Neurobiology of Cancer Interactions Between Nervous, Endocrine and Immune Systems as a Base for Monitoring and Modulating the Tumorigenesis by the Brain

This article appeared in a journal published by Elsevier. The attachedcopy is furnished to the author for internal non-commercial researchand education use, including for instruction at the authors institution

and sharing with colleagues.

Other uses, including reproduction and distribution, or selling orlicensing copies, or posting to personal, institutional or third party

websites are prohibited.

In most cases authors are permitted to post their version of thearticle (e.g. in Word or Tex form) to their personal website orinstitutional repository. Authors requiring further information

regarding Elsevier’s archiving and manuscript policies areencouraged to visit:

http://www.elsevier.com/copyright

http://www.elsevier.com/copyright

Author's personal copy

Seminars in Cancer Biology 18 (2008) 150–163

Review

Neurobiology of cancer: Interactions between nervous, endocrineand 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 Republicb 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 cancercells, and multilevel and bi-directional interactions between the nervous and immune systems constitute the basis for a hypothesis assuming thatthe brain might monitor and modulate the processes associated with the genesis and progression of cancer. The aim of this article is to describe thedata 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1512. Nervous system and tumorigenesis (tumor progression): facts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

2.1. Clinical and experimental data supporting the assumption that the brain monitors and modulates tumorigenesis . . . . . . . . . . . . . 1512.2. The impact of psychosocial factors on cancer incidence and progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

3. Nervous system and tumorigenesis: questions, assumptions, and hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1543.1. 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. . . . . . . . . . 1543.2. 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? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1543.2.1. Indirect transmission of information about cancer to the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1543.2.2. Direct transmission of information about cancer to the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

3.3. How are brain functions influenced by cancer? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1553.4. 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 cancerpatients, especially after exposing them to experimental stimuli? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

3.5. Mechanisms potentially enabling the brain to modulate tumorigenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1553.5.1. Indirect modulation of cancer by the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1553.5.2. Direct modulation of cancer by the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

3.6. Could the cholinergic anti-inflammatory pathway take part in the modulation of tumor growth? . . . . . . . . . . . . . . . . . . . . . . . . . . . 1583.7. 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: [email protected] (B. Mravec).

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


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? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1583.9. Modulation of tumorigenesis by the brain as a new therapeutic approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1593.10. What is the role of the CNS and tumor interactions in alternative therapeutic approaches? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

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

Homeostasis within the body of every higher animal is reg-ulated by three interwoven systems—the nervous, endocrineand immune systems. It is increasingly clear that the exchangeof information between these systems plays important roles invarious physiological as well as pathological processes [1].

The data accumulated in the past decades show that theinteractions between nervous, endocrine and immune systemsconstitute the basis for the involvement of the central ner-vous system (CNS) in etiopathogenesis of some pathologicalstates and diseases, in which the role of CNS was previouslyeither not recognized or neglected (e.g. arthritis, atherosclero-sis, diabetes mellitus, hemorrhagic shock, ischemia-reperfusion,ileus, pancreatitis, sepsis; [2–4]). However, it is necessary tonote that even when knowledge about the nervous systemfunctions are increasing exponentially, our understanding ofthe brain’s role in the pathogenesis of various diseases ofperipheral tissues is probably still at its beginnings and notprecise.

The development of cancer is a highly complex process, inwhich many known and unknown factors are involved, which wecannot now precisely quantify [5]. Close interactions betweenthe nervous and immune systems, and the important role of theimmune system in the development and progression of cancer[6,7] evoke the question whether the brain might monitor andmodulate the tumorigenesis (tumor growth; [8–12]).

The role of the immune system in tumorigenesis is of rele-vance to the CNS since the nervous and immune systems canbi-directionally communicate by using a common chemical lan-guage employing peptide and non-peptide neurotransmitters,hormones, cytokines and common receptors [13–15]. Throughthe sharing of ligands and receptors, the immune system couldserve as the “sixth sense” to detect signals that the body cannototherwise hear, see, smell, taste or touch. Pathogens, aller-gens as well as tumors may be detected with great sensitivityand specificity by the immune system. As the sixth sense, theimmune system may have the capacity to signal informationabout changes of these types of mutative challenges to the brain[16,17].

In recent years, it has become certain that also neuroimmunemechanisms play a role in the defense against cancer as wellas in its progression [18–20]. However, these interactions arehighly complex, and many variations are possible according tothe nature of the neoplasm involved [21]. This article depictsthe findings that strongly indicate the involvement of the brainin cancer monitoring and modulating. We anticipate that focus-ing on the study of interactions between the brain and cancer

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

2. Nervous system and tumorigenesis (tumorprogression): facts

2.1. Clinical and experimental data supporting theassumption that the brain monitors and modulatestumorigenesis

Involvement of the nervous system in modulating cancerdevelopment and its progression is indicated by various clinicaland experimental data.

The interruption of interconnection between the brain andorgans, namely that of vagal pathways, might cause aggrava-tion or acceleration of tumor growth [22]. Several retrospectivestudies of patients who have undergone vagotomy suggest anincreased risk of cancer development [23–26]. However, somecontroversial results were obtained from human and experimen-tal studies in animals [27–31]. Conflicting results on the risk ofcancer following vagotomy may be due to other factors suchas hypochlorhydria, Helicobacter pylori, bile reflux and smok-ing, which might also play a role in the increased incidence oftumorigenesis in these patients [25,26,32,33].

Involvement of the sensory neurons of the vagus nerve inmodulating the tumorigenesis is indicated by experiments inwhich mice were chemically vagotomized by capsaicin. Erinet al. [22] found out that chemical vagotomy increases metas-tasis of breast-cancer cells. Furthermore, when the tumor cellswere administered long after capsaicin challenge, hence allow-ing nerve regeneration, animals given capsaicin had no moremetastases when compared with placebo-treated mice. It is sug-gested that inactivation of sensory neurons with high dose ofcapsaicin enhanced metastases by promoting the growth of moreaggressive cells. Moreover, it is hypothesized that loss of sensorynerve mediators (e.g. substance P (SP), calcitonin gene-relatedpeptide (CGRP)) might have led to the loss of activators forcertain genes involved in inhibition of cancer growth [34].

In a series of studies, Hodgson and coworkers [35,36] foundthat administration of IL-1� in the cerebral ventricles led togreater tumor retention in the lung in an animal model of ade-nocarcinoma. Their data suggests that observed exaggerationof tumorigenesis was mediated by possible immunosuppressiveeffects of increased activity of the sympathetic nervous system(SNS) and hypothalamic–pituitary–adrenal (HPA) axis [36]. Itappears that effects of intracerebroventricularly administeredIL-1� on peripheral cancer is mediated in the brain via centralprostaglandins and in the periphery via �-adrenergic receptors[37].


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

It has been found that sympathectomy might influencetumorigenesis. The published data suggest that sympathectomymight suppress immune functions. Chemical sympathectomyin mice is followed by an increase in both hypothalamic Fosexpression and levels of circulating corticosterone [38]. Sym-pathectomy might influence the tumorigenesis by modulatingthe activity of the immune system in two ways—by reduc-ing the modulatory influences of catecholamines on immunecells as well as by increasing the secretion of glucocorti-coids. However, it was found that chemical sympathectomyinduced by 6-hydroxydopamine was connected with protec-tive effects against colon carcinogenesis [39]. The role of thesympathetic system in tumorigenesis is further complicatedby studies demonstrating that its neuroendocrine substancespromote the tumor progression. Norepinephrine can promotecertain tumors’ invasion angiogenesis via �-adrenergic recep-tors on various types of tumor cells (ovarian, nasopharyngeal),by increasing levels of vascular endothelial growth factor andmatrix-metalloproteins [40,41].

Experiments in which were used stimulatory and lesion meth-ods showed that specific immune functions are modulated bydiscrete brain areas [42]. Interestingly, lesion methods showedalso links between tumorigenesis and the brain. Lesions ofthe median hypothalamus were found to result in a signifi-cant rise in the proliferation rate of Yoshida ascites tumor inrats and Erlich’s tumors and L1210 ascites tumor in mice,and a significant increase in cell multiplication in inoculatedascitic and solid tumors in mice and rats. Pinealectomy is asso-ciated with an increased incidence of induced breast cancerin rats, and this can by reversed by melatonin administration[43]. These studies suggest the tumor-modulatory role of certainCNS regions, particularly those involved in important homeo-static and neuroendocrine functions (e.g. hypothalamus, pinealgland).

Surprisingly, there is only scattered data describing thechanges in neuronal activity in CNS in animals with tumors.Immunohistochemical investigation of CNS in tumor-bearingrats showed an increased activity of spinal cord and forebrainneurons [44,45]. Recently we have found that the advancedstage of tumorigenesis is accompanied by an increased activityof brainstem and hypothalamic neurons (unpublished results).It is well known that these neurons are also activated byvarious immune challenges [46]. Therefore, our data mightsupport the assumption that CNS receives signals related totumorigenesis.

