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Oncol Lett. 2013 Apr; 5(4): 11011111.

Published online 2013 Jan 31. doi: 10.3892/ol.2013.1168
PMCID: PMC3629128
Role of the nervous system in cancer metastasis
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This article has been cited by other articles in PMC.
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The notion that tumors lack innervation was proposed several years ago. However,
nerve fibers are irregulatedly found in some tumor tissues. Their terminals int
eraction with cancer cells are considered to be neuro-neoplastic synapses. Moreo
ver, neural-related factors, which are important players in the development and
activity of the nervous system, have been found in cancer cells. Thus, they esta
blish a direct connection between the nervous system and tumor cells. They modul
ate the process of metastasis, including degradation of base membranes, cancer c
ell invasion, migration, extravasation and colonization. Peripheral nerve invasi
on provides another pathway for the spread of cancer cells when blood and lympha
tic metastases are absent, which is based on the interactions between the microe
nvironments of nerve fibers and tumor cells. The nervous system also modulates a
ngiogenesis, the tumor microenvironment, bone marrow, immune functions and infla
mmatory pathways to influence metastases. Denervation of the tumor has been repo
rted to enhance cancer metastasis. Stress, social isolation and other emotional
factors may increase distant metastasis through releasing hormones from the brai
n, the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Disrupt
ion of circadian rhythms will also promote cancer metastasis through direct and
indirect actions of the nervous system. Therefore, the nervous system plays an i
mportant role in cancer metastasis.
Keywords: nervous system, cancer metastasis
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Search strategies and selection criteria
Connection, communication and interaction between the neural system and cancer c
Nerve invasion is another route for cancer cell dissemination
The nervous system modulates angiogenesis and microenvironments in tumors to aff
ect metastasis
Nervous system interacts with immune function and inflammation to influence canc
er metastasis
Interactions between bone marrow and nervous system: implication for cancer meta
Cancer as an independent organ is being recognized and should not be isolated fr
om the nervous system
Clinical and biological implications for the role of the nervous system in cance
r metastasis
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1. Introduction
Since the 1970s, it has been generally accepted in the field of pathology that t
umors lack innervation (1). However, the nervous system is a superordinate struc
ture in the body and controls the functions and activities of virtually all othe
r tissues and organs. Cancer tissues are not isolated structures within organism
s, therefore they should also interact with the neural system. This speculation
has been testified from clinical, epidemiological and experimental studies.
One the one hand, neural functions and tissues exert important functions on canc
er initiation and development. Firstly, psychological and behavioral factors, su
ch as chronic stress, depression and social isolation, are considered to contrib
ute to the initiation and progression of certain types of cancer (26). Stress is
inevitable in human life. The brain is the key organ of the response to stress (
7). In the whole brain, activation of the hypothalamic-pituitary-adrenal axis (H
PA) plays an important role in the response (2,7). Thus, acting on certain areas
in the brain has been reported to influence the growth and development of cance
r (810). Secondly, the peripheral nervous system is also involved in cancer. 6-Hy
droxydopamine was shown to influence the growth rate of certain tumors (11) and
induce neuronal changes on the sympathetic nervous system to augment the growth
of neuroblastoma (12), suggesting that an intact functional sympathetic nervous
system is necessary for certain tumors. Peripheral nerve fibers were found to in
nervate some tumors (1316). Neurons of dorsal root ganglia interact with cancer c
ells (1719). Denervation of a tumor also alters the behavior of tumor growth (2022
). Peripheral nerve invasion (PNI) induced by cancer is an independent factor fo
r poor prognosis in some cancer patients (2326).
On the other hand, cancer also has remote effects on neural tissues (2729). These
facts indicate that there is a bidirectional correlation between the nervous sy
stem and cancer and challenge the traditional view that cancers lack innervation
. Therefore, the role of the nervous system in cancer is gaining attention in ca
ncer research (5, 2931). Recently, the study by Sloan et al(32) study further sho
wed that stress increases distant metastases but has little effect on primary tu
mor growth, prompting our interest in investigating the role of the nervous syst
em in cancer metastasis.
