The Influence of Bio-Behavioural Factors on Tumour Biology: Pathways and Mechanisms

Abstract

Epidemiological studies indicate that stress, chronic depression and lack of social support might serve as risk factors for cancer development and progression. Recent cellular and molecular studies have identified biological processes that could potentially mediate such effects. This review integrates clinical, cellular and molecular studies to provide a mechanistic understanding of the interface between biological and behavioural influences in cancer, and identifies novel behavioural or pharmacological interventions that might help improve cancer outcomes.

Full text

Clinical studies indicate that stress, chronic
depression, social support and other psycho-
logical factors might influence cancer onset
and progression
1–5
. Recent mechanistic stud-
ies have identified biological signalling path-
ways that could contribute to such effects.
Environmental and psycho-social processes
initiate a cascade of information-processing
pathways in the central nervous system
(CNS) and periphery, which subsequently
trigger fight-or-flight stress responses in the
autonomic nervous system (ANS), or defeat/
withdrawal responses that are produced by
the hypothalamic–pituitary–adrenal axis
(HPA)
6
. FIGURE 1 shows the areas of the
brain that are thought to be responsible for
mediating stress responses and their effects
on the adrenal glands and other target
tissues. Cognitive and emotional feedback
from cortical and limbic areas of the brain
modulate the activity of hypothalamic and
brain-stem structures that directly control
HPA and ANS activity
7
.
HPA responses are mediated by hypo-
thalamic production of corticotrophin-
releasing factor and arginine vasopressin,
both of which activate the secretion of
pituitary hormones such as adrenocortico-
tropic hormone (
ACTH), enkephalins and
endorphins. ACTH induces downstream
release of glucocorticoids such as cortisol
from the adrenal cortex. Glucocorticoids
control growth, metabolism and immune
function, and have a pivotal role in regulat-
ing basal function and stress reactivity
across a wide variety of organ systems
8
. ANS
responses to stress are mediated primarily
by activation of the sympathetic nervous
system (SNS) and subsequent release of
catecholamines (principally noradrenaline
and adrenaline) from sympathetic neurons
and the adrenal medulla. Levels of catecho-
lamines are increased in individuals who
experience acute or chronic stress, and are
responsible for ANS effects on cardiac,
respiratory, vascular and other organ sys-
tems
8
. Examples of stressors associated with
alterations in the HPA and/or ANS include
marital disruption, bereavement, depression,
chronic sleep disruption, severe trauma and
post-traumatic stress disorder
9,10
.
The activation of these pathways prepares
an individual to survive a threat, and the
physiological stress responses are therefore
generally considered adaptive. However,
under chronic stress most physiological
systems are negatively affected by prolonged
exposure to glucocorticoids and catecho-
lamines
11
. These changes are manifested
by deleterious health consequences such
as increased risk for cardiac disease, slower
wound healing and increased risk from
infections
11
. In the past decade, it has become
increasingly clear that chronic alterations
in neuroendocrine dynamics can also alter
multiple physiological processes involved in
tumour pathogenesis
12–15
.
In this article, we review the clinical
and experimental evidence regarding the
effects of stress on tumour development,
growth and progression. Special emphasis
is placed on neuroendocrine influences
on the tumour microenvironment, viral
oncogenesis and the immune system
(FIG. 2).
Although the mechanisms and clinical
relevance of these pathways are described
separately, there are numerous interactions
between them, reflecting the complexity of
cancer pathogenesis. These pathways might
provide additional clues about factors that
regulate the course of disease in cancer
patients and might offer new opportunities
for therapeutic interventions.
Endocrine stress response and cancer
There is evidence linking stress, concomitant
behavioural response patterns and result-
ant neurohormonal and neurotransmitter
changes (all of which are referred to
collectively within this paper as bio-behav-
ioural factors) to cancer development and
progression. Epidemiological data show
that psychological and social characteristics
might be associated with differential cancer
onset, progression and mortality. For exam-
ple, a twofold increase in
breast cancer risk
is evident after disruption of marriage owing
to divorce, separation or death of a spouse
5
.