Finally, some studies in humans have found interesting differ-ences between cancer patients and control patients in the activityof various brain regions. Tashiro et al. [47,48] found a reducedprefrontal activation in cancer patients versus controls, and sug-gested that the brain’s response to a tumor resembles that ofdepressive states. This is important considering the prognosticrole of depression in some cancers [49]. However, these studiesneed to be viewed with caution since it is difficult to distinguishthe effects of the cancer per-se from the effects of cancer treat-ments (radiation, chemotherapy), that the patients underwent. Inaddition, the patients knew they had cancer, thus it is difficult toconclude whether these findings reflect any relationship between

brain activity and cancer or reflect an anxiety accompanying thediagnosis of cancer.

2.2. The impact of psychosocial factors on cancerincidence 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]. Canceris associated with many circumstances, e.g. fear of death, sideeffects of treatment, cancer pain, disruption of social activitiesand social isolation. Approximately half of all cancer patientssuffer from psychiatric disorders usually associated with depres-sion [53]. A hyperactive HPA axis and sympathoadrenal system,due to stress and possible depression, might influence cancerprogression by stimulating the tumor growth or immunosup-pression (mainly via modulating activity of natural-killer cells)[53–56]. Stimulation of tumor growth by hypercortisolemia canbe explained by a possible stimulation of angiogenesis, directstimulation of tumor growth in hormone-sensitive tumors, andaltered gluconeogenesis. The latter involves different responsesof tumor cells to glucocorticoid signals compared to normalcells leading to a selective deprivation of normal cells ofmetabolic 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 theirfunction [50]. Ben-Eliyahu et al. [57] showed that the effectsof stress on tumor growth were mediated by suppression of NKcell activity caused by catecholamines. Furthermore, as men-tioned above, the activation of �-adrenergic receptors on tumorcells may promote the tumor growth [40,56]. Another possi-ble mechanism of linking the stress with cancer progressionis that intermediated by pro-inflammatory cytokines. CerebralIL-1 may mediate the effects of helplessness [58] and cerebraladministration of IL-1 can enhance peripheral tumor progres-sion [35]. Since the peripheral IL-1 plays pivotal roles in tumorangiogenesis and metastasis [59], IL-1 may mediate the effectsof helplessness on tumor progression [60].

Psychosocial factors may also influence the disease by dis-ruption of neuroendocrine and immune circadian rhythms. Thedisruption of circadian systems was found in advanced cancer,and this is explained by the possible disruption of immune celltrafficking and cell proliferation cycles, as well as by alteredhormone 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. Stresswas 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 consistenteffects of stress on DNA-integrity in animal studies andpoints at significant associations between psychological fac-tors and DNA-damage in humans [63]. Given the centralrole of DNA-damage in the onset of cancer and in the alter-ations of established tumor antigens, psychological factorsmay influence the tumorigenesis and progression via affectingDNA-integrity.



Fig. 1. Pathways, which might provide base for monitoring of tumorigenesis by the brain. Direct effect on the nervous system: molecules released actively fromtumor 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 brainvia humoral pathway (A). Tumor cells might also influence vagal paraganglia (B), somatic afferents (C) or spinal visceral afferent nerves (D). Indirect effect mediatedby immune system: Circulating cytokines (e.g. IL-1, IL-6, TNF) produced by tumor-activated immune cells might influence brain activity via circumventricularorgans (e.g. subfornical organ, SFO, organum vasculosum laminae terminalis, OVLT, area postrema, AP) or via interaction with brain endothelial cells (A). Bindingof 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 vagusnerve afferents that transmit information to the nucleus of the solitary tract (NTS) (B). Endorphins (�-END) might bind to the endings of somatic afferents andproduce 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 schemeomits sentinel cells (e.g. tissue fibroblasts) which may also play an important role in modulating the inflammatory processes and tumorigenesis [187,188] and mightprocess and transmit signals from the immune system and tumor cells to the nervous system.



3. Nervous system and tumorigenesis: questions,assumptions, and hypotheses

3.1. The tight interconnection between the immune andnervous systems elicits a question as to whether the brainmight 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 agentsmonitor tumor cells [14]. While Blalock has only indirectlyapproached the problem of interconnections between tumorcells, the immune system, and the brain, others have delineatedthis relationship more clearly [9,11,12].

3.2. If we assume that the brain can modulate thetumorigenesis then the brain must be informed aboutcancer. How is this information transmitted to the brain?

Information about cancer might reach brain indirectly, usingthe immune system as a transducer. Moreover, we hypothesizethat some molecules released from tumor cells might repre-sent messengers that might directly “inform” the brain abouttumorigenesis (Fig. 1).

3.2.1. Indirect transmission of information about cancer tothe brain

The immune system might inform the brain about tumorigen-esis via two pathways: humoral and neural [64–66]. The humoralpathways are relatively slow and less informative regarding thelocation or source of the immune signals. The neural pathwaysare fast and location-specific (Fig. 1).

3.2.1.1. Humoral pathways. Cytokines transmit signals fromthe 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 informedabout cytokines that circulate in the blood at least by three differ-ent pathways: (a) cytokines may be actively transported by theendothelium across the blood–brain barrier (BBB); (b) cytokinespass 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 ofBBB, 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 theproduction of soluble molecules (prostaglandins, nitric oxide)that convey the signal from the circulation to CNS [71–75].Therefore, prostaglandins may represent crucial messengers thatconstitute the links between circulatory cytokines and CNS[70,76,77].

3.2.1.2. Neuronal pathways. Information from the immunesystem may reach the CNS also via peripheral nerves. Cytokinesplay a pivotal role in the transmission of signals from the immunesystem to peripheral nerves. However, other signaling moleculesare 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, growthhormone, prolactin, substance P, vasopressin, oxytocin, somato-statin, and neuropeptide Y [78–80]. These compounds do not actonly in a paracrine manner. For example, immune cell-derived�-endorphins might act on opioid receptors on the peripheralterminals of sensory neurons [81].

Peripheral nerves could receive information directly fromspecialized immune cells or from sentinel cells, e.g. dendriticcells and subpopulations of tissue fibroblasts. Sentinel cells pro-cess information about the immune status of surrounding tissueand may consequently transmit these signals to the peripheralnervous system via production of cytokines [82–84]. It is sug-gested that sentinel cells might represent an analogy to tastecells. Both, the sentinel and taste cells are in the first line ofcontact with the chemical stimulus, and respond by generatinga second signal capable of activating neural elements [65].

One of the most important visceral sensors is represented bythe vagus nerve. It innervates the thorax and abdomen with fiberscontaining a variety of sensory receptors [85]. The role of thevagus nerve in the transmission of information about peripheralinflammatory processes is well recognized. The data indicatesthat capsaicin-sensitive afferent fibers of the hepatic vagus nerveconstitute necessary components of the afferent mechanism ofthe first febrile phase [86]. This is supported by data showingthat vagal sensory neurons themselves express mRNA for IL-1receptors, suggesting a direct reaction of afferent vagal fibers toperipheral IL-1 [87]. Therefore, cytokines might activate thevagus nerve sensory afferents that transmit signals from theimmune system to CNS, particularly to the nucleus of the soli-tary tract [88,89]. While the role of the vagus in immune-to-braincommunication is quite established [87,90], this may be impor-tant especially in a situation when concentrations of peripheralpro-inflammatory cytokines are low [91]. This role may be per-tinent to low concentrations of inflammation that can promotetumorigenesis, as described below. Another group of importantvisceral sensors are paraganglia, which represent structures sup-porting the transmission of information from the immune systemto the brain via the vagus nerve [72]. Paraganglia, innervated bythe vagus nerve, contain cells that express IL-1 receptors. IL-1receptors appear to be located on dendritic-like cells as well ason cells interdigitating the vagus nerve parenchyma [92]. Thisarrangement constitutes an important link between the immuneand 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 transmitcertain immune-related information from the vagus innervation-free visceral regions of the body. Experiments using bacteriallipopolysaccharide-induced inflammation and local anesthesiaindicate that cutaneous sensory nerves can modestly partici-pate in the transmission of inflammatory information to CNS[95]. Tactile hypersensitivity during inflammatory diseases andobservations in patients with leprosies also suggest a possiblerole of cutaneous sensory afferent fibers in the transmission of



signals from the immune system to CNS [96]. It is presumed,that disruption of sensory C-fibers and sympathetic innervationin leprosies are responsible for the loss of anti-inflammatoryimmune–nervous system communicative and modulatory cir-cuits [97].

3.2.2. Direct transmission of information about cancer tothe brain

As it is hypothesized that interactions between the nervousand immune systems might constitute the basis for monitoringthe tumorigenesis, a question arises as to whether the brain isable to distinguish between inflammation and tumorigenesis?

Presumably, the spectrum of cytokines and other chemicalcompounds 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 releasedfrom tumor cells (CEA, PSA, CA125) or during their necro-sis (HMGB1, DNA fragments; [98]) might represent anotherkind of messengers that might inform the brain about peripheraltumorigenesis (Fig. 1). Other, but unspecific signals might rep-resent stimulation of tissue mechanoreceptors by tumor growth.Thus, although we cannot answer this question adequately, wepropose that a pattern of signals, specific to tumorigenesis, maysignal this process to the brain.