It is well known that metastasis is the major cause of mortality from solid carc
inomas. Despite great advances in metastasis research, the prognosis remains ext
remely poor. The formation of metastasis is a complex and sequential process, in
volving four basic steps: i) departure from the primary tumor, ii) survival in t
he circulatory system, iii) breaching of endothelium and basement membrane of ta
rget organs, and iv) establishment of a colony of metastatic cells (33). In thes
e steps, immune functions, inflammation, organic microenvironments and bone marr
ow are involved (3440), all of which are directly or indirectly regulated by the
nervous system. Thus, cancer metastasis may also establish connections with the
nervous system through these pathophysiological changes and functional organs. T
herefore, the nervous system may play an essential role in cancer metastasis. To
gain a more comprehensive understanding of the role of the nervous system in ca
ncer metastasis, we reviewed English-language literature on this topic and analy
zed how the nervous system exerts its functions in cancer metastasis.
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2. Search strategies and selection criteria
The literature-based review was conducted by searching for keywords in Pubmed an
d Google Scholar using the search terms: cancer, tumor, neoplasm, malignant, metasta
read pathway, stress, depression, cancer-related neural disease, immune, inflammati
endocrine, hypothalamic-pituitary-adrenal axis, innervation, nervous system, neurotra
itters, neurotrophic factors, semaphorins, psychoneuroimmunology, sympathetic, vaga
us. Only papers published in English prior to March 2012 and focusing on the asso
ciation between the nervous system and cancer metastasis were included.
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3. Connection, communication and interaction between the neural system and cancer
The nervous system is formed of the central and peripheral nervous systems, whic
h modulate the functions of the whole body through two main methods. The first i
s that they have a direct connection through a specific structure of classical o
r non-classical synapses. The other is that they interact with each other throug
h humoral modulations. If the two methods are also found in cancer, the connecti
on between the nervous system and cancer will be established.
Classical and non-classical synapse structures are the elements by which neurons
innervate other tissues. Several lines of evidence also support the existence o
f these anatomical structures in tumor tissues. Nerve fibers have been found in
certain tumor tissues, which may be due to i) the possibility of nerve fiber inn
ervation vessels in cancer tissues, ii) the persistence of pre-existing nerves,
or nerves becoming included within the cancer owing to the invasive character of
its growth, iii) nerve endings growing into cancer tissue, or iv) an integral p
art of the cancerous growth (41). The first possibility was excluded in the stud
y by Mitchell et al(42). Although the second possibility exists and often leads
to cancer pain, this type of nerve fiber is surrounded by cancer tissues and har
dly exerts any function on cancer cells. The latter two were also observed in pr
evious studies. Nerve fibers in central tumor areas were observed by Seifert et
al(13,14,43) using a transmission electron microscope. These nerve fibers in tum
or tissues were irregularly distributed and had abnormal morphologies, which ind
icated that occurrences of these abnormal nerve fibers were accompanied with tum
or tissues but not the pre-existing nerve fibers in corresponding normal tissues
(44). Experimental studies showed that rectal cancer cells stimulated neurogene
sis when they were cocultured with neuroepithelial cells (18). Thus, denervation
by resection, capsaicin or vagotomy slows tumor growth (2022) and promotes cance
r progression and metastasis (4547). These facts indicate that neuro-neoplastic s
ynapses may exist between nerve fibers and tumor cells (48,49), and that neuroge
nesis, like angiogenesis, is also a trait of cancer cells (18,48,50,51). Thus, i
n primary and pre-metastatic organs, cancer cells actively establish connections
with nerve fibers and receive signals from the nervous system.