Data from 3 eastern and midwestern states
in the United States indicate that cancer risk
increases after chronic depression that has
lasted for at least 6 years
16
. A third study
found that the combination of extreme
stress and low social support was related to a
ninefold increase in breast cancer incidence
4
.
However, findings have been inconsistent.
In general, stronger relationships have been
observed between psycho-social factors and
cancer progression than between psycho-
social factors and cancer incidence (see
REF. 3
for a discussion of the strengths and weak-
nesses of this literature). Data from patients
with existing tumours show that cancer
diagnosis and treatment cause substantial
distress, and that those who tend toward
depressive coping methods, such as hope-
lessness and helplessness, might experience
accelerated disease progression
2
. By contrast,
positive factors such as social support and
optimism have predicted longer survival
17,18
.
Additionally, there are important interac-
tions between behavioural stress factors and
health behaviours — including smoking,
insomnia, alcohol abuse and obesity — that
might have a further impact on cancer risk
19
.
Recent experimental studies have begun to
elucidate the mechanisms underlying these
observations.
Animal models have provided com-
pelling evidence regarding the effects
of behavioural stress on tumorigenesis
and the biological mechanisms involved
(TABLE 1). For example, immobilization
stress in rats that were given a carcinogen,
diethylnitrosamine, increased both the
OPINION
The influence of bio-behavioural
factors on tumour biology: pathways
and mechanisms
Michael H. Antoni, Susan K. Lutgendorf, Steven W. Cole, Firdaus S. Dhabhar,
Sandra E. Sephton, Paige Green McDonald, Michael Stefanek and Anil K. Sood
Abstract | Epidemiological studies indicate that stress, chronic depression and lack
of social support might serve as risk factors for cancer development and
progression. Recent cellular and molecular studies have identified biological
processes that could potentially mediate such effects. This review integrates
clinical, cellular and molecular studies to provide a mechanistic understanding of
the interface between biological and behavioural influences in cancer, and
identifies novel behavioural or pharmacological interventions that might help
improve cancer outcomes.
PERSPECTIVES
240
|
MARCH 2006
|
VOLUME 6 www.nature.com/reviews/cancer
© 2006 Nature Publishing Group

incidence and rate of tumour growth
20
.
Experimental stressors have also been
found to increase the pathogenesis of vari-
ous virally mediated tumours in animal
models (see below). Swim stress, surgical
stress, social confrontation and hypother-
mia resulted in increased lung metastasis
from injected breast cancer cells
21–24
. Swim
stress, laparotomy (opening the abdo-
men) and social confrontation caused
a 2- to 5-fold increase in the number of
rat MADB106 breast tumour metastases
present in the lung
24,25
and a similar
increase in the number of lung metastases
counted 3 weeks later
24–26
. β-Adrenergic
agonists (which simulate activation of
the SNS) such as metaproterenol show
dose-dependent increases in
lung tumour
metastases. Similarly, adrenaline injections
promoted mammary tumour metastasis
21–24
.
Perhaps most importantly, pre-treatment
of animals with β-adrenergic antagonists
(to block the activity of SNS activation) and
indomethacin (to block inflammation) syn-
ergistically blocked the effects of behavioural
stress on lung tumour metastasis
27
.
Cellular and molecular events that
promote cancer growth are also affected
by stress. Swim stress in rodents results in
induction of chromosomal aberrations and
sister chromatid exchanges
28
as well as lower
activity of metaphase nucleolar organizer
regions in bone marrow cells
29
. These find-
ings indicate that stress might compromise
DNA repair mechanisms. Stress can also
influence the expression of viral oncogenes
and replication of tumorigenic viruses (see
below). In an orthotopic murine model of
ovarian carcinoma, immobilization stress
increased tumour burden and enhanced
angiogenesis and tumour production of
vascular endothelial growth factor (
VEGF)
30
,
indicating that stress might promote tumour
growth by facilitating development of a blood
supply. VEGF is a pro-angiogenic molecule
that stimulates endothelial cell migration,
proliferation and proteolytic activity
31
.