3.3. How are brain functions influenced by cancer?

Anorexia–cachexia syndrome is observed in 80% of patientsin advanced stages of cancer. The findings suggest that can-cer anorexia–cachexia syndrome results from multifactorialprocesses involving various mediators, including cytokines, hor-mones and neuropeptides. It is likely that the hypothalamuscan provide the basis for close interactions among these medi-ators given its role in feeding behavior [99]. Tumors mightinduce anorexia by modifying the brain function via two path-ways, humoral and nervous. It was found, that the vagus nerverepresents an important structure involved in processes associ-ated with tumor-induced anorexia. Animals given a peripheralcarcinogen, and subsequently undergoing chemical or surgicalvagotomy, did not develop reduced food intake [100].

Depression represents another example of altered brain func-tion common in patients with cancer. Even minimal peripheralinflammation can lead to negative moods in healthy humans[101]. It is suggested that depression (and also anorexia) inpatients with cancer is caused by upregulation of production ofinflammatory cytokines as a consequence of the immunologicalresponse to tumors [102].

As the brain activity may be altered by tumorigenesis, it canby hypothesized, that a modification of transmission of infor-mation from cancer cells to the brain, which is responsible forthe induction of anorexia and depression, might represent a newpotential method of restricting the negative consequence of can-cer on the organism. On the other hand it can be hypothesizedthat the information related to tumorigenesis may induce thenegative-feedback anti-inflammatory response by HPA axis ordirectly by the descending vagus, which may slow down thetumorigenesis. If this assumption is correct then the benefi-

cial effect can by induced by the activation of selected brainstructures.

3.4. The monitoring of tumorigenesis by the brain as a newdiagnostic approach. Could any of the functional imagingtechniques (e.g. fMRI, PET) be able to detect an alteredresponse in certain brain areas in cancer patients,especially after exposing them to experimental stimuli?

In general, the tumorigenesis is a long-lasting process, and itmay induce changes in the activity of some brain regions. Canthese changes modulate the tumorigenesis and thus affect theprognosis of cancer disease? The nucleus of the solitary tract(NTS), which relays visceral information, might be modulatedfrom peripheral tumors by receiving tumor-related inflammatorysignals via the vagus nerve [9,12]. Other regions may representthe hypothalamic paraventricular (PVN) and suprachiasmatic(SCN) nuclei. The PVN is a coordinating center of autonomic,endocrine, and immune systems. Given the major roles of thesesystems in tumor development mentioned above, the PVN couldpotentially influence the tumorigenesis as well. The SCN is oneof the key regulators of the circadian rhythm. The activation ofSCN neurons by light induces complex neuroendocrine changeswhich can modulate the immune activity [103]. Therefore, it isnot 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 inducedtumors in animals. While the data in humans are conflicting, themajority of reports point toward protective actions of melatonin[43,105].

Whether the potential alteration of NTS neurons activityinfluences also the processing of gustatory information, and thusthe change in quality or quantity of food intake in patients withcancer, is unclear. Similarly, a possible interference betweencancer 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 andresponses of such brain regions to tumor-related inflammatorysignals may play a role in the early and later stages of can-cer progression. To the best of our knowledge, only Tashiro etal. [47,48] have examined brain activity in cancer patients andfound reduced pro-frontal activity, resembling the depressivesymptoms (see above).

3.5. Mechanisms potentially enabling the brain tomodulate tumorigenesis

We suggest that the brain might modulate the course oftumorigenesis indirectly by modulating the immune functions aswell as directly by released neurotransmitters that might locallyinfluence the activity of cancer cells (Fig. 2).

3.5.1. Indirect modulation of cancer by the brainThe nervous system can stimulate or inhibit activities of the

innate and adaptive immune systems via neural and humoralpathways (Fig. 2) [106,107]. Due to the role of immune fac-



Fig. 2. Pathways, which might provide base for modulation of tumorigenesis by the brain. Tumorigenesis might be modulated directly by compounds released bythe brain (e.g. melatonin; (A)) and by neurotransmitters released by vagal (acetylcholine; (B)) or sympathetic (norepinephrine, neuropeptide Y; (C)) postganglionicneurons. 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 postganglionicvagal neurons (VNpo) binds to the nicotine receptors of immune cells and produces an anti-inflammatory effect (B). Norepinephrine and neuropeptide Y releasedfrom postganglionic sympathetic neurons (SNpo) and epinephrine/norepinephrine released from adrenal medulla might influence immune functions after bindingto adrenergic receptors on the immune cells (C and D). Glucocorticoids released from adrenal cortex have complex effects on the immune system (E). The schemeomits the modulation of immune cells by somatic afferent sensory fibers that after being activated by inflammatory processes release neuropeptides via axonalreflex 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 giveneffects 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 playsimportant roles as well [108,109], possibly influencing the estab-

lishment of new immune cells and influencing the bone marrowmicroenvironment.

3.5.1.1. Humoral pathways. The main messengers of humoralcommunication between the brain and the immune system are



hormones released from the adenohypophysis [106]. It wasshown that after parturition, the function of the bone marrow,the thymus and the maintenance of immunocompetence becameall 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 actionon 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 shownthat �-MSH suppresses the nuclear factor-�B (NF-�B) activatedby 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 receptorsexpressed by immune cells. Whereas it was initially thoughtthat glucocorticoids mediate immunosuppression, more recentstudies indicate that they suppress Th1 and activate Th2 lym-phocytes [116]. Thus, ACTH-induced changes of the immunesystem activity are not always immunosuppressive, but ratherimmunomodulatory [67]. It is necessary to take into consid-eration that immune cells also possess a capacity to producesome hormones, e.g. PRL, GH [78]. Another humoral “effec-tor” of immunity is oxytocin, a hormone synthesized in thehypothalamus and secreted from the pituitary gland. Oxytocinhas immunomodulatory roles [117] and is relevant to tumori-genesis since it may have a role in suppressing the tumor cellproliferation [118]. As immune cells might synthesize some neu-rotransmitters, the interplay between hormones released fromCNS and immune cells might participate in the modulation ofimmune functions.

Neurohormones may suppress the activity of natural-killercells or cytotoxic T-cells, thus facilitating the tumors’ escapefrom immune surveillance [57,119]. Furthermore, the effectsof adrenal hormones on eliciting the Th2 immune profile mayinfluence the tumorigenesis since this profile has a prognosticvalue in certain cancers [120].

3.5.1.2. Neuronal pathways. Both the sympathetic andparasympathetic parts of the autonomic nervous system maymodulate immune processes in the organism. All lymphoidorgans receive autonomic innervation, and cells located in thelymphoid tissues possess receptors for transmitters releasedfrom 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]. Itis well documented that catecholamines released from sympa-thetic nerve endings modulate the function of many componentsof the immune system via adrenergic and purinergic receptorson immune cells [122,129–132]. Recent findings also show thatSNS plays an important role in the regulation of the egress ofhematopoietic cells from bone marrow [133]. Moreover, SNSmay modulate immune functions also by direct regulation ofblood flow via immune tissues [134]. Experimental data shows

that an interruption of SNS in animals produces either enhance-ment or suppression of inflammation, depending on the stage ofdevelopment, at which the system is ablated, and whether thesystem is interrupted at a local or systemic level [67].

It is well established that afferent neural pathways in thevagus nerve participate in the brain-mediated responses toinflammation [67]. In addition to this sensory function of thevagus nerve, an efferent or motor vagus nerve mechanism hasalso been described, by which acetylcholine, the principal vagusnerve neurotransmitter, inhibits cytokine release from residenttissue macrophages [135]. The findings show that both phar-macological and electrical stimulations of the vagus nerve canattenuate the systemic inflammatory response via cholinergicanti-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 haveimplications for tumorigenesis as well [9].

It is necessary to point out that lymphocytes of variousimmunological compartments were found to be equipped withthe key enzymes for the synthesis of both acetylcholine and cat-echolamines [138–140]. Therefore, the effects of acetylcholineand catecholamines released by immune cells in a paracrinemanner might co-operate/interfere with effect of neurotrans-mitters released by autonomic nerves within immunologicalcompartments.

3.5.2. Direct modulation of cancer by the brainIn analogy with the potential antimicrobial activity of

neuropeptides (substance P, neuropeptide Y, adrenomedullin,�-MSH, proenkephalin A) [141,142], arises a question as towhether the nervous system might produce substances withpotential tumor-modulating activity.

Receptors for neurotransmitters are often expressed in manyprimary human cancers [143]. Therefore, it is likely that tumorcells are susceptible to the same signal substances of the nervoussystem, 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 withdefined physiological action such as neurotransmitters, in themodulation of progression of cancer of various organs [144,145].