Although the above studies indicated that tumor tissues were innervated, others
do not support this theory (42,52,53). However, humoral modulation is the altern
ative means for the neural system to modulate other organs, which is also found
in cancer. The axes of the systems of the HPA and autonomic nervous system (ANS)
are typical pathways of humoral modulation through releasing hormones and neuro
transmitters to bind corresponding receptors in other tissues to modulate functi
ons of various tissues, including cancer. Thus, making lesions in these areas ha
ve significant effects on the behavior of cancer growth and metastasis. For exam
ple, Pollak et al(54) showed that hypophysectomy inhibited metastatic behavior i
n murine osteosarcoma. Function of the pineal gland and effect of spatial disori
entation had an important influence on metastasis (55). These effects were mainl
y via humoral modulators, including neurotransmitters and neuropeptides, neurotr
ophic factors, semaphorins and other axon growth factors. These modulators of ne
ural development and maintainence have been found to exert essential functions i
n cancer growth and development, and have been studied and reviewed by numerous
authors (5695). Cancer cells also express these molecules and their receptors. Fo
r example, breast cancer cells can express -endorphin (96), and transplantation o
f -endorphin neurons into the hypothalamus inhi it the growth and metastasis of m
ammary carcinoma (97). Cancer cells also promote neurite formation through gener
ating neutrophic factors and axon growth molecules (98). Thus, they will esta li
sh a connection with the nervous system through humoral modulation.
Thus, the existence of neuro-neoplastic synapses and receptors of neural markers
in cancer cells provides a su stantial asis for communication etween neurons
and cancer cells. Recent studies have shown that the nervous system influences t
he process of cancer metastasis through nerve endings and humoral modulations (3
2,40,4447,58,67,7579,85,97,98). For cancer cells to form metastases in ectopic sit
es, they must depart from the primary tumor and conquer the arriers of primary
tissue inhi ition. Proteolytic enzymes can help tumor cells escape from primary
cancer; i.e. y degrading the surrounding normal tissues. In this process, the o
verexpression of matrix metalloproteinases (MMPs) in tumor cells is one of the m
ost sustained events (99,100); this may e induced y stress, neural-related fac
tors and neurotransmitters. For example, Wu et al(101) reported that stress due
to social isolation enhanced invasion and metastasis of colon cancer cells throu
gh increasing proteolytic proteases. Yang et al(102) also found that stress modu
lates levels of MMPs through activation of the HPA and sympathetic-adrenal medul
lary (SAM) axes. Heregulin-1 and nerve growth factor, as essential factors in the
normal development of the nervous system, mediate the activation of MMP-9 and M
MP-2 to promote invasion of reast cancer cells (103) and pancreatic cancer cell
s (104,105). Neurotrophins also promote invasion y enhancing the production of
asement mem rane-degradative enzymes (106). Norepinephrine (NE) and -aminobutyri
c acid as classical neurotransmitters upreulate the expression of MMPs in nasop
haryneal cancer cells (107) and cancer cells of the prostate (108). Anoikis, a
form of apoptosis, results from loss of cell-matrix interactions and acts as a p
hysioloical barrier to metastasis (109). Tropomyosin receptor kinase B (TrkB),
a receptor of brain-derived neurotrophic factor (BDNF), induces cancer metastasi
s by suppression of anoikis (110112). Miration of cancer cells is a prerequisite
for metastasis. Axon-uidance molecules, such as slits, semaphorins and netrins
, can naviate or inhibit miration of cancer cells (77,85,113117). The neurotran
smitter/receptor system is also involved in cancer cell miration (118). NE, a c
lassical neurotransmitter, has a stimulatory effect on the miration of colon ca
rcinoma cells (119) and breast cancer cells (120). A similar role was also repor
ted for dopamine and neuropeptides, includin met-enkephalin, substance P and bo
mbesin (120). -aminobutyric acid as an inhibitory neurotransmitter in the brain i
nhibits the miratory activity of colon carcinoma cells (121). Althouh these su
bstances are also expressed in other orans (122) and tumor cells, inhibition of
the activity of correspondin neurons can reverse their effects on cancer cells
. For example, - lockers acting on the ANS inhi it the migration of cancer cells
induced y NE (119). Chemokines exerting important effects on neurogenesis and
rain development (123,124) are also important modulators of cancer metastasis (1
25127). In the process of cancer cell migration through the lood system, 99.9% o
f cancer cells are killed, which is called metastatic inefficiency (128). Mechan
ical forces including shear stress contri ute to this inefficiency (129,130) whi
le the shear force is mainly due to vasomotor changes. Nerve endings and recepto
rs of neuropeptides are distri uted in vascular walls (131). Based on the anatom
ical structures, the nervous system modulates the vascular functions, leading to
changes in vascular dilation and constriction that can produce mechanical force
s. Vascular permea ility is important for cancer cell extravasation and coloniza
tion. Neuropeptides increase vascular permea ility (132,133) to promote cancer c
ell extravasation and colonization. Thus, the process of cancer cell departure f
rom the primary tumor, invasion, migration, cancer cell inefficiency, extravasat
ion and colonization are associated with the nervous system.
