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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
SHA LI,1 YANLAI SUN,2,3 and DONGWEI GAO1
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Abstract
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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Contents
Introduction
Search strategies and selection criteria
Connection, communication and interaction between the neural system and cancer c
ells
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
stasis
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
Conclusions
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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
cells
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 upre
ulate the expression of MMPs in nasop
haryn
eal 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
hysiolo
ical 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). Mi
ration of cancer cells is a prerequisite
for metastasis. Axon-
uidance molecules, such as slits, semaphorins and netrins
, can navi
ate or inhibit mi
ration of cancer cells (77,85,113117). The neurotran
smitter/receptor system is also involved in cancer cell mi
ration (118). NE, a c
lassical neurotransmitter, has a stimulatory effect on the mi
ration 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 mi
ratory activity of colon carcinoma cells (121). Althou
h these su
bstances are also expressed in other or
ans (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
or.
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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
astasis
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
etastasis
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,
111,165,234,246250).
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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References
1. Willis RA. The Spread of Tumors in the Human Body. 3rd edition. Butterworths;
London: 1973.
2. Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immune system, and
cancer. Lancet Oncol. 2004;5:617625. [Pu Med]
3. Lutgendorf SK, Sood AK. Bio ehavioral factors and cancer progression: physiol
ogical pathways and mechanisms. Psychosom Med. 2011;73:724730. [PMC free article]
[Pu Med]
4. Thaker PH, Sood AK. Neuroendocrine influences on cancer iology. Semin Cancer
Biol. 2008;18:164170. [PMC free article] [Pu Med]
5. Armaiz-Pena GN, Lutgendorf SK, Cole SW, Sood AK. Neuroendocrine modulation of
cancer progression. Brain Behav Immun. 2009;23:1015. [PMC free article] [Pu Med]
6. Williams JB, Pang D, Delgado B, Kocherginsky M, Tretiakova M, Krausz T, Pan D
, He J, McClintock MK, Conzen SD. A model of gene-environment interaction reveal
s altered mammary gland gene expression and increased tumor growth following soc
ial isolation. Cancer Prev Res (Phila) 2009;2:850861. [PMC free article] [Pu Med]
7. McEwen BS. Physiology and neuro iology of stress and adaptation: central role
of the rain. Physiol Rev. 2007;87:873904. [Pu Med]
8. Toh YC. Inhi itory effect of hypothalamic lesions on liver tumor induction y
N-2-fluorenylacetamide in male rats. Cancer Res. 1978;38:4251. [Pu Med]
9. Karasek M, Pawlikowski M. Pineal gland, melatonin and cancer. NEL Review. Neu
ro Endocrinol Lett. 1999;20:139144. [Pu Med]
10. Bruni JE, Montemurro DG. Effect of hypothalamic lesions on the genesis of sp
ontaneous mammary gland tumors in the mouse. Cancer Res. 1971;31:854863. [Pu Med]
11. Chelmicka-Szorc E, Arnason BG. Effect of 6-hydroxydopamine on tumor growth.
Cancer Res. 1976;36:23822384. [Pu Med]
12. Chelmicka-Schorr E, Arnason BG. Modulatory effect of the sympathetic nervous
system on neuro lastoma tumor growth. Cancer Res. 1978;38:13741375. [Pu Med]
13. Seifert P, Spitznas M. Tumours may e innervated. Virchows Arch. 2001;438:22
8231. [Pu Med]
14. Seifert P, Benedic M, Effert P. Nerve fi ers in tumors of the human urinary
ladder. Virchows Arch. 2002;440:291297. [Pu Med]
15. Lu SH, Zhou Y, Que HP, Liu SJ. Peptidergic innervation of human esophageal a
nd cardiac carcinoma. World J Gastroenterol. 2003;9:399403. [PMC free article] [P
u Med]
16. Liang YJ, Zhou P, Wong a W, Guardiola J, Walker J, Yu J. Pulmonary innervati
on, inflammation and carcinogenesis. Sheng Li Xue Bao. 2010;62:191195. [Pu Med]
17. Li JH, Ma QY, Shen SG, Hu HT. Stimulation of dorsal root ganglion neurons ac
tivity y pancreatic cancer cell lines. Cell Biol Int. 2008;32:15301535. [Pu Med]
18. Al o D, Akay CL, Marshall CL, Wilks JA, Verstovsek G, Liu H, Agarwal N, Berg
er DH, Ayala GE. Neurogenesis in colorectal cancer is a marker of aggressive tum
or ehavior and poor outcomes. Cancer. 2011;117:48344845. [Pu Med]
19. Ayala GE, Wheeler TM, Shine HD, Schmelz M, Frolov A, Chakra orty S, Rowley D
. In vitro dorsal root ganglia and human prostate cell line interaction: redefin
ing perineural invasion in prostate cancer. Prostate. 2001;49:213223. [Pu Med]
20. Batkin S, Piette LH, Wildman E. Effect of muscle denervation on growth of tr
ansplanted tumor in mice. Proc Natl Acad Sci USA. 1970;67:15211527. [PMC free art
icle] [Pu Med]
21. Papageorgiou A, Trontzos C, Kallistratos H, Kokkas B, Grigoriadis N, Grammat
icos P. Slowing growth and histology changes in Lewis lung carcinoma implanted i
n a partly denervated muscle. Cancer Invest. 2003;21:869872. [Pu Med]
22. Romeo HE, Colom o LL, Esquifino AI, Rosenstein RE, Chuluyan HE, Cardinali DP
. Slower growth of tumours in sympathetically denervated murine skin. J Auton Ne
rv Syst. 1991;32:159164. [Pu Med]
23. Peng J, Sheng W, Huang D, Venook AP, Xu Y, Guan Z, Cai S. Perineural invasio
n in pT3N0 rectal cancer: the incidence and its prognostic effect. Cancer. 2011;
117:14151421. [Pu Med]
24. Feng FY, Qian Y, Stenmark MH, Halverson S, Blas K, Vance S, Sandler HM, Hams
tra DA. Perineural invasion predicts increased recurrence, metastasis, and death
from prostate cancer following treatment with dose-escalated radiation therapy.
Int J Radiat Oncol Biol Phys. 2011;81:e361e367. [Pu Med]
25. Poeschl EM, Pollheimer MJ, Kornprat P, Lindtner RA, Schlemmer A, Rehak P, Vi
eth M, Langner C. Perineural invasion: correlation with aggressive phenotype and
independent prognostic varia le in oth colon and rectum cancer. J Clin Oncol.