The data suggests that neurotransmitters might influenceapoptosis, mitogenesis, angiogenesis, and migration of cells aswell as the genesis of metastasis [19,20,146,147]. Therefore, itis not surprising that some researchers propose the use of com-pounds affecting of the neurotransmitters receptors as a noveland promising approach for treating patients with cancer [10].

The migration of breast, prostate and colon cancer cells isenhanced by the stress-related neurotransmitter norepinephrinein vitro, and this effect can be inhibited by �-blocker propranolol[148]. Serotonin is able to significantly increase the apoptosisof cells of Burkitt lymphoma. It is speculated that serotonergicinnervation 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]. Alsosubstance P is associated with various processes connected withtumorigenesis. SP might promote mitogenesis, angiogenesis,and genesis of metastasis [10]. It is suggested that SP released in



the skin might participate in photocarcinogenesis [151]. Whilethe majority of neurotransmitters have a stimulatory effect oncell migration, an endogenous substance amantadine and GABAexhibit an inhibitory effect [152,153]. The pineal gland and itsprincipal hormone melatonin are known to influence the ini-tiation and progression of cancer [154]. It is suggested thatmelatonin may have an anti-tumor activity [155]. Callaghan [43]hypothesized that melatonin is involved in the mechanism ofpsychological effects in the promotion of tumorigenesis. Dataindicates that brain-derived oxytocin might participate in modu-lation of the tumor progression [118]. This hormone has recentlybeen related to social support and synergistically interacts withits effects in reducing the stress-response [156]. Given that socialsupport predicts a better prognosis in several cancers [157], therole 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 thebrain or nerve endings in tumor tissues, or whether they aresynthesized by local non-neuronal (immune) cells and act inautocrine or paracrine manners [158].

Whereas the lack of innervation in tumors was a gener-ally accepted fact [159] recent experimental data suggests thatnerve cells infiltrate and innervate tumors [160,161]. Based onthese 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. Thesefactors may stimulate adjacent nerve cells to develop nerveaxons into the tumor. These nerve cells might in turn releaseneurotransmitters, for which the tumor cells are susceptible.It is suggested that innervations of the tumor might provideadditional support for a nerve-driven induction of metastasisdevelopment [20,164,165]. According to the concept of neuro-neoplastic synapse a question arises as to whether this structuremight represent a new target for cancer therapy [166].

3.6. Could the cholinergic anti-inflammatory pathway takepart 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 maybe regulated by NF-�B [167]. Therefore, the NF-�B pathwayplays an important role in linking the chronic inflammation withcancer [168], since disruption of the NF-�B pathway resultsin a strong reduction of cancer in models of colorectal andhepatocellular cancers [169].

Only recently it was discovered that there is a strong anti-inflammatory effect induced by the stimulation of efferent vagusnerve axons (the cholinergic anti-inflammatory pathway) [132].Even if some controversies regarding the anatomical and func-tional aspects of the cholinergic anti-inflammatory pathwayremains [124], it was repeatedly confirmed that acetylcholinereleased from postganglionic neurons of the vagus nerve inducesa profound inhibition of synthesis of pro-inflammatory cytokinesin 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 cholinergicanti-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 inhibitorof TNF production [172]. In the case of melanoma, the inter-pretation of these findings in relation to the vagus nerve needto be taken with caution since this nerve does not inner-vate the skin. Though CNI-1493 activates the efferent vagusfibers, it is possible that by the effects of the vagus on theHPA axis, a systemic suppression of circulating cytokines mayaid in melanoma treatment. Furthermore, anti-inflammatorypathways of the vagus nerve might also be activated by theoccupation 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 vagusefferent 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, preventcancer development [174]. Interestingly, it was shown thatNSAIDs modulate peripheral inflammation not only in regionsof inflammation, but also by affecting the CNS [175]. There-fore, the preventive effects of NSAIDs on cancer developmentmight be potentially mediated also by their actions via theCNS.

3.7. Is there a role for axon reflexes in modulation oftumorigenesis?

The main role of peripheral sensory nerve fibers is the trans-mission of information to the CNS allowing the host to sense andrespond to peripheral stimuli. However, peripheral sensory nervefibers are also capable of transmitting the signals antidromicallyvia branches of the peripheral nerves to transmit signals in thereverse direction back to the peripheral innervated tissues. Viathis so-called axon reflex, neuropeptides (e.g. SP, CGRP) arereleased from peripheral nerve endings into the tissues wherethey 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 andtumorigenesis.

3.8. Could a disrupted neural mechanism mean anincreased risk for accelerated tumorigenesis?

Czura and Tracey [123] suggest that autonomic dysfunctionof 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-associatedcachexia. Moreover, the presence of systemic inflammation isnow clearly linked with adverse prognosis in patients with can-cer, the fact of which cannot be fully explained by the association



with weight loss alone. Therefore, it is suggested, that the sys-temic inflammation remains an important therapeutic targetin combating the cachexia [176]. Whether the dysfunction ofneuroendocrine and immune interactions (e.g. cholinergic anti-inflammatory pathway) might predispose to cancer diseases andinfluence the progression of tumorigenesis needs to be investi-gated.

Shanks and Lightman [177] focused on the importance of thematernal–neonatal neuroimmune interactions. Some environ-mental stimuli might alter the development of these interactionsduring the intrauterine period. Shanks and Lightman [177] sug-gest that an altered neuroimmune developmental course mightcontribute to individual vulnerability to stress-related diseasesas well as inflammation in adulthood. Whether intrauter-ine alterations of neuroimmune system interactions mightpotentially increase the vulnerability to cancer remains to beinvestigated.

A rather simple manner for measuring such interactions is totest relations between pro-inflammatory cytokines and heart-ratevariability, the latter (primarily its high-frequency component)reflecting descending vagal activity. Normally, an inverse rela-tion exists between such parameters [178]. Future studies maywish to test whether the magnitude of (inverse) relations betweensuch parameters predicts a risk of cancer or cancer prognosis,reflecting poor neuroimmune modulation.

3.9. Modulation of tumorigenesis by the brain as a newtherapeutic approach

Various immunomodulatory methods for cancer therapy havebeen developed in recent years [179]. It is hypothesized thatimmunomodulation by the autonomic nervous system mightrepresent a new therapeutic approach for cancer [180].

Tracey [4] proposed a hypothetical “immunologicalhomunculus” which regulates various immune functions byselected brain areas. For example, elevated right-hemisphereactivity is associated with reduced natural-killer activity[181], which could be relevant to eradicating tumor cells.We suggest that modifying the activity of specific brainstructures involved in regulation of selected immune func-tions might represent one possible way of cancer therapyby immunomodulation. Finally, Gidron et al. [9] proposesto test the effects of vagal nerve stimulation on tumorige-nesis. Such efforts are currently underway by our researchteam.

3.10. What is the role of the CNS and tumor interactions inalternative therapeutic approaches?

Pavlov et al. [66] suggest a role of alternative therapeuticapproaches (e.g. hypnosis, biofeedback, acupuncture, and evenPavlovian conditioning) in modulating the inflammatory dis-eases. On the basis of the data reviewed in this article, it canbe suggested that all of these methods can potentially modulatethe inflammatory processes connected with the progression ofcancer via modulating the CNS–tumor interactions since thesetherapies influence the sympathoadrenal system and vagal activ-

ity [182,183] as well as immune functioning in cancer patients[184,185].

4. Conclusion

The data accumulated in the past decades indicate that thebrain is involved in etiopathogenesis of a much wider spectrumof diseases than previously expected. Various experimental andclinical data indicate that the brain might also be involved inetiopathogenesis of cancer. However, detection and modulationof tumorigenesis by the brain might represent a highly complexprocess with many unknown features.

Known facts:• The transmission of information from the immune system

to the central nervous system indicates that the brain mightbe involved in the monitoring of tumorigenesis or at least inmonitoring of the tumor-associated inflammatory and othersignals.

• The transmission of signals from the brain to the immunesystem constitutes the basis for modulating the cancergrowth by the brain.

• The brain might also modulate tumorigenesis directly vianeurotransmitters 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 thesesignals.

• Investigate the details of the role of the central nervoussystem in modulating the tumorigenesis.

• Answer the question as to whether the differences in mod-ulating the tumorigenesis by the brain (e.g. the density ofvagal innervation; changes in cholinergic anti-inflammatorypathway activity) might predispose to the development ofcancer.

• Develop the methods of modulating the complex processesassociated with tumorigenesis, from the level of cancer cellsto the level of the brain. We expect that cancer researchthat focuses on the role of the brain in tumorigenesis mightmarkedly extend our knowledge on the biology of cancer.

We suggest that solely interdisciplinary and integrativeoncological and neuroscientific approaches might effectivelyilluminate the possibility that the brain might “know” abouttumorigenesis 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 witha possible impact on prevention, diagnosis and therapy of tumordiseases.



Acknowledgments

This work was supported by the Slovak Research and Devel-opment Agency under the contract no. APVV-0045-06 andVEGA grant (1/4312/07).

References

[1] Besedovsky HO, Rey AD. Physiology of psychoneuroimmunology: apersonal view. Brain Behav Immun 2007;21:34–44.

