetic 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
157
that an interruption of SNS in animals produces either enhance-
ment 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 phar-
macological and electrical stimulations of the vagus nerve can
attenuate the systemic inflammatory response via cholinergic
anti-inflammatory pathways [136]. Given the role of inflamma-
tory 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 cat-
echolamines [138–140]. Therefore, the effects of acetylcholine
and catecholamines released by immune cells in a paracrine
manner might co-operate/interfere with effect of neurotrans-
mitters 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 evi-
dence 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 com-
pounds 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 reg-
ulate 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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158 B. Mravec et al. / Seminars in Cancer Biology 18 (2008) 150–163
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 ini-
tiation 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 modu-
lation 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 neurotrans-
mitters 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 gener-
ally 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 neuro-
neoplastic 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 pri-
marily 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 anti-
inflammatory effect induced by the stimulation of efferent vagus
nerve axons (the cholinergic anti-inflammatory pathway) [132].
Even if some controversies regarding the anatomical and func-
tional 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 nico-
tinic receptors inhibits nuclear activity of NF-␬B [170]. Thus,
the activation of cholinergic anti-inflammatory pathways might
inhibit chronic inflammation and perhaps modulate tumorigen-
esis.
It was observed that guanylhydrazone CNI-1493 has anti-
inflammatory effects that may take place through the cholinergic
anti-inflammatory pathway [171]. CNI-1493 was already stud-
ied 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 inter-
pretation of these findings in relation to the vagus nerve need
to be taken with caution since this nerve does not inner-
vate 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 pos-
sible 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 “stimu-
late” a defensive reaction against tumor cells.
Accumulated data suggests that non-steroidal anti-
inflammatory 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]. There-
fore, 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 trans-
mission 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 con-
stitute 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 predis-
pose some individuals to excessive inflammatory responses.
Pro-inflammatory processes are clearly implicated in hyper-
metabolism and weight loss associated with cancer-associated
cachexia. Moreover, the presence of systemic inflammation is
now clearly linked with adverse prognosis in patients with can-
cer, the fact of which cannot be fully explained by the association
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B. Mravec et al. / Seminars in Cancer Biology 18 (2008) 150–163
with weight loss alone. Therefore, it is suggested, that the sys-
temic inflammation remains an important therapeutic target
in combating the cachexia [176]. Whether the dysfunction of
neuroendocrine and immune interactions (e.g. cholinergic anti-
inflammatory pathway) might predispose to cancer diseases and
influence the progression of tumorigenesis needs to be investi-
gated.
Shanks and Lightman [177] focused on the importance of the
maternal–neonatal neuroimmune interactions. Some environ-
mental stimuli might alter the development of these interactions
during the intrauterine period. Shanks and Lightman [177] sug-
gest that an altered neuroimmune developmental course might
contribute to individual vulnerability to stress-related diseases
as well as inflammation in adulthood. Whether intrauter-
ine 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 rela-
tion 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 func-
tions 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 tumorige-
nesis. 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 dis-
eases. 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-
159
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 end-
ings 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 respon-
sible 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 mod-
ulating 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, neurobiol-
ogy 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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160 B. Mravec et al. / Seminars in Cancer Biology 18 (2008) 150–163
Acknowledgments
This work was supported by the Slovak Research and Devel-
opment Agency under the contract no. APVV-0045-06 and
VEGA grant (1/4312/07).
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