Therefore, the connections etween the neural system and cancer through synapse,
non-synapse or humoral modulation make it possi le to esta lish reciprocal inte
ractions and communications etween cancers and neurons.
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4. Nerve invasion is another route for cancer cell dissemination
Tumor dissemination from primary cancer is the first step in the formation of me
tastatic tumors at distant sites. Three major routes are considered to e involv
ed in the spread of tumor cells: lymphatic vessels, lood vessels and serosal su
rfaces (130). The route of cancer cells along nerve fi ers has een a forgotten
pathway (134). Recently, PNI has een found in certain types of malignancies and
identified to e another pathway for cancer cell dissemination, particularly in
the a sence of lymphatic or hematogenous metastasis (26). Although PNI has not
een considered as a routine test in pathological reports, it has een identifie
d as a key pathological feature in tumors and is used to predict clinical outcom
es in many cancers (18,2326,135143).
It remains unknown what drives cancer cells to migrate along nerve fi ers. In ad
dition, since PNI has een accepted as an emerging route for cancer cell dissemi
nation, PNI requires further definition. For the past 40 years, the predominant
theory regarding the pathogenesis of PNI is that distri uted tumor cells have th
e privilege of a low-resistance plane in the neural sheaths, which serves as a c
onduit for their migration. However, recent studies have shown that reciprocal s
ignaling interactions etween tumor cells and nerves may contri ute to PNI. To e
xplore these interactions, it is necessary to clarify the process of neurite for
mation. It has een shown that neurotrophic factors (NGF) and axonal guidance mo
lecules are vital for axonal growth (144149). These molecules and their correspon
ding receptors are also found in tumor cells (61,64,84,86,115), which provide th
e possi ility for cancer cells to ind to the neurite (150). In addition, stroma
l cells, extracellular matrix and their releasing factors are also involved in t
he process of axonal formation (151), and are also important for tumor cell migr
ation. Thus, these tumor cells spreading along neural fi ers may acquire the a i
lity to respond to proinvasive signals within the peripheral nerve milieu and e
come neurotrophic. It is known that nerve fi ers are composed of three layers, t
he epineurium, perineurium and endoneurium, from the outside to the inside. Acco
rding to the definition of Lie ig et al, when tumor cells are found within any o
f the three layers of the nerve sheath or tumor foci outside of the nerve with i
nvolvement of 33% of the nerve's circumference, PNI may e diagnosed (26). This
definition provides a new concept in the study of cancer cell dissemination.
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5. The nervous system modulates angiogenesis and microenvironments in tumors and a
ffects metastasis
Angiogenesis is vital for the development of metastasis (152154). Vascular endoth
elial growth factor (VEGF) plays an important role in the process of angiogenesi
s. Several reports have demonstrated that psychological factors influence tumor
angiogenesis in certain types of cancer through regulating of VEGF level. Chroni
c stress is common in cancer patients and often causes depression and ad moods.