[2] Razavi R, Chan Y, Afifiyan FN, Liu XJ, Wan X, Yantha J, et al. TRPV1+sensory neurons control beta cell stress and islet inflammation in autoim-mune diabetes. Cell 2006;127:1123–35.

[3] Gidron Y, Kupper N, Kwaijtaal M, Winter J, Denollet J. Vagus-braincommunication in atherosclerosis-related inflammation: a neuroim-munomodulation perspective of CAD. Atherosclerosis 2007;195:1–9.

[4] Tracey KJ. Physiology and immunology of the cholinergic antiinflamma-tory pathway. J Clin Invest 2007;117:289–96.

[5] Mareel M, Leroy A. Clinical, cellular, and molecular aspects of cancerinvasion. Physiol Rev 2003;83:337–76.

[6] Balkwill F, Coussens LM. Cancer: an inflammatory link. Nature2004;431:405–6.

[7] de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immunesystem during cancer development. Nat Rev Cancer 2006;6:24–37.

[8] Prolo P, Chiappelli F, Bernard G, Fiala M, Ibarra A, Sartori ML,et al. Neuroendocrine-immune surveillance of osteosarcoma: emerginghypothesis. J Dent Res 2003;82:417–21.

[9] Gidron Y, Perry H, Glennie M. Does the vagus nerve inform thebrain about preclinical tumours and modulate them? Lancet Oncol2005;6:245–8.

[10] Esteban F, Munoz M, Gonzalez-Moles MA, Rosso M. A role for substanceP in cancer promotion and progression: a mechanism to counteract intra-cellular death signals following oncogene activation or DNA damage.Cancer Metastasis Rev 2006;25:137–45.

[11] Mravec B, Hulin I. Does vagus nerve constitute a self-organization com-plexity or a “hidden network”? Bratisl Lek Listy 2006;107:3–8.

[12] Mravec B, Gidron Y, Kukanova B, Bizik J, Kiss A, Hulin I.Neural–endocrine–immune complex in the central modulation oftumorigenesis: facts, assumptions, and hypotheses. J Neuroimmunol2006;180:104–16.

[13] Serafeim A, Gordon J. The immune system gets nervous. Curr OpinPharmacol 2001;1:398–403.

[14] Blalock JE. The immune system as the sixth sense. J Intern Med2005;257:126–38.

[15] Meredith EJ, Chamba A, Holder MJ, Barnes NM, Gordon J. Closeencounters of the monoamine kind: immune cells betray their nervousdisposition. Immunology 2005;115:289–95.

[16] Ferencik M, Stvrtinova V. Is the immune system our sixth sense? Rela-tion between the immune and neuroendocrine systems. Bratisl Lek Listy1997;98:187–98.

[17] Blalock JE, Smith EM. Conceptual development of the immune systemas a sixth sense. Brain Behav Immun 2007;21:23–33.

[18] Berczi I, Chow DA, Baral E, Nagy E. Neuroimmunoregulation and cancer(review). Int J Oncol 1998;13:1049–60.

[19] Entschladen F, Drell 4th TL, Lang K, Joseph J, Zaenker KS. Neurotrans-mitters and chemokines regulate tumor cell migration: potential for anew pharmacological approach to inhibit invasion and metastasis devel-opment. Curr Pharm Des 2005;11:403–11.

[20] Lang K, Bastian P. Neurotransmitter effects on tumor cells and leukocytes.Prog Exp Tumor Res 2007;39:99–121.

[21] Conti A. Oncology in neuroimmunomodulation. What progress has beenmade? Ann NY Acad Sci 2000;917:68–83.

[22] Erin N, Boyer PJ, Bonneau RH, Clawson GA, Welch DR. Capsaicin-mediated denervation of sensory neurons promotes mammary tumormetastasis to lung and heart. Anticancer Res 2004;24:1003–9.

[23] Watt PC, Patterson CC, Kennedy TL. Late mortality after vagotomy anddrainage for duodenal ulcer. Br Med J (Clin Res Ed) 1984;288:1335–8.

[24] Caygill CP, Hill MJ, Kirkham JS, Northfield TC. Mortality from col-orectal and breast cancer in gastric-surgery patients. Int J Colorectal Dis1988;3:144–8.

[25] Caygill CP, Knowles RL, Hall R. Increased risk of cancer mortality aftervagotomy for peptic ulcer: a preliminary analysis. Eur J Cancer Prev1991;1:35–7.

[26] Ekbom A, Lundegardh G, McLaughlin JK, Nyren O. Relation of vago-tomy to subsequent risk of lung cancer: population based cohort study.BMJ 1998;316:518–9.

[27] Nelson RL, Briley S, Vaz OP, Abcarian H. The effect of vagotomyand pyloroplasty on colorectal tumor induction in the rat. J Surg Oncol1992;51:281–6.

[28] Caygill CP, Hill MJ, Kirkham JS, Northfield TC. Oesophageal cancer ingastric surgery patients. Ital J Gastroenterol 1993;25:168–70.

[29] Fisher SG, Davis F, Nelson R, Weber L, Haenszel W. Large bowel can-cer following gastric surgery for benign disease: a cohort study. Am JEpidemiol 1994;139:684–92.

[30] Lundegardh G, Ekbom A, McLaughlin JK, Nyren O. Gastric cancer riskafter vagotomy. Gut 1994;35:946–9.

[31] Bayon LAM, Landa GI, Alcalde EJ, Rodriguez DS, Ortega ML, BalibreaCJL. Colonic carcinogenesis in vagotomyzed rats. Rev Esp Enferm Dig2001;93:576–86.

[32] Bahmanyar S, Ye W, Dickman PW, Nyren O. Long-term risk of gastriccancer by subsite in operated and unoperated patients hospitalized forpeptic ulcer. Am J Gastroenterol 2007;102:1185–91.

[33] Jenkins JT, Duncan JR, Hole D, O’dwyer PJ, McGregor JR. Malignantdisease in peptic ulcer surgery patients after long term follow-up: a cohortstudy of 1992 patients. Eur J Surg Oncol 2007;33:706–12.

[34] Erin N, Zhao W, Bylander J, Chase G, Clawson G. Capsaicin-inducedinactivation of sensory neurons promotes a more aggressive geneexpression phenotype in breast cancer cells. Breast Cancer Res Treat2006;99:351–64.

[35] Hodgson DM, Yirmiya R, Chiappelli F, Taylor AN. Intracerebral HIVglycoprotein (gp120) enhances tumor metastasis via centrally releasedinterleukin-1. Brain Res 1998;781:244–51.

[36] Hodgson DM, Yirmiya R, Chiappelli F, Taylor AN. Intracerebralinterleukin-1beta impairs response to tumor invasion: involvement ofadrenal catecholamines. Brain Res 1999;816:200–8.

[37] Hodgson DM, Yirmiya R, Taylor AN. Intracerebroventricular interleukin-1beta impairs clearance of tumor cells from the lungs: role of brainprostaglandins. J Neuroimmunol 2001;119:57–63.

[38] Leo NA, Bonneau RH. Chemical sympathectomy alters cytotoxic T lym-phocyte responses to herpes simplex virus infection. Ann N Y Acad Sci2000;917:923–34.

[39] Tatsuta M, Iishi H, Baba M, Taniguchi H. Inhibition of azoxymethane-induced experimental colon carcinogenesis in Wistar rats by 6-hydroxydopamine. Int J Cancer 1992;50:298–301.

[40] Sood AK, Bhatty R, Kamat AA, Landen CN, Han L, Thaker PH, et al.Stress hormone-mediated invasion of ovarian cancer cells. Clin CancerRes 2006;12:369–75.

[41] Yang EV, Sood AK, Chen M, Li Y, Eubank TD, Marsh CB, et al. Nore-pinephrine up-regulates the expression of vascular endothelial growthfactor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyn-geal carcinoma tumor cells. Cancer Res 2006;66:10357–64.

[42] Wrona D. Neural–immune interactions: an integrative view of thebidirectional relationship between the brain and immune systems. J Neu-roimmunol 2006;172:38–58.

[43] Callaghan BD. Does the pineal gland have a role in the psychologicalmechanisms involved in the progression of cancer? Med Hypotheses2002;59:302–11.

[44] Kergozien S, Delcros JG, Jouan H, Moulinoux JP. Induction of Fos proteinexpression in spinal cord neurons of tumour-bearing rats. Br J Cancer1999;80:1512–7.

[45] Konsman JP, Blomqvist A. Forebrain patterns of c-Fos and FosB induc-tion during cancer-associated anorexia–cachexia in rat. Eur J Neurosci2005;21:2752–66.



[46] Hollis JH, Lightman SL, Lowry CA. Integration of systemic and vis-ceral sensory information by medullary catecholaminergic systems duringperipheral inflammation. Ann N Y Acad Sci 2004;1018:71–5.

[47] Tashiro M, Kubota K, Itoh M, Yoshioka T, Yoshida M, Nakagawa Y, etal. Hypometabolism in the limbic system of cancer patients observed bypositron emission tomography. Psychooncology 1999;8:283–6.