2010;28:e358e360. e361e362. [Pu Med]
26. Lie ig C, Ayala G, Wilks JA, Berger DH, Al o D. Perineural invasion in cance
r: a review of the literature. Cancer. 2009;115:33793391. [Pu Med]
27. Khasraw M, Posner JB. Neurological complications of systemic cancer. Lancet
Neurol. 2010;9:12141227. [Pu Med]
28. Toothaker TB, Ru in M. Paraneoplastic neurological syndromes: a review. Neur
ologist. 2009;15:2133. [Pu Med]
29. Mravec B, Gidron Y, Hulin I. Neuro iology of cancer: Interactions etween ne
rvous, endocrine and immune systems as a ase for monitoring and modulating the
tumorigenesis y the rain. Semin Cancer Biol. 2008;18:150163. [Pu Med]
30. Entschladen F, Palm D, Niggemann B, Zaenker KS. The cancer's nervous tooth:
Considering the neuronal crosstalk within tumors. Semin Cancer Biol. 2008;18:1711
75. [Pu Med]
31. Ondicova K, Mravec B. Role of nervous system in cancer aetiopathogenesis. La
ncet Oncol. 2010;11:596601. [Pu Med]
32. Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, Arevalo
JM, Morizono K, Karanikolas BD, Wu L, Sood AK, Cole SW. The sympathetic nervous
system induces a metastatic switch in primary reast cancer. Cancer Res. 2010;7
0:70427052. [PMC free article] [Pu Med]
33. Gupta GP, Massague J. Cancer metastasis: uilding a framework. Cell. 2006;12
7:679695. [Pu Med]
34. de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system
during cancer development. Nat Rev Cancer. 2006;6:2437. [Pu Med]
35. DeNardo DG, Johansson M, Coussens LM. Immune cells as mediators of solid tum
or metastasis. Cancer Metastasis Rev. 2008;27:1118. [Pu Med]
36. Wu Y, Zhou BP. Inflammation: a driving force speeds cancer metastasis. Cell
Cycle. 2009;8:32673273. [PMC free article] [Pu Med]
37. Solinas G, Marchesi F, Garlanda C, Mantovani A, Allavena P. Inflammation-med
iated promotion of invasion and metastasis. Cancer Metastasis Rev. 2010;29:243248
. [Pu Med]
38. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-speci
fic colonization. Nat Rev Cancer. 2009;9:274284. [Pu Med]
39. Sung SY, Hsieh CL, Wu D, Chung LW, Johnstone PA. Tumor microenvironment prom
otes cancer progression, metastasis, and therapeutic resistance. Curr Pro l Canc
er. 2007;31:36100. [Pu Med]
40. Calorini L, Bianchini F. Environmental control of invasiveness and metastati
c dissemination of tumor cells: the role of tumor cell-host cell interactions. C
ell Commun Signal. 2010;8:24. [PMC free article] [Pu Med]
41. Shapiro DM, Warren S. Cancer innervation. Cancer Res. 1949;9:707711. [Pu Med]
42. Mitchell BS, Schumacher U, Stau er VV, Kaiserling E. Are reast tumours inne
rvated? Immunohistological investigations using anti odies against the neuronal
marker protein gene product 95 (PGP 95) in enign and malignant reast lesions.
Eur J Cancer. 1994;30A:11001103. [Pu Med]
43. Seifert P, Spitznas M. Axons in human choroidal melanoma suggest the partici
pation of nerves in the control of these tumors. Am J Ophthalmol. 2002;133:711713
. [Pu Med]
44. Feng F, Yang J, Tong L, Yuan S, Tian Y, Hong L, Wang W, Zhang H. Su stance P
immunoreactive nerve fi res are related to gastric cancer differentiation statu
s and could promote proliferation and migration of gastric cancer cells. Cell Bi
ol Int. 2011;35:623629. [Pu Med]
45. Gidron Y, Perry H, Glennie M. Does the vagus nerve inform the rain a out pr
eclinical tumours and modulate them? Lancet Oncol. 2005;6:245248. [Pu Med]
46. Erin N, Boyer PJ, Bonneau RH, Clawson GA, Welch DR. Capsaicin-mediated dener
vation of sensory neurons promotes mammary tumor metastasis to lung and heart. A
nticancer Res. 2004;24:10031009. [Pu Med]
47. Erin N, Akdas BG, Harms JF, Clawson GA. Vagotomy enhances experimental metas
tases of 4THMpc reast cancer cells and alters su stance P level. Regul Pept. 20
08;151:3542. [Pu Med]
48. Palm D, Entschladen F. Neoneurogenesis and the neuroneoplastic synapse. Prog
Exp Tumor Res. 2007;39:9198. [Pu Med]
49. Zanker KS. The neuro-neoplastic synapse: does it exist? Prog Exp Tumor Res.
2007;39:154161. [Pu Med]
50. Varner JA. Stem cells and neurogenesis in tumors. Prog Exp Tumor Res. 2007;3
9:122129. [Pu Med]
51. Ayala GE, Dai H, Powell M, Li R, Ding Y, Wheeler TM, Shine D, Kadmon D, Thom
pson T, Miles BJ, Ittmann MM, Rowley D. Cancer-related axonogenesis and neurogen
esis in prostate cancer. Clin Cancer Res. 2008;14:75937603. [Pu Med]
52. Mitchell BS, Schumacher U, Kaiserling E. Are tumours innervated? Immunohisto
logical investigations using anti odies against the neuronal marker protein gene
product 95 (PGP 95) in enign, malignant and experimental tumours. Tumour Biol.
1994;15:269274. [Pu Med]
53. Terada T, Matsunaga Y. S-100-positive nerve fi ers in hepatocellular carcino
ma and intrahepatic cholangiocarcinoma: an immunohistochemical study. Pathol Int
. 2001;51:8993. [Pu Med]
54. Pollak M, Sem AW, Richard M, Tetenes E, Bell R. Inhi ition of metastatic eh
avior of murine osteosarcoma y hypophysectomy. J Natl Cancer Inst. 1992;84:96697
1. [Pu Med]
55. Giraldi T, Perissin L, Zorzet S, Rapozzi V, Rodani MG. Metastasis and neuroe
ndocrine system in stressed mice. Int J Neurosci. 1994;74:265278. [Pu Med]
56. Marchetti B, Spinola PG, Pelletier G, La rie F. A potential role for catecho
lamines in the development and progression of carcinogen-induced mammary tumors:
hormonal control of eta-adrenergic receptors and correlation with tumor growth
. J Steroid Biochem Mol Biol. 1991;38:307320. [Pu Med]
57. Fava G, Marucci L, Glaser S, Francis H, De Morrow S, Benedetti A, Alvaro D,
Venter J, Meininger C, Patel T, Taffetani S, Marzioni M, Summers R, Reichen ach
R, Alpini G. Gamma-Amino utyric acid inhi its cholangiocarcinoma growth y cycli
c AMP-dependent regulation of the protein kinase A/extracellular signal-regulate
d kinase 1/2 pathway. Cancer Res. 2005;65:1143711446. [Pu Med]
58. Al-Wadei HA, Plummer HK, III, Schuller HM. Nicotine stimulates pancreatic ca
ncer xenografts y systemic increase in stress neurotransmitters and suppression
of the inhi itory neurotransmitter gamma-amino utyric acid. Carcinogenesis. 200
9;30:506511. [PMC free article] [Pu Med]
59. Yamanaka Y, Mammoto T, Kirita T, Mukai M, Mashimo T, Sugimura M, Kishi Y, Na
kamura H. Epinephrine inhi its invasion of oral squamous carcinoma cells y modu
lating intra-cellular cAMP. Cancer Lett. 2002;176:143148. [Pu Med]
60. Wang T, Huang W, Chen F. Baclofen, a GABAB receptor agonist, inhi its human
hepatocellular carcinoma cell growth in vitro and in vivo. Life Sci. 2008;82:5365
41. [Pu Med]
61. Ellis LM. The role of neuropilins in cancer. Mol Cancer Ther. 2006;5:10991107
. [Pu Med]
62. Rizzolio S, Tamagnone L. Multifaceted role of neuropilins in cancer. Curr Me
d Chem. 2011;18:35633575. [Pu Med]
63. Kreuter M, Bielen erg D, Hida Y, Hida K, Klags run M. Role of neuropilins an
d semaphorins in angiogenesis and cancer. Ann Hematol. 2002;81(Suppl 2):S74. [Pu
Med]
64. Chedotal A, Kerjan G, Moreau-Fauvarque C. The rain within the tumor: new ro
les for axon guidance molecules in cancers. Cell Death Differ. 2005;12:10441056.