It has een reported that chronic stress mediates the vascularization of intrap
eritoneal metastasis and enhances tumor angiogenesis in the xenograft models of
ovarian cancer via increasing VEGF expression (155,156). SNS can e activated in
stressed animals (155) and may release neurotransmitters. These neurotransmitte
rs, such as NE, dopamine and radykinin, have een reported to induce or suppres
s VEGF expression (132,158161). Thus, the possi le mechanism for chronic stress t
o enhance tumor angiogenesis may e that neurotransmitters released y activated
SNS regulate VEGF expression to promote angiogenesis, which is also applica le
to social isolation. It was reported that a perceived lack of social isolation w
as associated with elevated intratumoral NE in ovarian carcinoma patients. The e
levated NE levels were correlated with high grade and advanced stage tumor (162)
and indicated metastasis, which may e due to that NE induce VEGF expression an
d thus lead to stimulate angiogenesis (158). Other neural-related factors also h
ave important effects on tumor angiogenesis. Axon growth molecules such as neuro
pilins and semaphorins can promote or inhi it angiogenesis (63,86,163166). A neur
opeptide, calcitonin gene-related peptide (CGRP), can facilitate tumor-associate
d angiogenesis (167). Although it is expressed y other tissues, this experiment
testifies that it is derived from neuronal systems. Neuropeptide Y also promote
s angiogenesis through regulation of VEGF (168). Circadian rhythm is a asic reg
ulator of normal physiology. Its disruption can also accelerate tumor growth thr
ough a Wnt signaling pathway (169), a critical pathway to regulate angiogenesis
(170,171). Thus, the neural system is capa le of modulating the process of angio
genesis. Moreover, neurogenesis also exists as a trait of certain types of cance
r. Cancer cells also express these neural-related factors and their receptors. I
n fact, there are common molecules etween angiogenesis and neurogenesis (172174)
, indicating that they may occur in concert in tumors and collectively exert fun
ctions on cancer metastasis (175).
The microenvironment regulates not only the growth of primary cancer ut also th
e formation of metastasis, which is formed mainly of stromal cells and signal mo
lecules. On the one hand, these cells and molecules have a direct or indirect co
rrelation with the nervous system (73). Within the tumor microenvironment, strom
al cells express -adrenergic receptors that may e activated y neurotransmitters
from local sympathetic nerve fi ers and circulating lood. Macrophages in tumor
microenvironments are important players in cancer metastasis, and are the key t
argets of -adrenergic regulation in several cancer contexts (73). Certain molecul
es produced and released y neural tissues are the important origins of signals
in the tumor microenvironment (176). However, stromal and tumor cells produce ne
ural-related factors to stimulate neurite formation, receive nervous signals and
act on the nervous system. Thus, cancer cells are a le to take advantage of the
factors produced y the nerve fi ers to generate a positive microenvironment fo
r cell survival and proliferation in the primary site and secondary organ. There
fore, the microenvironments and neural system esta lish a feed ack loop. They al
so collectively contri ute to the growth of primary cancer and the secondary tum
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6. Nervous system interacts with immune function and inflammation to influence can
cer metastasis
The immune system has een identified to play a vital role in cancer metastasis
(35,177,178). The association etween the immune system and the nervous system h
as een widely studied and reviewed y many neuro iologists and immunologists (1
79,180). Several pathways are involved in the interaction etween them. Among th
em, the neuroendocrine and neuronal pathways are the most significant, and are i
nvolved in the control of the humoral and cellular immune responses including th
e immunosuppressive effect, immunosurveillance and immunoenhancement. However, t
he immune system also influences the central nervous system. The idirectional n
eural-immune interactions mainly occur through the neural and immune signal mole
cules including hormones, neurotransmitters, neuropeptides, cytokines or their r
eceptors, all of which have een demonstrated to contri ute to the process of me
tastasis (181183). Thus, the neural system modulates cancer metastasis through th
e immune system. For example, mood disorders, such as stress and depression, inh
i it the immune system y decreasing cytotoxic T-cell and natural killer (NK) ce
lls involved in innate immunity that can surveil for cancer metastasis (2). Ther
efore, stress enhances tumor metastasis via suppression of the immune system (18
4,185). It also has een identified that mood and relevant immunological status,
along with important iological prognostic varia les may contri ute to the nota
le outcome variance in early-stage reast cancer (186). Circadian rhythm modula
tes the immune system y conveying timing information. Circadian disruption may
lead to vulnera ilitys to infection and other diseases, including cancer (187,18
8). Therefore, the nervous system and its psychological or ehavioral factors mo
dulate metastasis through immune molecules, cells and effects (189).