[48] Tashiro M, Itoh M, Kubota K, Kumano H, Masud MM, Moser E, et al.Relationship between trait anxiety, brain activity and natural killer cellactivity in cancer patients: a preliminary PET study. Psychooncology2001;10:541–6.

[49] Watson M, Haviland JS, Greer S, Davidson J, Bliss JM. Influence ofpsychological response on survival in breast cancer: a population-basedcohort study. Lancet 1999;354:1331–6.

[50] Spiegel D, Kato PM. Psychosocial influences on cancer incidence andprogression. Harv Rev Psychiatry 1996;4:10–26.

[51] Kiecolt-Glaser JK, Glaser R. Psychoneuroimmunology and cancer: factor fiction? Eur J Cancer 1999;35:1603–7.

[52] Petticrew M, Bell R, Hunter D. Influence of psychological coping onsurvival and recurrence in people with cancer: systematic review. BMJ2002;325:1066.

[53] Spiegel D. Cancer and depression. Br J Psychiatry Suppl 1996;109:16.[54] Spiegel D. Embodying the mind in psychooncology research. Adv Mind

Body Med 1999;15:267–73.[55] Reiche EM, Morimoto HK, Nunes SM. Stress and depression-induced

immune dysfunction: implications for the development and progressionof cancer. Int Rev Psychiatry 2005;17:515–27.

[56] Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, McDon-ald PG, et al. The influence of bio-behavioural factors on tumour biology:pathways and mechanisms. Nat Rev Cancer 2006;6:240–8.

[57] Ben-Eliyahu S, Shakhar G, Page GG, Stefanski V, Shakhar K. Suppres-sion of NK cell activity and of resistance to metastasis by stress: a rolefor adrenal catecholamines and beta-adrenoceptors. Neuroimmunomod-ulation 2000;8:154–64.

[58] Maier SF, Watkins LR. Intracerebroventricular interleukin-1 receptorantagonist blocks the enhancement of fear conditioning and interferencewith escape produced by inescapable shock. Brain Res 1995;695:279–82.

[59] Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y,et al. IL-1 is required for tumor invasiveness and angiogenesis. Proc NatlAcad Sci USA 2003;100:2645–50.

[60] Argaman M, Gidron Y, Ariad S. Interleukin-1 may link helplessness–hopelessness with cancer progression: a proposed model. Int J BehavMed 2005;12:161–70.

[61] Sephton S, Spiegel D. Circadian disruption in cancer: a neuroendocrine–immune pathway from stress to disease? Brain Behav Immun2003;17:321–8.

[62] Heffner KL, Loving TJ, Robles TF, Kiecolt-Glaser JK. Examining psy-chosocial factors related to cancer incidence and progression: in searchof the silver lining. Brain Behav Immun 2003;17:109–11.

[63] Gidron Y, Russ K, Tissarchondou H, Warner J. The relation betweenpsychological factors and DNA-damage: a critical review. Biol Psychol2006;72:291–304.

[64] Dantzer R, Konsman JP, Bluthe RM, Kelley KW. Neural and humoralpathways of communication from the immune system to the brain: parallelor convergent? Auton Neurosci 2000;85:60–5.

[65] Goehler LE, Gaykema RP, Hansen MK, Anderson K, Maier SF, WatkinsLR. Vagal immune-to-brain communication: a visceral chemosensorypathway. Auton Neurosci 2000;85:49–59.

[66] Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergicanti-inflammatory pathway: a missing link in neuroimmunomodulation.Mol Med 2003;9:125–34.

[67] Sternberg EM. Neural–immune interactions in health and disease. J ClinInvest 1997;100:2641–7.

[68] Mantovani A. The chemokine system: redundancy for robust outputs.Immunol Today 1999;20:254–7.

[69] Rothwell NJ, Hopkins SJ. Cytokines and the nervous system II: actionsand mechanisms of action. Trends Neurosci 1995;18:130–6.

[70] Quan N, Herkenham M. Connecting cytokines and brain: a review ofcurrent issues. Histol Histopathol 2002;17:273–88.

[71] Turrin NP, Rivest S. Unraveling the molecular details involved in theintimate link between the immune and neuroendocrine systems. Exp BiolMed 2004;229:996–1006.

[72] Watkins LR, Maier SF, Goehler LE. Cytokine-to-brain communi-cation: a review and analysis of alternative mechanisms. Life Sci1995;57:1011–26.

[73] Nadeau S, Rivest S. Effects of circulating tumor necrosis factor on theneuronal activity and expression of the genes encoding the tumor necrosisfactor receptors (p55 and p75) in the rat brain: a view from the blood–brainbarrier. Neuroscience 1999;93:1449–64.

[74] Szelenyi J. Cytokines and the central nervous system. Brain Res Bull2001;54:329–38.

[75] Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness behaviour:mechanisms and implications. Trends Neurosci 2002;25:154–9.

[76] Turnbull AV, Rivier CL. Regulation of the hypothalamic–pituitary–adrenal axis by cytokines: actions and mechanisms of action. PhysiolRev 1999;79:1–71.

[77] Rivest S. How circulating cytokines trigger the neural circuits that con-trol the hypothalamic–pituitary–adrenal axis. Psychoneuroendocrinology2001;26:761–88.

[78] Savino W, Dardenne M. Immune–neuroendocrine interactions. ImmunolToday 1995;16:318–22.

[79] Petrovsky N. Towards a unified model of neuroendocrine–immune inter-action. Immunol Cell Biol 2001;79:350–7.

[80] Shepherd AJ, Downing JE, Miyan JA. Without nerves, immunol-ogy remains incomplete—in vivo veritas. Immunology 2005;116:145–63.

[81] Blalock JE. The syntax of immune–neuroendocrine communication.Immunol Today 1994;15:504–11.

[82] Smith RS, Smith TJ, Blieden TM, Phipps RP. Fibroblasts as sentinel cells.Synthesis of chemokines and regulation of inflammation. Am J Pathol1997;151:317–22.

[83] Buckley CD, Pilling D, Lord JM, Akbar AN, Scheel-Toellner D, SalmonM. Fibroblasts regulate the switch from acute resolving to chronic per-sistent inflammation. Trends Immunol 2001;22:199–204.

[84] Kaufman J, Graf BA, Leung EC, Pollock SJ, Koumas L, Reddy SY, etal. Fibroblasts as sentinel cells: role of the CDcd40–CDcd40 ligand sys-tem in fibroblast activation and lung inflammation and fibrosis. Chest2001;120:S53–5.

[85] Paintal AS. Vagal sensory receptors and their reflex effects. Physiol Rev1973;53:159–227.

[86] Romanovsky AA, Ivanov AI, Szekely M. Neural route of pyrogen sig-naling to the brain. Clin Infect Dis 2000;31:S162–7.

[87] Ek M, Kurosawa M, Lundeberg T, Ericsson A. Activation of vagal affer-ents after intravenous injection of interleukin-1beta: role of endogenousprostaglandins. J Neurosci 1998;18:9471–9.

[88] Maier SF, Goehler LE, Fleshner M, Watkins LR. The role of thevagus nerve in cytokine-to-brain communication. Ann N Y Acad Sci1998;840:289–300.

[89] Perry VH. The impact of systemic inflammation on brain inflammation.ACNR 2004;4:8–9.

[90] Goehler LE, Gaykema RP, Hammack SE, Maier SF, Watkins LR.Interleukin-1 induces c-Fos immunoreactivity in primary afferent neuronsof the vagus nerve. Brain Res 1998;804:306–10.

[91] Hansen MK, Daniels S, Goehler LE, Gaykema RP, Maier SF,Watkins LR. Subdiaphragmatic vagotomy does not block intraperi-toneal lipopolysaccharide-induced fever. Auton Neurosci 2000;85:83–7.

[92] Licinio J, Wong ML. Pathways and mechanisms for cytokine signalingof the central nervous system. J Clin Invest 1997;100:2941–7.

[93] Goehler LE, Relton JK, Dripps D, Kiechle R, Tartaglia N, Maier SF, etal. Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist:a possible mechanism for immune-to-brain communication. Brain ResBull 1997;43:357–64.

[94] Goehler LE, Gaykema RP, Nguyen KT, Lee JE, Tilders FJ, MaierSF, et al. Interleukin-1beta in immune cells of the abdominal vagusnerve: a link between the immune and nervous systems? J Neurosci1999;19:2799–806.



[95] Roth J, De Souza GE. Fever induction pathways: evidence fromresponses to systemic or local cytokine formation. Braz J Med Biol Res2001;34:301–14.

[96] Hermann GE, Holmes GM, Rogers RC. TNF(alpha) modulation ofvisceral and spinal sensory processing. Curr Pharm 2005;11:1391–409.

[97] Rook GA, Lightman SL, Heijnen CJ. Can nerve damage disrupt neu-roendocrine immune homeostasis? Leprosy as a case in point. TrendsImmunol 2002;23:18–22.