[Pu Med]
65. Nakagawara A. Trk receptor tyrosine kinases: a ridge etween cancer and neu
ral development. Cancer Lett. 2001;169:107114. [Pu Med]
66. Wong HP, Ho JW, Koo MW, Yu L, Wu WK, Lam EK, Tai EK, Ko JK, Shin VY, Chu KM,
 Cho CH. Effects of adrenaline in human colon adenocarcinoma HT-29 cells. Life S
ci. 2011;88:11081112. [Pu Med]
67. Marin YE, Chen S. Involvement of meta otropic glutamate receptor 1, a G prot
ein coupled receptor, in melanoma development. J Mol Med (Berl) 2004;82:735749. [
Pu Med]
68. Castro-Rivera E, Ran S, Brekken RA, Minna JD. Semaphorin 3B inhi its the pho
sphatidylinositol 3-kinase/Akt pathway through neuropilin-1 in lung and reast c
ancer cells. Cancer Res. 2008;68:82958303. [PMC free article] [Pu Med]
69. Kigel B, Varshavsky A, Kessler O, Neufeld G. Successful inhi ition of tumor
development y specific class-3 semaphorins is associated with expression of app
ropriate semaphorin receptors y tumor cells. PLoS One. 2008;3:e3287. [PMC free
article] [Pu Med]
70. Pisick E, Jagadeesh S, Salgia R. Receptor tyrosine kinases and inhi itors in
lung cancer. Scientific World Journal. 2004;4:589604. [Pu Med]
71. Muller JM. Potential inhi ition of the neuro-neoplastic interactions: the cl
ue of a GPCR-targeted therapy. Prog Exp Tumor Res. 2007;39:130153. [Pu Med]
72. Fitzgerald PJ. Is norepinephrine an etiological factor in some types of canc
er? Int J Cancer. 2009;124:257263. [Pu Med]
73. Cole SW, Sood AK. Molecular pathways: eta-adrenergic signaling pathways in
cancer. Clin Cancer Res. 2011;18:12011206. [PMC free article] [Pu Med]
74. Al-Wadei HA, Plummer HK, III, Ullah MF, Unger B, Brody JR, Schuller HM. Soci
al stress promotes and -aminobutyric acid inhibits tumor
rowth in mouse models o
f non-small cell lun
cancer. Cancer Prev Res (Phila) 2012;5:189196. [PMC free ar
ticle] [PubMed]
75. Casazza A, Ki
el B, Maione F, Capparuccia L, Kessler O, Giraudo E, Mazzone M
, Neufeld G, Tama
none L. Tumour
rowth inhibition and anti-metastatic activity
of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol Med. 2012;4:234250.
[PMC free article] [PubMed]
76. Erin N, Zhao W, Bylander J, Chase G, Clawson G. Capsaicin-induced inactivati
on of sensory neurons promotes a more a

ressive
ene expression phenotype in br
east cancer cells. Breast Cancer Res Treat. 2006;99:351364. [PubMed]
77. Nasarre P, Potiron V, Drabkin H, Roche J. Guidance molecules in lun
cancer.
Cell Adh Mi
r. 2010;4:130145. [PMC free article] [PubMed]
78. Weick A, Au
ustin HG. Double attack on tumors by tar
etin
with
uidance mol
ecules. Arterioscler Thromb Vasc Biol. 2011;31:721722. [PubMed]
79. Bernet A, Fitamant J. Netrin-1 and its receptors in tumour
rowth promotion.
Expert Opin Ther Tar
ets. 2008;12:9951007. [PubMed]
80. Schuller HM, Al-Wadei HA. Neurotransmitter receptors as central re
ulators o
f pancreatic cancer. Future Oncol. 2010;6:221228. [PMC free article] [PubMed]
81. Novotny A, Ryber
K, Heiman UJ, Nilsson L, Khorram-Manesh A, Nord
ren S, Del
bro DS, Nylund G. Is acetylcholine a si
nalin
molecule for human colon cancer p
ro
ression? Scand J Gastroenterol. 2011;46:446455. [PubMed]
82. Al-Wadei HA, Al-Wadei MH, Schuller HM. Cooperative re
ulation of non-small c
ell lun
carcinoma by nicotinic and beta-adrener
ic receptors: a novel tar
et fo
r intervention. PLoS One. 2012;7:e29915. [PMC free article] [PubMed]
83. Al-Wadei HA, Ullah MF, Al-Wadei M. GABA (-aminobutyric acid), a non-protein a
mino acid counters the -adrenergic cascade-activated oncogenic signaling in pancr
eatic cancer: a review of experimental evidence. Mol Nutr Food Res. 2011;55:17451
758. [Pu Med]
84. Neufeld G, Shraga-Heled N, Lange T, Guttmann-Raviv N, Herzog Y, Kessler O. S
emaphorins in cancer. Front Biosci. 2005;10:751760. [Pu Med]
85. Rizzolio S, Tamagnone L. Semaphorin signals on the road to cancer invasion a
nd metastasis. Cell Adh Migr. 2007;1:6268. [PMC free article] [Pu Med]
86. Chen C, Li M, Chai H, Yang H, Fisher WE, Yao Q. Roles of neuropilins in neur
onal development, angiogenesis, and cancers. World J Surg. 2005;29:271275. [Pu Me
d]
87. Ba a T, Kariya M, Higuchi T, Mandai M, Matsumura N, Kondoh E, Miyanishi M, F
ukuhara K, Takakura K, Fujii S. Neuropilin-1 promotes unlimited growth of ovaria
n cancer y evading contact inhi ition. Gynecol Oncol. 2007;105:703711. [Pu Med]
88. Warrington RJ, Lewis KE. Natural anti odies against nerve growth factor inhi
 it in vitro prostate cancer cell metastasis. Cancer Immunol Immunother. 2011;60
:187195. [Pu Med]
89. Arakawa H. Netrin-1 and its receptors in tumorigenesis. Nat Rev Cancer. 2004
;4:978987. [Pu Med]
90. Kalariti N, Pissimissis N, Koutsilieris M. The glutamatergic system outside
the CNS and in cancer iology. Expert Opin Investig Drugs. 2005;14:14871496. [Pu
Med]
91. Watana e M, Maemura K, Oki K, Shiraishi N, Shi ayama Y, Katsu K. Gamma-amino
utyric acid (GABA) and cell proliferation: focus on cancer cells. Histol Histop
athol. 2006;21:11351141. [Pu Med]
92. Chang HJ, Yoo BC, Lim SB, Jeong SY, Kim WH, Park JG. Meta otropic glutamate
receptor 4 expression in colorectal carcinoma and its prognostic significance. C
lin Cancer Res. 2005;11:32883295. [Pu Med]
93. Park SY, Lee SA, Han IH, Yoo BC, Lee SH, Park JY, Cha IH, Kim J, Choi SW. Cl
inical significance of meta otropic glutamate receptor 5 expression in oral squa
mous cell carcinoma. Oncol Rep. 2007;17:8187. [Pu Med]
94. Palma C. Tachykinins and their receptors in human malignancies. Curr Drug Ta
rgets. 2006;7:10431052. [Pu Med]
95. Ruscica M, Dozio E, Motta M, Magni P. Relevance of the neuropeptide Y system
in the iology of cancer progression. Curr Top Med Chem. 2007;7:16821691. [Pu Me
d]
96. Chatikhine VA, Delpech B, Duval C, Chauzy C, D'Aniou J, Chevrier A. Expressi
on of eta-endorphin in human reast cancer and adenofi romas. Ann NY Acad Sci.