VEGF also interferes with the development
of T cells and the functional maturation of
dendritic cells
32,33
, indicating possible effects
on anti-tumour immune responses (see
below). In line with these findings, recent
clinical studies have shown links between
higher levels of social support and lower
serum levels of VEGF in patients with
ovarian
cancer
34
. Furthermore, social support has also
been linked to lower levels of interleukin-6
(IL-6), another pro-angiogenic factor, both in
peripheral blood and in ascites from patients
with ovarian cancer
35
.
Understanding the mechanisms
responsible for mediating the effects of
stress on human tumour tissues is crucial
for determining the full impact of stress
on tumorigenesis and for devising effec-
tive interventions. Experimental evidence
indicates that stress hormones have multiple
effects on human tumour biology. Hormones
that are associated with SNS activation might
favour angiogenesis in human tumours.
Noradrenaline has been shown to upregulate
VEGF in adipose tissue and two ovarian
cancer cell lines through the β-adrenergic
receptor (βAR)–cyclic AMP (cAMP)–
protein kinase A (PKA) pathway
36,37
. This
effect was abolished by a β-blocker,
propranolol, and was mimicked by isopro-
terenol (a synthetic drug that mimics the
effects of SNS stimulation), and was therefore
thought to be mediated through βARs
36,37
.
Noradrenaline also promotes various steps
that are essential to tumour metastasis,
including invasion and migration. In
in vitro experimental models, noradrenaline
increased colon cancer cell migration, an
effect that was inhibited by β-blockers
38
. Both
adrenaline and noradrenaline promoted
in vitro invasion of ovarian cancer cells by
increasing the expression levels of matrix
metalloproteinase 2 (MMP2) and MMP9
12
.
βARs, which mediate most of the effects
of catecholamines, have been identified on
breast and ovarian cancer cells
12,13
. In both
of these studies,
β
2
AR was the dominant
adrenergic receptor present. βARs are G-
protein-coupled receptors whose primary
function is the transmission of information
from the extracellular environment to the
interior of the cell, leading to activation of
adenylyl cyclase and accumulation of the
second messenger cAMP
39
. In mammary
tumours, activation of βARs has been linked
to accelerated tumour growth
13–15
. The
cAMP-responsive-element-binding (CREB)
protein is an important transcription factor
that is activated by multiple signal-transduc-
tion pathways in response to external stimuli,
including stress hormones
40,41
. Several studies
have shown a role for the CREB family of pro-
teins in tumour cell proliferation, migration,
angiogenesis and inhibition of apoptosis
40–42
,
as well as the expression of viral oncogenes
(see below). An additional cAMP target,
EPAC (also known as Rap guanine-nucle-
otide-exchange factor 3 (RAPGEF3)) is an
exchange protein that is directly activated by
cAMP. EPAC was recently shown to control
a number of cellular processes that were
previously attributed to PKA
43
. For example,
βAR-mediated activation of cAMP promotes
ovarian cancer cell adhesion through the
EPAC–RAP1 pathway
44
. Collectively, these
studies demonstrate the growing evidence
that mediators of SNS activate cellular
pathways within tumours that contribute
to growth and progression. However, the
clinical relevance in human studies of the
bio-behavioural stress mechanisms described
above remains to be demonstrated.