The immune effect can induce an inflammatory response. However, unlike the assoc
iation etween the nervous system and immune system, the role of the nervous sys
tem in inflammation has only recently een descri ed. It was also found that as
well as controlling heart rate and other vital functions in real time, the nervo
us system reflexively regulates the inflammatory response (190,191). The vagus n
erve, the arc of the reflex and neural-related factors such as netrin-1 and neur
opeptides, are all involved in the control of inflammation (131,192200). Thus, th
e nervous system modulation of cancer development via inflammatory responses has
een recognized. Inflammation has een thought to e a driving force for cancer
metastasis (36). The inflammatory cells and pathways are the players in cancer
metastasis. These players are reported to e influenced y the nervous system. M
acrophages are key players not only for inflammation ut also metastasis, and ar
e regulated y neuromediators (196,198). Stress has een demonstrated to increas
e the level of IL-6 (201), which is a proinflammatory factor and plays an import
ant role in cancer metastasis. NE and -adrenergic receptors that can e induced
y stress also regulate IL-6 (202,203). The transcription factor NF-B is a signifi
cant inflammatory factor that has been identified to play a role in cancer devel
opment and metastasis (183,204). The neuronal guidance molecule netrin-1 is a di
rect transcriptional target of NF-B and demonstrates upregulation under inflammat
ory conditions (205). Therefore, the nervous system modulates cancer metastasis
through immunity and inflammation.
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7. Interactions between bone marrow and nervous system: implication for cancer met
A recent discovery revealed the mechanism of bone marrow recruiting disseminated
tumor cells (206). Moreover, it also plays an important role in sustaining tumo
r angiogenesis (207), microenvironment (208,209) and formation of the preniche f
or cancer cells arriving in pre-metastatic organs (210,211). Bone marrow recruit
s disseminated tumor cells by a recently discovered mechanism (206). It has been
found that bone marrow can be innervated by the nervous system, including the A
NS and noradrenergic sympathetic nerve fibers (212216). Preprotachyinin-I (PPT-I
) peptides, a family of neuropeptides released by the ANS, are hematopoietic mod
ulators and are highly expressed in cancer cells, which may explain the early in
tegration of cancer cells in the bone marrow (217,218). Progenitor cells of bone
marrow may contribute to tumor vascularization (207,219,220). The neurotransmit
ter dopamine regulates the process of mobilization of endothelial progenitor cel
ls from bone marrow to tumor (221). Stromal cells of the bone marrow are an impo
rtant source of tumor microenvironments (222), including formation of the pre-me
tastatic niche in metastatic organs. For example, tumor macrophages, which are d
erived from bone marrow, contribute to metastasis (223225). During migration, the
y are navigated by the nervous system (226228). Bone marrow stem cells play an im
portant role in the repair of tissue injury, and are also thought to contribute
to neurogenesis in cancer (50). They migrate from bone marrow to a terminal, the
n lodge and mature in the terminal under the control of the nervous system (228,
229). Therefore, the role of bone marrow in cancer metastasis is modulated by th
e nervous system.
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8. Cancer as an independent organ is being recognized and should not be isolated f
rom the nervous system
As cancer is formed of cancer cells and their surrouding tissues, and there are
interactions between tumor cells and their micro- and macroenvironment, cancer i
s now being considered as a new organ or an independent structure in the body (2
30). Egeblad et al(231) considered tumors to be independent from other organs in
the whole organism. This cancer organ is comprised of tumor cells, extracellula
r matrix, stromal cells and vessels. Although these components are abnormal, the
y can be organized into a new organ in a pathophysiological manner, which furthe
r exchanges and interacts with other organs. Thus, metastasis is viewed to be a
result of the interactions between the tumor and the rest of the body. Mareel et
al(232) viewed cancer as an ecosystem inside a living organism. The ecosystem c
omprises the primary tumor, lymph node and distant metastasis, bone marrow, bloo
d and lymph circulation. The five elements constitute a vicious circle and inter
act with each other, finally leading to an influence on the whole system. Egebla
d et al and Mareel et al had different views on cancer but shared the understand
ing that cancer is an independent system from other organ systems of the body. I
n this system, the components exchange information and communicate with other sy
stems. However, these two views do not refer to the nerve system. It is well no
wn that the constitutive elements of organs as well as microecosystems are all u
nder the control of nervous system. In the process of metastasis, these elements
exchange information with the nervous system. More importantly, the role of the
neural system cannot be replaced by other systems. As a central system, it proc
esses and stores information released by cancer cells. In clinical phenomena of
cancer metastasis, metastatic tumors still resemble their primary cancers even a
fter decades of dormancy. Comparisons between primary tumors and matched metasta
sis reveals similarities both at cancer cell and stromal levels, which may be mo
dulated by the neural system.