1993;680:473475. [Pu Med]
97. Sarkar DK, Zhang C, Murugan S, Dokur M, Boyadjieva NI, Ortiguela M, Reuhl KR
, Mojtehedzadeh S. Transplantation of eta-endorphin neurons into the hypothalam
us promotes immune function and restricts the growth and metastasis of mammary c
arcinoma. Cancer Res. 2011;71:62826291. [PMC free article] [Pu Med]
98. Mancino M, Ametller E, Gascon P, Almendro V. The neuronal influence on tumor
progression. Biochim Biophys Acta. 2011;1816:105118. [Pu Med]
99. MacDougall JR, Matrisian LM. Contri utions of tumor and stromal matrix metal
loproteinases to tumor progression, invasion and metastasis. Cancer Metastasis R
ev. 1995;14:351362. [Pu Med]
100. Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. C
ancer Metastasis Rev. 2006;25:934. [Pu Med]
101. Wu W, Yamaura T, Murakami K, Ogasawara M, Hayashi K, Murata J, Saiki I. Inv
olvement of TNF-alpha in enhancement of invasion and metastasis of colon 26-L5 c
arcinoma cells in mice y social isolation stress. Oncol Res. 1999;11:461469. [Pu
Med]
102. Yang EV, Bane CM, MacCallum RC, Kiecolt-Glaser JK, Malarkey WB, Glaser R. S
tress-related modulation of matrix metalloproteinase expression. J Neuroimmunol.
2002;133:144150. [Pu Med]
103. Yao J, Xiong S, Klos K, Nguyen N, Grijalva R, Li P, Yu D. Multiple signalin
g pathways involved in activation of matrix metalloproteinase-9 (MMP-9) y hereg
ulin- eta1 in human reast cancer cells. Oncogene. 2001;20:80668074. [Pu Med]
104. Okada Y, Ei l G, Guha S, Duffy JP, Re er HA, Hines OJ. Nerve growth factor
stimulates MMP-2 expression and activity and increases invasion y human pancrea
tic cancer cells. Clin Exp Metastasis. 2004;21:285292. [Pu Med]
105. Okada Y, Ei l G, Duffy JP, Re er HA, Hines OJ. Glial cell-derived neurotrop
hic factor upregulates the expression and activation of matrix metalloproteinase
-9 in human pancreatic cancer. Surgery. 2003;134:293299. [Pu Med]
106. Menter DG, Herrmann JL, Nicolson GL. The role of trophic factors and autocr
ine/paracrine growth factors in rain metastasis. Clin and Exp Metastasis. 1995;
13:6788. [Pu Med]
107. Yang EV, Sood AK, Chen M, Li Y, Eu ank TD, Marsh CB, Jewell S, Flavahan NA,
Morrison C, Yeh PE, Lemeshow S, Glaser R. Norepinephrine up-regulates the expre
ssion of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, a
nd MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res. 2006;66:1035710364.
[Pu Med]
108. Azuma H, Inamoto T, Sakamoto T, Kiyama S, U ai T, Shinohara Y, Maemura K, T
suji M, Segawa N, Masuda H, Takahara K, Katsuoka Y, Watana e M. Gamma-amino utyr
ic acid as a promoting factor of cancer metastasis; induction of matrix metallop
roteinase production is potentially its underlying mechanism. Cancer Res. 2003;6
3:80908096. [Pu Med]
109. Simpson CD, Anyiwe K, Schimmer AD. Anoikis resistance and tumor metastasis.
Cancer Lett. 2008;272:177185. [Pu Med]
110. Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS.
Suppression of anoikis and induction of metastasis y the neurotrophic receptor
TrkB. Nature. 2004;430:10341039. [Pu Med]
111. Geiger TR, Peeper DS. The neurotrophic receptor TrkB in anoikis resistance
and metastasis: a perspective. Cancer Res. 2005;65:70337036. [Pu Med]
112. Geiger TR, Peeper DS. Critical role for TrkB kinase function in anoikis sup
pression, tumorigenesis, and metastasis. Cancer Res. 2007;67:62216229. [Pu Med]
113. Strizzi L, Bianco C, Raafat A, A dallah W, Chang C, Raafat D, Hirota M, Ham
ada S, Sun Y, Normanno N, Callahan R, Hinck L, Salomon D. Netrin-1 regulates inv
asion and migration of mouse mammary epithelial cells overexpressing Cripto-1 in
vitro and in vivo. J Cell Sci. 2005;118:46334643. [Pu Med]
114. Christensen C, Am artsumian N, Gilestro G, Thomsen B, Comoglio P, Tamagnone
L, Guld erg P, Lukanidin E. Proteolytic processing converts the repelling signa
l Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res. 200
5;65:61676177. [Pu Med]
115. Kruger RP, Aurandt J, Guan KL. Semaphorins command cells to move. Nat Rev M
ol Cell Biol. 2005;6:789800. [Pu Med]
116. Kim HK, Zhang H, Li H, Wu TT, Swisher S, He D, Wu L, Xu J, Elmets CA, Athar
M, Xu XC, Xu H. Slit2 inhi its growth and metastasis of fi rosarcoma and squamo
us cell carcinoma. Neoplasia. 2008;10:14111420. [PMC free article] [Pu Med]
117. Casazza A, Finisguerra V, Capparuccia L, Camperi A, Swiercz JM, Rizzolio S,
Rolny C, Christensen C, Bertotti A, Sarotto I, Risio M, Trusolino L, Weitz J, S
chneider M, Mazzone M, Comoglio PM, Tamagnone L. Sema3E-Plexin D1 signaling driv
es human cancer cell invasiveness and meta-static spreading in mice. J Clin Inve
st. 2010;120:26842698. [PMC free article] [Pu Med]
118. Entschladen F, Lang K, Drell TL, Joseph J, Zaenker KS. Neurotransmitters ar
e regulators for the migration of tumor cells and leukocytes. Cancer Immunol Imm
unother. 2002;51:467482. [Pu Med]
119. Masur K, Niggemann B, Zanker KS, Entschladen F. Norepinephrine-induced migr
ation of SW 480 colon carcinoma cells is inhi ited y eta- lockers. Cancer Res.
2001;61:28662869. [Pu Med]
120. Drell TT, Joseph J, Lang K, Niggemann B, Zaenker KS, Entschladen F. Effects
of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human re
ast carcinoma cells. Breast Cancer Res Treat. 2003;80:6370. [Pu Med]
121. Joseph J, Niggemann B, Zaenker KS, Entschladen F. The neurotransmitter gamm
a-amino utyric acid is an inhi itory regulator for the migration of SW 480 colon
carcinoma cells. Cancer Res. 2002;62:64676469. [Pu Med]
122. Watana e M, Maemura K, Kan ara K, Tamayama T, Hayasaki H. GABA and GABA rec
eptors in the central nervous system and other organs. Int Rev Cytol. 2002;213:14
7. [Pu Med]
123. Miller RJ, Rostene W, Apartis E, Banisadr G, Bi er K, Milligan ED, White FA
, Zhang J. Chemokine action in the nervous system. J Neurosci. 2008;28:1179211795
. [PMC free article] [Pu Med]
124. Zhang N, Oppenheim JJ. Crosstalk etween chemokines and neuronal receptors
ridges immune and nervous systems. J Leukoc Biol. 2005;78:12101214. [Pu Med]
125. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murph
y E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A. Involvemen
t of chemokine receptors in reast cancer metastasis. Nature. 2001;410:5056. [Pu
Med]
126. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4:540550.