Glucocorticoids and other mediators
Glucocorticoids regulate a wide variety of
cellular processes through glucocorticoid-
receptor-mediated activation or repres-
sion of target genes. Recent studies have
demonstrated that whereas glucocorticoid
hormones induce apoptosis in lymphocytes
45
,
Figure 1 | Important components of the central
and peripheral stress systems. Stressful
experiences activate components of the limbic
system, which includes the hypothalamus, the
hippocampus, the amygdala, and other nearby
areas. In response to neurosensory signals, the
hypothalamus secretes corticotrophin-releasing
factor (CRF) and arginine vasopressin (AVP), both
of which activate the pituitary to produce
hormones such as adrenocorticotropic hormone
(ACTH). Circulating ACTH stimulates the
production of glucocorticoids from the adrenal
cortex. The sympathetic nervous system
originates from the brainstem, and the pre-
ganglionic neurons terminate in the ganglia near
the spinal column. From these ganglia, post-
ganglionic fibres run to the effector organs. The
main neurotransmitter of the pre-ganglionic
sympathetic fibres is acetylcholine and the typical
neurotransmitter released by the post-ganglionic
neurons is noradrenaline. The adrenal medulla
contains chromaffin cells, which release mainly
adrenaline.
Paraventricular nucleus
AVP
CRF
Pituitary
ACTH
Adrenal
gland
Cortisol
Adrenaline
Noradrenaline
Noradrenaline
Neuropeptides
Sympathetic
ganglion
Locus coeruleus
(noradrenergic system)
Noradrenaline
PERSPECTIVES
NATURE REVIEWS
|
CANCER VOLUME 6
|
MARCH 2006
|
241
© 2006 Nature Publishing Group

these hormones activate survival genes
that protect cancer cells from the effects of
chemotherapy in both in vitro and in vivo
experimental models
46,47
. Glucocorticoids can
also activate oncogenic viruses and inhibit
anti-tumour and antiviral cellular immune
responses (see below). Glucocorticoids such
as cortisol might function in a synergistic
fashion with catecholamines to facilitate
cancer growth. For example, in lung carci-
noma cells cortisol increased βAR density
and potentiated the isoproterenol-induced
increase in cAMP accumulation
48
. So, it is
plausible that stressful situations character-
ized by both increased catecholamine
and cortisol concentrations (for example,
uncontrollable stress) might have the greatest
impact on cancer-related processes.
The expression levels of other hormones
affected by stress include prolactin, which
increases with stress
49,50
, and oxytocin and
dopamine, which decrease with stress
51
.
Prolactin can promote cell growth and
survival in breast tumour and other tumour
cells
52
. Oxytocin inhibits the growth of epi-
thelial cell (such as breast and endometrial)
tumours and those of neuronal or bone ori-
gin, but the hormone has a growth-stimu-
lating effect in trophoblast and endothelium
tumours
53
. For example, exogenous oxytocin
has a dose-dependent mitogenic effect on
human small-cell lung cancer cell lines,
which is blocked by an oxytocin receptor
antagonist
54
. Dopamine, which is known
to inhibit the growth of several types of
malignant tumours
55
, blocks VEGF-induced
angiogenesis both in vitro and in vivo,
primarily by inducing endocytosis of VEGF
receptor 2 in endothelial cells
56
.
Effect of circadian deregulation on cancer
Evidence indicates that circadian deregula-
tion influences the secretion of some
stress-associated hormones, and this might
explain the associations between stress
and cancer
57,58
. Data from separate lines of
investigation show that stress can disrupt cir-
cadian glucocorticoid rhythms
57,59
and favour
tumour initiation and progression
57,58,60
.
Night-time shift work, a condition that is
known to disrupt endocrine rhythms, is a
risk factor for breast and colorectal cancer
61
.
Mice with circadian disruption owing to Per1
(period 1) or Per2 gene mutations are prone
to tumour development and early death
62,63
.
Tumour-bearing animals and cancer patients
have disrupted endocrine, metabolic and
immunological cycles, with greater disrup-
tion in cases where the tumour is advanced
or fast-growing
64
. In murine studies, tumour
progression and mortality are dramatically
Figure 2 | Effects of stress-associated factors on the tumour microenvironment.