[98] Ito N, DeMarco RA, Mailliard RB, Han J, Rabinowich H, Kalinski P, etal. Cytolytic cells induce HMGB1 release from melanoma cell lines. JLeukoc Biol 2007;81:75–83.

[99] Ramos EJ, Suzuki S, Marks D, Inui A, Asakawa A, Meguid MM. Canceranorexia–cachexia syndrome: cytokines and neuropeptides. Curr OpinClin Nutr Metab Care 2004;7:427–34.

[100] Bernstein IL. Neutral mediation of food aversions and anorexiainduced by tumor necrosis factor and tumors. Neurosci Biobehav Rev1996;20:177–81.

[101] Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, etal. Cytokine-associated emotional and cognitive disturbances in humans.Arch Gen Psychiatry 2001;58:445–52.

[102] Illman J, Corringham R, Robinson Jr D, Davis HM, Rossi JF, Cella D, et al.Are inflammatory cytokines the common link between cancer-associatedcachexia and depression? J Support Oncol 2005;3:37–50.

[103] Roberts JE. Light and immunomodulation. Ann N Y Acad Sci2000;917:435–45.

[104] Filipski E, King VM, Li X, Granda TG, Mormont MC, Liu X, et al. Hostcircadian clock as a control point in tumor progression. J Natl Cancer Inst2002;94:690–7.

[105] Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186–95.[106] Berczi I. Neuroimmune biology—an introduction. In: Berczi I, Gorezyn-

ski RM, editors. New foundation of biology. Amsterdam: ElsevierScience; 2001. p. 3–45.

[107] Brogden KA, Guthmiller JM, Salzet M, Zasloff M. The nervous sys-tem and innate immunity: the neuropeptide connection. Nat Immunol2005;6:558–64.

[108] Broome CS, Miyan JA. Neuropeptide control of bone marrow neutrophilproduction. A key axis for neuroimmunomodulation. Ann N Y Acad Sci2000;917:424–34.

[109] Maestroni GJ. Neurohormones and catecholamines as functional com-ponents of the bone marrow microenvironment. Ann N Y Acad Sci2000;917:29–37.

[110] Berczi I. The role of the growth and lactogenic hormone family in immunefunction. Neuroimmunomodulation 1994;1:201–16.

[111] Berczi I. Pituitary hormones and immune function. Acta Paediatr1997;423:70–5.

[112] Fabris N, Mocchegiani E, Provinciali M. Pituitary–thyroid axis andimmune system: a reciprocal neuroendocrine–immune interaction. HormRes 1995;43:29–38.

[113] Vamvakopoulos NC, Chrousos GP. Hormonal regulation of humancorticotropin-releasing hormone gene expression: implications forthe stress response and immune/inflammatory reaction. Endocr Rev1994;15:409–20.

[114] Manna SK, Aggarwal BB. Alpha-melanocyte-stimulating hormoneinhibits the nuclear transcription factor NF-kappa B activation inducedby various inflammatory agents. J Immunol 1998;161:2873–80.

[115] Ichiyama T, Sato S, Okada K, Catania A, Lipton JM. The neu-roimmunomodulatory peptide alpha-MSH. Ann N Y Acad Sci2000;917:221–6.

[116] Almawi WY, Melemedjian OK, Rieder MJ. An alternate mechanism ofglucocorticoid anti-proliferative effect: promotion of a Th2 cytokine-secreting profile. Clin Transplant 1999;13:365–74.

[117] Yang H, Wang L, Ju G. Evidence for hypothalamic paraventricularnucleus as an integrative center of neuroimmunomodulation. Neuroim-munomodulation 1997;4:120–7.

[118] Cassoni P, Sapino A, Marrocco T, Chini B, Bussolati G. Oxytocin andoxytocin receptors in cancer cells and proliferation. J Neuroendocrinol2004;16:362–4.

[119] Ben-Eliyahu S, Yirmiya R, Liebeskind JC, Taylor AN, Gale RP. Stressincreases metastatic spread of a mammary tumor in rats: evidence formediation by the immune system. Brain Behav Immun 1991;5:193–205.

[120] Inagaki A, Ishida T, Ishii T, Komatsu H, Iida S, Ding J, et al. Clini-cal significance of serum Th1-, Th2- and regulatory T cells-associatedcytokines in adult T-cell leukemia/lymphoma: high interleukin-5 and-10 levels are significant unfavorable prognostic factors. Int J Cancer2006;118:3054–61.

[121] Dardenne M, Savino W. Control of thymus physiology by peptidic hor-mones and neuropeptides. Immunol Today 1994;15:518–23.

[122] Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve-anintegrative interface between two supersystems: the brain and the immunesystem. Pharmacol Rev 2000;52:595–638.

[123] Czura CJ, Tracey KJ. Autonomic neural regulation of immunity. J InternMed 2005;257:156–66.

[124] Nance DM, Sanders VM. Autonomic innervation and regulation of theimmune system (1987–2007). Brain Behav Immun 2007;21:736–45.

[125] Weigent DA, Blalock JE. Interactions between the neuroendocrineand immune systems: common hormones and receptors. Immunol Rev1987;100:79–108.

[126] Stevens-Felten SY, Bellinger DL. Noradrenergic and peptidergic inner-vation of lymphoid organs. Chem Immunol 1997;69:99–131.

[127] Basu S, Dasgupta PS. Dopamine, a neurotransmitter, influences theimmune system. J Neuroimmunol 2000;102:113–24.

[128] Denes A, Boldogkoi Z, Uhereczky G, Hornyak A, Rusvai M, PalkovitsM, et al. Central autonomic control of the bone marrow: multisy-naptic tract tracing by recombinant pseudorabies virus. Neuroscience2005;134:947–63.

[129] Elenkov IJ, Hasko G, Kovacs KJ, Vizi ES. Modulation oflipopolysaccharide-induced tumor necrosis factor-alpha production byselective alpha- and beta-adrenergic drugs in mice. J Neuroimmunol1995;61:123–31.

[130] Vizi ES, Orso E, Osipenko ON, Hasko G, Elenkov IJ. Neurochemical,electrophysiological and immunocytochemical evidence for a noradren-ergic link between the sympathetic nervous system and thymocytes.Neuroscience 1995;68:1263–76.

[131] Hasko G, Szabo C. Regulation of cytokine and chemokine productionby transmitters and co-transmitters of the autonomic nervous system.Biochem Pharmacol 1998;56:1079–87.

[132] Tracey KJ. The inflammatory reflex. Nature 2002;420:853–9.[133] Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA, et

al. Signals from the sympathetic nervous system regulate hematopoieticstem cell egress from bone marrow. Cell 2006;124:407–21.

[134] Vizi ES. Receptor-mediated local fine-tuning by noradrenergic inner-vation of neuroendocrine and immune systems. Ann N Y Acad Sci1998;851:388–96.

[135] Borovikova LV, Ivanova S, Nardi D, Zhang M, Yang H, Ombrellino M, etal. Vagus nerve stimulation attenuates the systemic inflammatory responseto endotoxin. Nature 2000;405:458–62.

[136] Bernik TR, Friedman SG, Ochani M, DiRaimo R, Ulloa L, Yang H,et al. Pharmacological stimulation of the cholinergic antiinflammatorypathway. J Exp Med 2002;195:781–8.

[137] Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al.NF-kappaB functions as a tumour promoter in inflammation-associatedcancer. Nature 2004;431:461–6.

[138] Rinner I, Felsner P, Liebmann PM, Hofer D, Wolfler A, Globerson A, etal. Adrenergic/cholinergic immunomodulation in the rat model-in vivoveritas? Dev Immunol 1998;6:245–52.

[139] Kawashima K, Fujii T. The lymphocytic cholinergic system and its bio-logical function. Life Sci 2003;72:2101–9.

[140] Qiu YH, Peng YP, Jiang JM, Wang JJ. Expression of tyrosine hydroxylasein lymphocytes and effect of endogenous catecholamines on lymphocytefunction. Neuroimmunomodulation 2004;11:75–83.

[141] Kowalska K, Carr DB, Lipkowski AW. Direct antimicrobial properties ofsubstance P. Life Sci 2002;71:747–50.

[142] Metz-Boutigue MH, Goumon Y, Strub JM, Lugardon K, AunisD. Antimicrobial chromogranins and proenkephalin-A-derived pep-



tides: Antibacterial and antifungal activities of chromogranins andproenkephalin-A-derived peptides. Ann N Y Acad Sci 2003;992:168–78.

[143] Reubi JC. Peptide receptors as molecular targets for cancer diagnosis andtherapy. Endocr Rev 2003;24:389–427.

[144] Heasley LE. Autocrine and paracrine signaling through neuropeptidereceptors in human cancer. Oncogene 2001;20:1563–9.

[145] Schuller HM. Neurotransmitter receptor-mediated signaling pathwaysas modulators of carcinogenesis. Prog Exp Tumor Res 2007;39:45–63.

[146] Drell 4th TL, Joseph J, Lang K, Niggemann B, Zaenker KS, EntschladenF. Effects of neurotransmitters on the chemokinesis and chemotaxis ofMDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat2003;80:63–70.