[Pu Med]
127. Singh S, Sadanandam A, Singh RK. Chemokines in tumor angiogenesis and metas
tasis. Cancer Metastasis Rev. 2007;26:453467. [PMC free article] [Pu Med]
128. Weiss L. Cancer cell traffic from the lungs to the liver: an example of met
astatic inefficiency. Int J Cancer. 1980;25:385392. [Pu Med]
129. Weiss L. Deformation-driven, lethal damage to cancer cells. Its contri utio
n to metastatic inefficiency. Cell Biophys. 1991;18:7379. [Pu Med]
130. Bacac M, Stamenkovic I. Metastatic cancer cell. Annu Rev Pathol. 2008;3:2212
47. [Pu Med]
131. Brain SD. Sensory neuropeptides: their role in inflammation and wound heali
ng. Immunopharmacology. 1997;37:133152. [Pu Med]
132. Ishihara K, Kamata M, Hayashi I, Yamashina S, Majima M. Roles of radykinin
in vascular permea ility and angiogenesis in solid tumor. Int Immunopharmacol.
2002;2:499509. [Pu Med]
133. O'Connor TM, O'Connell J, O'Brien DI, Goode T, Bredin CP, Shanahan F. The r
ole of su stance P in inflammatory disease. J Cell Physiol. 2004;201:167180. [Pu
Med]
134. Marchesi F, Piemonti L, Mantovani A, Allavena P. Molecular mechanisms of pe
rineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine
Growth Factor Rev. 2010;21:7782. [Pu Med]
135. Jhawer M, Coit D, Brennan M, Qin LX, Gonen M, Klimstra D, Tang L, Kelsen DP
, Shah MA. Perineural invasion after preoperative chemotherapy predicts poor sur
vival in patients with locally advanced gastric cancer: gene expression analysis
with pathologic validation. Am J Clin Oncol. 2009;32:356362. [Pu Med]
136. Bilici A, Seker M, Ustaalioglu BB, Kefeli U, Yildirim E, Yavuzer D, Aydin F
M, Salepci T, Oncel M, Gumus M. Prognostic significance of perineural invasion i
n patients with gastric cancer who underwent curative resection. Ann Surg Oncol.
2010;17:20372044. [Pu Med]
137. Ceyhan GO, Lie l F, Maak M, Schuster T, Becker K, Langer R, Demir IE, Harte
l M, Friess H, Rosen erg R. The severity of neural invasion is a crucial prognos
tic factor in rectal cancer independent of neoadjuvant radiochemotherapy. Ann Su
rg. 2010;252:797804. [Pu Med]
138. Binmadi NO, Basile JR. Perineural invasion in oral squamous cell carcinoma:
a discussion of significance and review of the literature. Oral Oncol. 2011;47:
10051010. [Pu Med]
139. Tai SK, Li WY, Chu PY, Chang SY, Tsai TL, Wang YF, Huang JL. Risks and clin
ical implications of perineural invasion in T1-2 oral tongue squamous cell carci
noma. Head Neck. 2011;34:9941001. [Pu Med]
140. Miller ME, Palla B, Chen Q, Elashoff DA, A emayor E, St John JM, Lai CK. A
novel classification system for perineural invasion in noncutaneous head and nec
k squamous cell carcinoma: histologic su categories and patient outcomes. Am J O
tolaryngol. 2012;33:212215. [Pu Med]
141. Hi i T, Mori T, Fukuma M, Yamazaki K, Hashiguchi A, Yamada T, Tana e M, Aiu
ra K, Kawakami T, Ogiwara A, Kosuge T, Kitajima M, Kitagawa Y, Sakamoto M. Synuc
lein-gamma is closely involved in perineural invasion and distant metastasis in
mouse models and is a novel prognostic factor in pancreatic cancer. Clin Cancer
Res. 2009;15:28642871. [Pu Med]
142. Karak SG, Quatrano N, Buckley J, Ricci AJ. Prevalence and significance of p
erineural invasion in invasive reast carcinoma. Conn Med. 2010;74:1721. [Pu Med]
143. Meinel A, Fischer U, Bilek K, Hentschel B, Horn LC. Morphological parameter
s associated with perineural invasion (PNI) in carcinoma of the cervix uteri. In
t J Surg Pathol. 2011;19:159163. [Pu Med]
144. Bix y JL, Harris WA. Molecular mechanisms of axon growth and guidance. Annu
Rev Cell Biol. 1991;7:117159. [Pu Med]
145. Gold erg JL. How does an axon grow? Genes Dev. 2003;17:941958. [Pu Med]
146. Pasterkamp RJ, Peschon JJ, Spriggs MK, Kolodkin AL. Semaphorin 7A promotes
axon outgrowth through integrins and MAPKs. Nature. 2003;424:398405. [Pu Med]
147. Chilton JK. Molecular mechanisms of axon guidance. Dev Biol. 2006;292:1324.
[Pu Med]
148. Winckler B. BDNF instructs the kinase LKB1 to grow an axon. Cell. 2007;129:
459460. [Pu Med]
149. Artigiani S, Comoglio PM, Tamagnone L. Plexins, semaphorins, and scatter fa
ctor receptors: a common root for cell guidance signals? Iu m Life. 1999;48:4774
82. [Pu Med]
150. Iwahashi N, Nagasaka T, Tezel G, Iwashita T, Asai N, Murakumo Y, Kiuchi K,
Sakata K, Nimura Y, Takahashi M. Expression of glial cell line-derived neurotrop
hic factor correlates with perineural invasion of ile duct carcinoma. Cancer. 2
002;94:167174. [Pu Med]
151. Tomaselli KJ, Reichardt LF, Bix y JL. Distinct molecular interactions media
te neuronal process outgrowth on nonneuronal cell surfaces and extracellular mat
rices. J Cell Biol. 1986;103:26592672. [PMC free article] [Pu Med]
152. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol
. 2002;29:1518. [Pu Med]
153. Hillen F, Griffioen AW. Tumour vascularization: sprouting angiogenesis and
eyond. Cancer Metastasis Rev. 2007;26:489502. [PMC free article] [Pu Med]
154. Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic
targets. Nat Med. 2011;17:13591370. [Pu Med]
155. Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J, Ja ari S, Rainwate
r K, Ritchie JM, Yang M, Sood AK. Stress-related mediators stimulate vascular en
dothelial growth factor secretion y two ovarian cancer cell lines. Clin Cancer
Res. 2003;9:45144521. [Pu Med]
156. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Ar
maiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Cole
man RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM
, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK. Chronic stress p
romotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat
Med. 2006;12:939944. [Pu Med]
157. Tilan J, Kitlinska J. Sympathetic neurotransmitters and tumor angiogenesis
- link etween stress and cancer progression. J Oncol. 2010:539706. [PMC free ar
ticle] [Pu Med]
158. Park SY, Kang JH, Jeong KJ, Lee J, Han JW, Choi WS, Kim YK, Kang J, Park CG
, Lee HY. Norepinephrine induces VEGF expression and angiogenesis y a hypoxia-i
nduci le factor-1 protein-dependent mechnism. Int J Cncer. 2011;128:23062316. [P
ubMed]
159. Chkroborty D, Srkr C, Bsu B, Dsgupt PS, Bsu S. Ctecholmines regul
te tumor ngiogenesis. Cncer Res. 2009;69:37273730. [PubMed]
160. Chkroborty D, Srkr C, Mitr RB, Bnerjee S, Dsgupt PS, Bsu S. Deplete
d dopmine in gstric cncer tissues: dopmine tretment retrds growth of gstr
ic cncer by inhibiting ngiogenesis. Clin Cncer Res. 2004;10:43494356. [PubMed]
161. Bsu S, Ngy JA, Pl S, Vsile E, Eckelhoefer IA, Bliss VS, Mnseu EJ, Ds
gupt PS, Dvork HF, Mukhopdhyy D. The neurotrnsmitter dopmine inhibits ngi