The responses to stressors involve central nervous system (CNS) perceptions of threat and
subsequent activation of the autonomic nervous system (ANS) and the hypothalamic–pituitary–
adrenal (HPA) axis. Catecholamines, glucocorticoids and other stress hormones are subsequently
released from the adrenal gland, brain and sympathetic nerve terminals and can modulate the
activity of multiple components of the tumour microenvironment. Effects include the promotion
of tumour-cell growth, migration and invasive capacity, and stimulation of angiogenesis by
inducing production of pro-angiogenic cytokines. Stress hormones can also activate oncogenic
viruses and alter several aspects of immune function, including antibody production, cytokine
production profiles and cell trafficking (see
REF. 6 for a comprehensive review of immune effects).
Collectively, these downstream effects create a permissive environment for tumour initiation,
growth and progression. CRF, corticotrophin-releasing factor; IL-6, interleukin-6; MMP, matrix
metalloproteinase; VEGF, vascular endothelial growth factor.
Optimism
Perceived stress
Depression
Psychological responsesStressors
Social isolation
Negative life events
Socio-economic burden
ACTH
Autonomic nervous system
• Noradrenaline
• Adrenaline
• Other neuropeptides
Adrenal gland
CRF/locus coeruleus
↓ Oxytocin
↓ Dopamine
•Noradrenaline/adrenaline •Cortisol
Immune cells
↓ Immune response
↓ Activity
Cancer cells
↑ Migration and invasion
↑ Proteases (MMPs)
• Altered DNA repair
Blood vessel
↑ Angiogenesis/pro-angiogenic
cytokines (VEGF, IL-6)
Viruses
↑ Oncogene transcription
↑ Viral replication
↑ Host-cell cycling
Neuroendocrine activity
Tumour microenvironment
Fibroblasts
Immune cells
Blood vessel
Tumour cell
PERSPECTIVES
242
|
MARCH 2006
|
VOLUME 6 www.nature.com/reviews/cancer
© 2006 Nature Publishing Group

accelerated after elimination of circadian
rhythms by manipulation of light–dark cycles
(imposed ‘jet-lag’) and by the use of bilateral
electrolytic lesions to destroy the suprachias-
matic nuclei (SCN), which eliminates circa-
dian rhythms
60
. Two clinical studies have also
shown that the status of circadian cycles, such
as cortisol or the 24-hour-rest–activity cycle,
can predict long-term cancer survival
58,65
.
Stress-related disruption of circadian
cycles might impair cancer-defence
mechanisms through genetic and/or gluco-
corticoid and immune pathways. Animal
studies show that behavioural factors such
as imposed chronic jet-lag can alter Per1
expression in the SCN
60
, and circadian
genes, including Per1, regulate tumour
suppression, cellular response to DNA
damage, and apoptosis
63
. Glucocorticoid
rhythms that are driven by the SCN
62
are
linked to both enumerative and functional
immunity
66
. Sleep disruption can increase
the release of cortisol as well as increase the
expression of pro-inflammatory cytokines
(for example, IL-6 and tumour-necrosis
factor-α (TNFα)) in cancer patients
67
.
Pro-inflammatory cytokines might promote
tumorigenesis by inducing DNA damage
or inhibiting DNA repair through the
generation of reactive oxygen species. Pro-
inflammatory cytokines can also lead to the
inactivation of tumour-suppressor genes,
the promotion of autocrine or paracrine
growth and survival of tumour cells, the
stimulation of angiogenesis, or the subversion
of the immune response (which leads to the
activation of B cells rather than T cells in the
tumour microenvironment)
68
. Conversely,
agents that are capable of re-establishing
circadian regulation (for example, melatonin)
might have anti-tumour effects. Research on
oestrogen-receptor-positive MCF-7 human
breast cancer cells has shown that melatonin
reversibly inhibits cell proliferation, increases
p53 expression, modulates the cell cycle, and
reduces metastatic capacity by increasing
the expression of cell-surface adhesion pro-
teins
69,70
. Taken together, these data indicate a
potentially important role of circadian regula-
tion in cancer defence and treatment
62
.