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9. Clinical and biological implications for the role of nervous system in cancer m
From the above findings, we can conclude that the neural system has an important
influence on cancer metastasis. Stress, depression and social isolation as psyc
hological factors have been reported to promote distant metastasis, which is due
to them suppressing immune functions (185), promoting angiogenesis, activating
macrophages and releasing proinflammatory factors, such as IL-6 (201) and TNF- (1
01) nd cting on the HPA nd ANS (3,233) to relese neurotrnsmitters (234). Ci
rcdin rhythm lso influences distnt metstsis through modultion of ngiogen
esis (235), the HPA nd the immune system (187,236,237). The brin modultes cn
cer development including cncer metstsis through the vgus nerve (45). It hs
significnt biologicl nd clinicl relevnce.
Firstly, stress is  common phenomenon nd prompts cncer metstsis, indicting
tht suppressing stress nd modulting mood will be helpful for cncer ptients
(234,238). Thus, psychologiclly effective interventions on individuls with 
vriety of cncers cn be resistnt to cncer progression nd improve clinicl o
utcome for dvnced cncer ptients (239). Secondly, under circumstnces without
lymph node nd blood metstsis, PNI offers nother pthwy for the spred of c
ncer cells. Determining the mechnism of PNI my provide dditionl options for
the prevention nd tretment of metstsis by inhibiting the pthwy. Thirdly,
neongiogenesis nd neurogenesis my exert their effects in concert on cncer me
tstsis. Inhibition of neongiogenesis lone hs little nd even reverse effect
s on treting metstsis (240). For exmple, VEGF inhibitors hve been reported
to hve no vlue in metsttic brest cncer (241) nd even enhnce metstsis i
n niml studies (240,242). Estblishing the common molecules between the two ty
pes of genesis in cncer tissues nd identify them s new trgets is likely to 
id in treting cncer metstsis. Fourthly, modulting the ctivities of the ner
vous system hs n importnt influence on cncer metstsis. The brin is ble t
o show functionl or pthologicl chnges when other orgns in the whole orgnis
m re ffected by cncer. The monitoring of these chnges in the brin my be 
new dignostic pproch to detect tumorigenesis nd cncer recurrence. The vgus
nerve is centrl in the response to extrinsic nd intrinsic stressors nd recei
ving the signls of the brin nd other viscerl orgns, including cncer. Thus,
inhibition of the ctivity of the vgus nerve is nother strtegy to prevent c
ncer metstsis (243245). For exmple, - lockers are eing considered to e a nove
l adjuvant to existing therapeutic strategies in clinical oncology (73). Finally
, as important modulators in the nervous system and cancer, neurotrophic factors
, neuropilins, axonal guidance molecules, neurotransmitters and their receptors
are eing considered to exploit new drugs to e used to treat metastasis (78,82,
The study of metastasis is multifaceted (251). Numerous investigators have devot
ed themselves to metastasis from their own profession. Although their studies ha
ve made great advances, a num er of questions remain to e addressed. The connec
tion etween the neural system and cancer that we propose in this review is not
ased on analogy of the association etween the nervous system and the immune sy
stem ut on current studies. The aim of this review was to aid individuals to ga
in a deeper understanding of cancer metastasis to a certain extent. Although it
may not produce major reakthroughs in cancer metastsis, the role of the nervous
system in cancer metastasis should not e neglected.
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10. Conclusions
In conclusion, the possi le existing synapses in tumor cells and neural-related
factors, such as neurotrophic factors and neurotransmitters, make it possi le to
esta lish direct connections etween the nervous system and cancer. PNI offers
another pathway for cancer cell distri ution. On an anatomical asis, the nervou
s system is involved in the processes of metastasis, including tumor cell growth
, proliferation, angiogenesis, apoptosis, departure from primary cancer, migrati
on, extravasation and colonization, metastatic inefficiency, and modulators of c
ancer metastasis such as immunity, inflammation and one marrow. Therefore, the
nervous system plays an important role in cancer metastasis. Understanding its m
echanism has important implications for exploring the iology of metastasis and
the management of cancer metastasis.
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