ogenesis induced by vsculr permebility fctor/vsculr endothelil growth fc
tor. Nt Med. 2001;7:569574. [PubMed]
162. Lutgendorf SK, DeGeest K, Dhmoush L, Frley D, Penedo F, Bender D, Goodhe
rt M, Buekers TE, Mendez L, Krueger G, Clevenger L, Lubroff DM, Sood AK, Cole S
W. Socil isoltion is ssocited with elevted tumor norepinephrine in ovrin
crcinom ptients. Brin Behv Immun. 2011;25:250255. [PMC free rticle] [PubMed
]
163. Bsile JR, Cstilho RM, Willims VP, Gutkind JS. Semphorin 4D provides  l
ink between xon guidnce processes nd tumor-induced ngiogenesis. Proc Ntl Ac
d Sci USA. 2006;103:90179022. [PMC free rticle] [PubMed]
164. Kigel B, Rbinowicz N, Vrshvsky A, Kessler O, Neufeld G. Plexin-A4 promot
es tumor progression nd tumor ngiogenesis by enhncement of VEGF nd bFGF sign
ling. Blood. 2011;118:42854296. [PubMed]
165. Cszz A, Fu X, Johnsson I, Cpprucci L, Andersson F, Giustcchini A, S
qudrito ML, Venneri MA, Mzzone M, Lrsson E, Crmeliet P, De Plm M, Nldini
L, Tmgnone L, Rolny C. Systemic nd trgeted delivery of semphorin 3A inhibit
s tumor ngiogenesis nd progression in mouse tumor models. Arterioscler Thromb
Vsc Biol. 2011;31:741749. [PubMed]
166. Skuri A, Doci C, Gutkind JS. Semphorin signling in ngiogenesis, lymph
ngiogenesis nd cncer. Cell Res. 2012;22:2332. [PMC free rticle] [PubMed]
167. Tod M, Suzuki T, Hosono K, Hyshi I, Hshib S, Onum Y, Amno H, Kurihr
 Y, Kurihr H, Okmoto H, Hok S, Mjim M. Neuronl system-dependent fcilit
tion of tumor ngiogenesis nd tumor growth by clcitonin gene-relted peptide.
Proc Ntl Acd Sci USA. 2008;105:1355013555. [PMC free rticle] [PubMed]
168. Lee EW, Michlkiewicz M, Kitlinsk J, Klezic I, Switlsk H, Yoo P, Sngkh
rt A, Ji H, Li L, Michlkiewicz T, Ljubisvljevic M, Johnsson H, Grnt DS, Zu
kowsk Z. Neuropeptide Y induces ischemic ngiogenesis nd restores function of
ischemic skeletl muscles. J Clin Invest. 2003;111:18531862. [PMC free rticle] [
PubMed]
169. Filipski E, Levi F. Circdin disruption in experimentl cncer processes.
Integr Cncer Ther. 2009;8:298302. [PubMed]
170. Goodwin AM, D'Amore PA. Wnt signling in the vsculture. Angiogenesis. 200
2;5:19. [PubMed]
171. Msckuchn TN, Kitjewski J. Wnt/Frizzled signling in the vsculture: ne
w ngiogenic fctors in sight. Physiology (Bethesd) 2006;21:181188. [PubMed]
172. Adms RH, Eichmnn A. Axon guidnce molecules in vsculr ptterning. Cold
Spring Hrb Perspect Biol. 2010;2:1875. [PMC free rticle] [PubMed]
173. Melni M, Weinstein BM. Common fctors regulting ptterning of the nervous
nd vsculr systems. Annu Rev Cell Dev Biol. 2010;26:639665. [PubMed]
174. Crmeliet P, Tessier-Lvigne M. Common mechnisms of nerve nd blood vessel
wiring. Nture. 2005;436:193200. [PubMed]
175. Entschlden F, Plm D, Drell TT, Lng K, Zenker KS. Connecting  tumor to
the environment. Curr Phrm Des. 2007;13:34403444. [PubMed]
176. Cpprucci L, Tmgnone L. Semphorin signling in cncer cells nd in cel
ls of the tumor microenvironment - two sides of  coin. J Cell Sci. 2009;122:172
31736. [PubMed]
177. Schirrmcher V, Fogel M, Russmnn E, Bosslet K, Altevogt P, Beck L. Antigen
ic vrition in cncer metstsis: immune escpe versus immune control. Cncer M
etstsis Rev. 1982;1:241274. [PubMed]
178. Tn W, Zhng W, Strsner A, Grivennikov S, Cheng JQ, Hoffmn RM, Krin M. T
umour-infiltrting regultory T cells stimulte mmmry cncer metstsis throug
h RANKL-RANK signlling. Nture. 2011;470:548553. [PMC free rticle] [PubMed]
179. Rbin BS, Cohen S, Gnguli R, Lysle DT, Cunnick JE. Bidirectionl intercti
on between the centrl nervous system nd the immune system. Crit Rev Immunol. 1
989;9:279312. [PubMed]
180. Steinmn L. Connections between the immune system nd the nervous system. P
roc Ntl Acd Sci USA. 1993;90:79127914. [PMC free rticle] [PubMed]
181. Grivennikov SI, Greten FR, Krin M. Immunity, inflmmtion, nd cncer. Cel
l. 2010;140:883899. [PMC free rticle] [PubMed]
182. Lin WW, Krin M. A cytokine-medited link between innte immunity, inflmm
tion, nd cncer. J Clin Invest. 2007;117:11751183. [PMC free rticle] [PubMed]
183. Krin M, Greten FR. NF-kppB: linking inflmmtion nd immunity to cncer
development nd progression. Nt Rev Immunol. 2005;5:749759. [PubMed]
184. Ben-Eliyhu S, Yirmiy R, Liebeskind JC, Tylor AN, Gle RP. Stress incres
es metsttic spred of  mmmry tumor in rts: evidence for medition by the i
mmune system. Brin Behv Immun. 1991;5:193205. [PubMed]
185. Ben-Eliyhu S, Pge GG, Yirmiy R, Shkhr G. Evidence tht stress nd surg
icl interventions promote tumor development by suppressing nturl killer cell
ctivity. Int J Cncer. 1999;80:880888. [PubMed]
186. Levy SM, Herbermn RB, Lippmn M, D'Angelo T, Lee J. Immunologicl nd psyc
hosocil predictors of disese recurrence in ptients with erly-stge brest c
ncer. Behv Med. 1991;17:6775. [PubMed]
187. Logn RW, Srkr DK. Circdin nture of immune function. Mol Cell Endocrin
ol. 2012;349:8290. [PubMed]
188. Rn S, Mhmood S. Circdin rhythm nd its role in mlignncy. J Circdin
Rhythms. 2010;8:3. [PMC free rticle] [PubMed]
189. Kiecolt-Glser JK, Glser R. Psychoneuroimmunology nd cncer: fct or fict
ion? Eur J Cncer. 1999;35:16031607. [PubMed]
190. Trcey KJ. The inflmmtory reflex. Nture. 2002;420:853859. [PubMed]
191. Libert C. Inflmmtion: A nervous connection. Nture. 2003;421:328329. [PubM
ed]
192. Ross-Bllin M, Trcey KJ. Cholinergic control of inflmmtion. J Intern M
ed. 2009;265:663679. [PMC free rticle] [PubMed]
193. Rosenberger P, Schwb JM, Mirkj V, Msekowsky E, Mger A, Morote-Grci J
C, Unertl K, Eltzschig HK. Hypoxi-inducible fctor-dependent induction of netri
n-1 dmpens inflmmtion cused by hypoxi. Nt Immunol. 2009;10:195202. [PubMed]
194. Trcey KJ. Reflex control of immunity. Nt Rev Immunol. 2009;9:418428. [PMC
free rticle] [PubMed]
195. Vn Der Znden EP, Boeckxstens GE, de Jonge WJ. The vgus nerve s  modul
tor of intestinl inflmmtion. Neurogstroenterol Motil. 2009;21:617. [PubMed]
196. Ley S, Weigert A, Brune B. Neuromeditors in inflmmtion -  mcrophge/ne
rve connection. Immunobiology. 2010;215:674684. [PubMed]
197. Meregnni J, Clrencon D, Vivier M, Peinnequin A, Mouret C, Sinniger V, Pic
q C, Job A, Cnini F, Jcquier-Srlin M, Bonz B. Anti-inflmmtory effect of v
gus nerve stimultion in  rt model of inflmmtory bowel disese. Auton Neuros
ci. 2011;160:8289. [PubMed]
198. Pohnk M, Snopkov S, Hvlickov K, Bostik P, Sinkorov Z, Fusek J, Kuc K
, Pikul J. Mcrophge-ssisted inflmmtion nd phrmcologicl regultion of t
he cholinergic nti-inflmmtory pthwy. Curr Med Chem. 2011;18:539551. [PubMed]
199. Cerejeir J, Nogueir V, Luis P, Vz-Serr A, Muketov-Ldinsk EB. The ch
olinergic system nd inflmmtion: common pthwys in delirium pthophysiology.