Influences on viral oncogenesis
The first experimental demonstration that
bio-behavioural factors could promote
cancer came from animal studies of tumour
viruses
71
. Many studies have demonstrated
the accelerated growth of virally induced
tumours in stressed animals, as well as
the more surprising protective effects
of handling, fighting and crowding
72,73
.
Neuroendocrine function has a central role
in these processes because it can modulate
viral replication, activate viral oncogenes,
increase tumour metabolism and regulate
the immune response
74–76
. The evidence for
a viral contribution to human cancer has
grown
77
(BOX 1), and stress hormones have
Table 1 | Effects of stress and stress-associated hormones on cancer
Experimental
manipulation
Animal Biological effect Tumour type Effect on tumour
growth
References
Confrontation Rats NA Breast Increased metastasis of
tumour cells to the lung
25
Restraint stress Rats Decreased numbers of T cells Mammary Increased growth
during stress
144
Forced swim Rats Decreased natural-killer-cell activity Leukaemia Increased mortality 22
Abdominal
surgery
Rats Decreased natural-killer-cell activity Mammary Increased metastasis of
tumour cells to the lung
22
High versus low
dopaminergic
reactivity
Rats Decreased angiogenesis with high
dopaminergic reactivity
Mammary Fewer lung metastasis
with increased
dopaminergic reactivity
145
Dopamine
administration
Mice Decreased angiogenesis; decreased VEGF–
VEGFR2 binding and phosphorylation
Ovarian Decreased ascites
formation
56
Dopamine
administration
Mice Decreased angiogenesis Gastric Decreased growth 55
Social isolation Mice Decreased macrophage activity Ehrlich Increased growth 146
Immobilization
stress
Mice Increased angiogenesis Ovarian Increased growth 30
Restraint stress Mice
Decreased IL-12, IFNγ, CCL27 (also known as
CTACK) and numbers of infiltrating T cells;
increased numbers of suppressor cells
Skin and squamous cell
carcinoma
Increased incidence,
number, size and
density
110
CTACK, cutaneous T-cell attracting chemokine; IL-12, interleukin-12; IFNγ, interferon-γ; NA, not available; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2.
Box 1 | Physiological pathways, bio-behavioural processes and oncogenesis
• Environmental and social processes activate interpretive processes in the central nervous system
(CNS) that can subsequently trigger fight-or-flight stress responses in the autonomic nervous
system (ANS) or defeat/withdrawal responses through the activation of the hypothalamic–
pituitary–adrenal axis (HPA)
141
.
• Individual differences in perception and evaluation of external events (coping) creates variability
in individual ANS and HPA activity levels.
• Over long periods of time, these neuroendocrine dynamics can alter various physiological
processes involved in tumorigenesis, including oxidative metabolism, DNA repair, oncogene
expression by viruses and somatic cells, and production of growth factors and other regulators of
cell growth.
• Once a tumour is initiated, neuroendocrine factors can also regulate the activity of proteases,
angiogenic factors, chemokines and adhesion molecules involved in invasion, metastasis and
other aspects of tumour progression.
• CNS processes can also shape behavioural processes that govern cancer risk (for example,
smoking, transmission of oncogenic viruses or exposure to genotoxic compounds).
PERSPECTIVES
NATURE REVIEWS
|
CANCER VOLUME 6
|
MARCH 2006
|
243
© 2006 Nature Publishing Group

been found to influence the activity of vari-
ous human tumour viruses
(BOX 2; TABLE 2).