[147] Zukowska Z, Grant DS, Lee EW. Neuropeptide Y: a novel mecha-nism for ischemic angiogenesis. Trends Cardiovasc Med 2003;13:86–92.

[148] Lang K, Drell 4th TL, Lindecke A, Niggemann B, Kaltschmidt C, ZaenkerKS, et al. Induction of a metastatogenic tumor cell type by neurotransmit-ters and its pharmacological inhibition by established drugs. Int J Cancer2004;112:231–8.

[149] Serafeim A, Grafton G, Chamba A, Gregory CD, Blakely RD, BoweryNG, et al. 5-Hydroxytryptamine drives apoptosis in biopsylike Burkittlymphoma cells: reversal by selective serotonin reuptake inhibitors. Blood2002;99:2545–53.

[150] Tarr JM, Eggleton P, Winyard PG. Nitric oxide and the regulation ofapoptosis in tumour cells. Curr Pharm Des 2006;12:4445–68.

[151] Legat FJ, Wolf P. Photodamage to the cutaneous sensory nerves: rolein photoaging and carcinogenesis of the skin? Photochem Photobiol Sci2006;5:170–6.

[152] Joseph J, Niggemann B, Zaenker KS, Entschladen F. The neurotransmittergamma-aminobutyric acid is an inhibitory regulator for the migra-tion of SW 480 colon carcinoma cells. Cancer Res 2002;62:6467–9.

[153] Joseph J, Niggemann B, Zaenker KS, Entschladen F. Anandamide is anendogenous inhibitor for the migration of tumor cells and T lymphocytes.Cancer Immunol Immunother 2004;53:723–8.

[154] Giannoulia-Karantana A, Vlachou A, Polychronopoulou S, Papas-sotiriou I, Chrousos GP. Melatonin and immunomodulation: con-nections and potential clinical applications. Neuroimmunomodulation2006;13:133–44.

[155] Kajdaniuk D, Marek B, Kos-Kudła B, Ciesielska-Kopacz N, Buntner B.Oncostatic effect of melatonin action—facts and hypotheses. Med SciMonit 1999;5:RA350–6.

[156] Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U. Social supportand oxytocin interact to suppress cortisol and subjective responses topsychosocial stress. Biol Psychiatry 2003;54:1389–98.

[157] Soler-Vila H, Kasl SV, Jones BA. Prognostic significance of psychoso-cial factors in African–American and white breast cancer patients: apopulation-based study. Cancer 2003;98:1299–308.

[158] Russo P, Catassi A, Cesario A, Servent D. Development of novel thera-peutic strategies for lung cancer: targeting the cholinergic system. CurrMed Chem 2006;13:3493–512.

[159] Vachkov IH, Huang X, Yamada Y, Tonchev AB, Yamashima T, Kato S, etal. Inhibition of axonal outgrowth in the tumor environment: involvementof class 3 semaphorins. Cancer Sci 2007;98:1192–7.

[160] Seifert P, Spitznas M. Tumours may be innervated. Virchows Arch2001;438:228–31.

[161] Seifert P, Benedic M, Effert P. Nerve fibers in tumors of the human urinarybladder. Virchows Arch 2002;440:291–7.

[162] Palm D, Entschladen F. Neoneurogenesis and the neuro-neoplasticsynapse. Prog Exp Tumor Res 2007;39:91–8.

[163] Zanker KS. The neuro-neoplastic synapse: does it exist? Prog Exp TumorRes 2007;39:154–61.

[164] Entschladen F, Palm D, Lang K, Drell 4th TL, Zaenker KS. Neoneu-rogenesis: tumors may initiate their own innervation by the release ofneurotrophic factors in analogy to lymphangiogenesis and neoangiogen-esis. Med Hypotheses 2006;67:33–5.

[165] Lang K, Entschladen F, Weidt C, Zaenker KS. Tumor immune escapemechanisms: impact of the neuroendocrine system. Cancer ImmunolImmunother 2006;55:749–60.

[166] Muller JM. Potential inhibition of the neuro-neoplastic interactions: theclue of a GPCR-targeted therapy. Prog Exp Tumor Res 2007;39:130–53.

[167] Houghton J, Morozov A, Smirnova I, Wang TC. Stem cells and cancer.Semin Cancer Biol 2007;17:191–203.

[168] Li Q, Withoff S, Verma IM. Inflammation-associated cancer: NF-kappaBis the lynchpin. Trends Immunol 2005;26:318–25.

[169] Maeda A, Ebata T, Matsunaga K, Kanemoto H, Bando E, Yamaguchi S, etal. Primary liver cancer with bidirectional differentiation into hepatocytesand biliary epithelium. J Hepatobiliary Pancreat Surg 2005;12:484–7.

[170] Gallowitsch-Puerta M, Pavlov VA. Neuro-immune interactions via thecholinergic anti-inflammatory pathway. Life Sci 2007;80:2325–9.

[171] Borovikova LV, Ivanova S, Nardi D, Zhang M, Yang H, Ombrellino M,et al. Role of vagus nerve signaling in CNI-1493-mediated suppressionof acute inflammation. Auton Neurosci 2000;85:141–7.

[172] Atkins MB, Redman B, Mier J, Gollob J, Weber J, Sosman J, et al. A phaseI study of CNI-1493, an inhibitor of cytokine release, in combination withhigh-dose interleukin-2 in patients with renal cancer and melanoma. ClinCancer Res 2001;7:486–92.

[173] Guarini S, Cainazzo MM, Giuliani D, Mioni C, Altavilla D, Marini H,et al. Adrenocorticotropin reverses hemorrhagic shock in anesthetizedrats through the rapid activation of a vagal anti-inflammatory pathway.Cardiovasc Res 2004;63:357–65.

[174] Shiff SJ, Shivaprasad P, Santini DL. Cyclooxygenase inhibitors: drugsfor cancer prevention. Curr Opin Pharmacol 2003;3:352–61.

[175] Catania A, Arnold J, Macaluso A, Hiltz ME, Lipton JM. Inhibition ofacute inflammation in the periphery by central action of salicylates. ProcNatl Acad Sci USA 1991;88:8544–7.

[176] Deans C, Wigmore SJ. Systemic inflammation, cachexia and prognosisin patients with cancer. Curr Opin Clin Nutr Metab Care 2005;8:265–9.

[177] Shanks N, Lightman SL. The maternal–neonatal neuro-immune inter-face: are there long-term implications for inflammatory or stress-relateddisease? J Clin Invest 2001;108:1567–73.

[178] Janszky I, Ericson M, Lekander M, Blom M, Buhlin K, Georgiades A,et al. Inflammatory markers and heart rate variability in women withcoronary heart disease. J Intern Med 2004;256:421–8.

[179] Waldmann TA. Effective cancer therapy through immunomodulation.Annu Rev Med 2006;57:65–81.

[180] Abo T, Kawamura T. Immunomodulation by the autonomic nervous sys-tem: therapeutic approach for cancer, collagen diseases, and inflammatorybowel diseases. Ther Apher 2002;6:348–57.

[181] Davidson RJ, Coe CC, Dolski I, Donzella B. Individual differences inprefrontal activation asymmetry predict natural killer cell activity at restand in response to challenge. Brain Behav Immun 1999;2:93–108.

[182] Bernardi L, Sleight P, Bandinelli G, Cencetti S, Fattorini L, Wdowczyc-Szulc J, et al. Effect of rosary prayer and yoga mantras on autonomiccardiovascular rhythms: comparative study. BMJ 2001;323:1446–9.

[183] Infante JR, Torres-Avisbal M, Pinel P, Vallejo JA, Peran F, Gonzalez F, etal. Catecholamine levels in practitioners of the transcendental meditationtechnique. Physiol Behav 2001;72:141–6.

[184] Gruber BL, Hersh SP, Hall NR, Waletzky LR, Kunz JF, Carpenter JK,et al. Immunological responses of breast cancer patients to behavioralinterventions. Biofeedback Self Regul 1993;18:1–22.

[185] Bakke AC, Purtzer MZ, Newton P. The effect of hypnotic-guided imageryon psychological well-being and immune function in patients with priorbreast cancer. J Psychosom Res 2002;53:1131–7.

[186] Sidransky D. Emerging molecular markers of cancer. Nat Rev Cancer2002;2:210–9.

[187] Silzle T, Randolph GJ, Kreutz M, Kunz-Schughart LA. The fibroblast:sentinel cell and local immune modulator in tumor tissue. Int J Cancer2004;108:173–80.

[188] Tlsty TD, Hein PW. Know thy neighbor: stromal cells can contributeoncogenic signals. Curr Opin Genet Dev 2001;11:54–9.

[189] Straub RH, Westermann J, Scholmerich J, Falk W. Dialogue betweenthe CNS and the immune system in lymphoid organs. Immunol Today1998;19:409–13.

Documents

Neurobiology of Cancer Interactions Between Nervous, Endocrine and Immune Systems as a Base for Monitoring and Modulating the Tumorigenesis by the Brain