J Am Geritr Soc. 2012;60:669675. [PubMed]
200. Peterson CY, Krzyznik M, Coimbr R, Chng DC. Vgus nerve nd postinjury
inflmmtory response. Arch Surg. 2012;147:7680. [PubMed]
201. Kiecolt-Glser JK, Precher KJ, McCllum RC, Atkinson C, Mlrkey WB, Gls
er R. Chronic stress nd ge-relted increses in the proinflmmtory cytokine I
L-6. Proc Ntl Acd Sci USA. 2003;100:90909095. [PMC free rticle] [PubMed]
202. Mdden KS, Szpunr MJ, Brown EB. bet-Adrenergic receptors (bet-AR) regul
te VEGF nd IL-6 production by divergent pthwys in high bet-AR-expressing bre
st cncer cell lines. Brest Cncer Res Tret. 2011;130:747758. [PMC free rticl
e] [PubMed]
203. Yng EV, Kim SJ, Donovn EL, Chen M, Gross AC, Webster MJ, Brsky SH, Glse
r R. Norepinephrine upregultes VEGF, IL-8, nd IL-6 expression in humn melnom
 tumor cell lines: implictions for stress-relted enhncement of tumor progres
sion. Brin Behv Immun. 2009;23:267275. [PMC free rticle] [PubMed]
204. Stthopoulos GT, Sherrill TP, Hn W, Sdikot RT, Yull FE, Blckwell TS, Fin
gleton B. Host nucler fctor-kppB ctivtion potentites lung cncer metsts
is. Mol Cncer Res. 2008;6:364371. [PubMed]
205. Prdisi A, Mehlen P. Netrin-1,  missing link between chronic inflmmtion
nd tumor progression. Cell Cycle. 2010;9:12531262. [PubMed]
206. Pntel K, Brkenhoff RH. Dissecting the metsttic cscde. Nt Rev Cncer.
2004;4:448456. [PubMed]
207. Rfii S, Lyden D, Benezr R, Httori K, Heissig B. Vsculr nd hemtopoie
tic stem cells: novel trgets for nti-ngiogenesis therpy? Nt Rev Cncer. 200
2;2:826835. [PubMed]
208. Direkze NC, Hodivl-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, Aliso
n MR, Wright NA. Bone mrrow contribution to tumor-ssocited myofibroblsts nd
fibroblsts. Cncer Res. 2004;64:84928495. [PubMed]
209. Ishii G, Sngi T, Od T, Aoygi Y, Hsebe T, Knomt N, Endoh Y, Okumur
C, Okuhr Y, Mge J, Emur M, Ochiy T, Ochii A. Bone-mrrow-derived myofibro
blsts contribute to the cncer-induced stroml rection. Biochem Biophys Res Co
mmun. 2003;309:232240. [PubMed]
210. Psil B, Lyden D. The metsttic niche: dpting the foreign soil. Nt Rev
Cncer. 2009;9:285293. [PMC free rticle] [PubMed]
211. Kpln RN, Rib RD, Zchroulis S, Brmley AH, Vincent L, Cost C, McDonl
d DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Por
t ER, Ruggero D, Shmelkov SV, Jensen KK, Rfii S, Lyden D. VEGFR1-positive hem
topoietic bone mrrow progenitors initite the pre-metsttic niche. Nture. 200
5;438:820827. [PMC free rticle] [PubMed]
212. Miyn JA, Broome CS, Whetton AD. Neurl regultion of bone mrrow. Blood. 1
998;92:29712973. [PubMed]
213. Cnni J, Kollet O, Lpidot T. Neurl regultion of bone, mrrow, nd the
microenvironment. Front Biosci. 2011;3:10211031. [PubMed]
214. Benestd HB, Strom-Gundersen I, Iversen PO, Hug E, Nj A. No neuronl regu
ltion of murine bone mrrow function. Blood. 1998;91:12801287. [PubMed]
215. Artico M, Bosco S, Cvllotti C, Agostinelli E, Giulini-Piccri G, Sciorio
S, Cocco L, Vitle M. Nordrenergic nd cholinergic innervtion of the bone mr
row. Int J Mol Med. 2002;10:7780. [PubMed]
216. Imi S, Tokung Y, Med T, Kikkw M, Hukud S. Clcitonin gene-relted p
eptide, substnce P, nd tyrosine hydroxylse-immunorective innervtion of rt
bone mrrows: n immunohistochemicl nd ultrstructurl investigtion on possib
le efferent nd fferent mechnisms. J Orthop Res. 1997;15:133140. [PubMed]
217. Singh D, Joshi DD, Hmeed M, Qin J, Gscon P, Mloof PB, Mosenthl A, Rme
shwr P. Incresed expression of preprotchykinin-I nd neurokinin receptors in
humn brest cncer cells: implictions for bone mrrow metstsis. Proc Ntl Ac
d Sci USA. 2000;97:388393. [PMC free rticle] [PubMed]
218. Cstro TA, Cohen MC, Rmeshwr P. The expression of neurokinin-1 nd prepro
tchykinin-1 in brest cncer cells depends on the reltive degree of invsive 
nd metsttic potentil. Clin Exp Metstsis. 2005;22:621628. [PubMed]
219. Lyden D, Httori K, Dis S, Cost C, Blikie P, Butros L, Chdburn A, Heiss
ig B, Mrks W, Witte L, Wu Y, Hicklin D, Zhu Z, Hckett NR, Crystl RG, Moore MA
, Hjjr KA, Mnov K, Benezr R, Rfii S. Impired recruitment of bone-mrrow-d
erived endothelil nd hemtopoietic precursor cells blocks tumor ngiogenesis 
nd growth. Nt Med. 2001;7:11941201. [PubMed]
220. Rjntie I, Ilmonen M, Alminite A, Ozerdem U, Alitlo K, Slven P. Adult b
one mrrow-derived cells recruited during ngiogenesis comprise precursors for p
eriendothelil vsculr murl cells. Blood. 2004;104:20842086. [PMC free rticle]
[PubMed]
221. Chkroborty D, Chowdhury UR, Srkr C, Brl R, Dsgupt PS, Bsu S. Dopmi
ne regultes endothelil progenitor cell mobiliztion from mouse bone mrrow in
tumor vsculriztion. J Clin Invest. 2008;118:13801389. [PMC free rticle] [PubM
ed]
222. Zhng W. Mesenchyml stem cells in cncer: friends or foes. Cncer Biol The
r. 2008;7:252254. [PubMed]
223. Pollrd JW. Tumour-educted mcrophges promote tumour progression nd met
stsis. Nt Rev Cncer. 2004;4:7178. [PubMed]
224. Condeelis J, Pollrd JW. Mcrophges: obligte prtners for tumor cell migr
tion, invsion, nd metstsis. Cell. 2006;124:263266. [PubMed]
225. Qin BZ, Pollrd JW. Mcrophge diversity enhnces tumor progression nd me
tstsis. Cell. 2010;141:3951. [PMC free rticle] [PubMed]
226. Mestroni GJ. Ctecholminergic regultion of hemtopoiesis in mice. Blood.
1998;92:29712973. [PubMed]
227. Mestroni GJ. Dendritic cell migrtion controlled by lph 1b-drenergic re
ceptors. J Immunol. 2000;165:67436747. [PubMed]
228. Ktym Y, Bttist M, Ko WM, Hidlgo A, Peired AJ, Thoms SA, Frenette P
S. Signls from the sympthetic nervous system regulte hemtopoietic stem cell
egress from bone mrrow. Cell. 2006;124:407421. [PubMed]
229. Mendez-Ferrer S, Lucs D, Bttist M, Frenette PS. Hemtopoietic stem cell
relese is regulted by circdin oscilltions. Nture. 2008;452:442447. [PubMed
]
230. Bissell MJ, Rdisky D. Putting tumours in context. Nt Rev Cncer. 2001;1:4
654. [PMC free rticle] [PubMed]
231. Egebld M, Nksone ES, Werb Z. Tumors s orgns: complex tissues tht inte
rfce with the entire orgnism. Dev Cell. 2010;18:884901. [PMC free rticle] [Pub
Med]
232. Mreel M, Oliveir MJ, Mdni I. Cncer invsion nd metstsis: interctin
g ecosystems. Virchows Arch. 2009;454:599622. [PubMed]
233. Ben-Eliyhu S, Shkhr G, Pge GG, Stefnski V, Shkhr K. Suppression of N
K cell ctivity nd of resistnce to metstsis by stress:  role for drenl c
techolmines nd bet-drenoceptors. Neuroimmunomodult. 2000;8:154164. [PubMed]
234. Schuller HM, Al-Wdei HA, Ullh MF, Plummer HK., III Regultion of pncret
ic cncer by neuropsychologicl stress responses:  novel trget for interventio
n. Crcinogenesis. 2012;33:191196. [PMC free rticle] [PubMed]
235. Ysuniw Y, Izumi H, Wng KY, Shimjiri S, Ssguri Y, Kwi K, Ksi H, Sh
imd T, Miyke K, Kshiwgi E, Hirno G, Kidni A, Akiym M, Hn B, Wu Y, Ieir
i I, Higuchi S, Kohno K. Circdin disruption ccelertes tumor growth nd ngio
/stromgenesis through  Wnt signling pthwy. PLoS One. 2010;5:e15330. [PMC fr
ee rticle] [PubMed]
236. Arjon A, Srkr DK. Are circdin rhythms the code of hypothlmic-immune
communiction? Insights from nturl killer cells. Neurochem Res. 2010;33:708718.
[PubMed]
237. Filipski E, King VM, Li X, Grnd TG, Mormont MC, Liu X, Clustrt B, Hsti
ngs MH, Levi F. Host circdin clock s  control point in tumor progression. J
Ntl Cncer Inst. 2002;94:690697. [PubMed]
238. Andersen BL, Kiecolt-Glser JK, Glser R. A biobehviorl model of cncer s
tress nd disese course. Am Psychol. 1994;49:389404. [PMC free rticle] [PubMed]
239. Spiegel D. Mind mtters in cncer survivl. Psychooncology. 2012;21:588593.
[PMC free rticle] [PubMed]
240. Ebos JM, Lee CR, Cruz-Munoz W, Bjrnson GA, Christensen JG, Kerbel RS. Acc
elerted metstsis fter short-term tretment with  potent inhibitor of tumor
ngiogenesis. Cncer Cell. 2009;15:232239. [PMC free rticle] [PubMed]
241. Rugo HS. Inhibiting ngiogenesis in brest cncer: the beginning of the end
or the end of the beginning? J Clin Oncol. 2012;30:898901. [PubMed]
242. Pez-Ribes M, Allen E, Hudock J, Tked T, Okuym H, Vils F. Antingiogenic
therpy elicits mlignnt progression of tumors to incresed locl invsion nd
distnt metstsis. Cncer Cell. 2009;15:220231. [PMC free rticle] [PubMed]
243. Powe DG, Entschlden F. Trgeted therpies: Using bet-blockers to inhibit
brest cncer progression. Nt Rev Clin Oncol. 2011;8:511512. [PubMed]
244. Brron TI, Connolly RM, Shrp L, Bennett K, Visvnthn K. Bet blockers n
d brest cncer mortlity:  popultion-bsed study. J Clin Oncol. 2011;29:263526
44. [PubMed]
245. Syromitnikov AV, Alistrtov AV. Chnges in the efferent impulstion in the
vgus nerves during the metstsis of Lewis lung crcinom in mice. Eksp Onkol.
1989;11:4750. [PubMed]
246. Li ZJ, Cho CH. Neurotrnsmitters, more thn meets the eye--neurotrnsmitter
s nd their perspectives in cncer development nd therpy. Eur J Phrmcol. 201
1;667:1722. [PubMed]
247. Schuller HM, Al-Wdei HA, Mjidi M. GABA B receptor is  novel drug trget
for pncretic cncer. Cncer. 2008;112:767778. [PMC free rticle] [PubMed]
248. Yng ZF, Ho DW, Lm CT, Luk JM, Lum CT, Yu WC, Poon RT, Fn ST. Identifict
ion of brin-derived neurotrophic fctor s  novel functionl protein in hepto
cellulr crcinom. Cncer Res. 2005;65:219225. [PubMed]
249. Hrburg GC, Hinck L. Nvigting brest cncer: xon guidnce molecules s b
rest cncer tumor suppressors nd oncogenes. J Mmmry Glnd Biol Neoplsi. 20
11;16:257270. [PMC free rticle] [PubMed]
250. Mehlen P, Delloye-Bourgeois C, Chedotl A. Novel roles for Slits nd netrin
s: xon guidnce cues s nticncer trgets? Nt Rev Cncer. 2011;11:188197. [Pub
Med]
251. Welch DR, Cooper CR, Hurst DR, Lynch CC, Mrtin MD, Vidy KS, VnSun MN,
Mstro AM. Metstsis Reserch Society-Americn Assocition For Cncer Reserch
Joint Conference on Metstsis. Cncer Res. 2008;68:95789582. [PMC free rticle]
[PubMed]