Epstein–Barr virus (EBV) is reactivated
in healthy people who experience pro-
longed psychological stress
78,79
. In these
studies HPA activity increased in parallel
with reactivation of EBV
79,80
, and gluco-
corticoid hormones were subsequently
found to increase EBV gene expression
in vitro
80,81
. High-risk human papilloma
viruses (HPVs), which contribute to cervi-
cal and rectal carcinomas, also respond to
glucocorticoids by activating gene expres-
sion
82–84
, interacting with cellular proto-
oncogenes such as HRAS
85
, and evading
cellular immune responses by downregu-
lating the expression of tumour MHC-I
(major histocompatibility complex class I)
molecules
86
. Clinical studies have identi-
fied stressful life events as a risk factor for
increased progression of cervical dysplasia
in HPV-positive women
87,88
. Furthermore,
glucocorticoid antagonists can inhibit HPV
activity in vitro
89–91
, providing a molecular
rationale for clinical interventions that
target HPA activity. Although hepatitis B
and C viruses come from different viral
lineages, glucocorticoids increase gene
expression in and replication of both
viruses
90,92–94
. These dynamics are so pro-
nounced that glucocorticoids are employed
clinically to activate hepatitis B and C
viruses for eradication by replication-
dependent antiviral drugs
93,95
.
Cancer-related viruses are also sensitive
to catecholamines and the PKA signal-
ling pathway. Molecular mechanisms are
especially well defined for AIDS-associ-
ated malignancies. Catecholamines can
accelerate human immunodeficiency
virus 1 (HIV1) replication by increasing
cellular susceptibility to infection
96,97
,
activating viral gene transcription
96
and
suppressing antiviral cytokines
98
. People
with heightened ANS activity show an
increased viral load in the plasma and
an impaired response to antiretroviral
therapy
96
, placing them at increased risk
for AIDS-associated B-cell lymphomas
99
.
Catecholamines can also activate the
Kaposi sarcoma-associated herpesvirus
(KSHV) through PKA induction of the
viral transcription factor Rta
100
. Human
T-cell lymphotropic viruses 1 and 2
(HTLV1 and HTLV2, respectively) are
sensitive to PKA-mediated induction of
the oncogenic Tax transcription factor
101
.
Hormonal regulation of viral replica-
tion represents an important pathway
by which bio-behavioural factors might
influence malignant processes, but it also
indicates novel therapeutic approaches
such as β-adrenergic priming of viral
genomes for clearance by replication-
dependent nucleoside analogue drugs.
In addition to direct effects on viral
gene expression, bio-behavioural factors
can also indirectly affect tumour viruses
by modulating host immune responses
(see below). Antiviral vaccines will have an
increasing role in the primary prevention
of virally mediated cancers, and bio-
behavioural influences on vaccine-induced
immune responses will become especially
relevant
102,103
. Neuroendocrine influences
on the immune response might also explain
why oncogenic viruses so consistently
acquire hormone-responsive replication
dynamics. Viruses that coordinate their
gene expression with periods of hormone-
induced immunosuppression should enjoy
a significant survival advantage. Similar
selective pressures might also shape the
evolution of non-viral malignancies
104
such
that genomic alterations are selected based
on their ability to evade immune clearance
or to synergize with endocrine dynamics to
optimize tumour growth and metastasis.
Influences on immune mechanisms
Chronic stress has been shown to suppress
different facets of immune function
2
such
as antigen presentation, T-cell proliferation,
and humoral and cell-mediated immunity,
mainly through the release of catecholamine
and/or glucocorticoid hormones
105–107
.
Relevant neuroendocrine and immune sys-
tem interactions include direct synapse-like
connections between sympathetic nerves
and lymphocytes in lymphoid organs
108
,
neural and endocrine modulation of lym-
phocyte trafficking
109
, and modulation of
leukocyte function through glucocorticoid
receptors and other receptors
70
. Tumour inci-
dence and progression based on modulation
of the immune response by chronic stress has
been demonstrated in many animal models
(see above). Recent studies have shown that
chronic stress experienced during exposure
to non-blistering ultraviolet radiation
significantly increases susceptibility to squa-
mous cell carcinoma by suppressing type 1
cytokines and the infiltration of protective
T cells. Regulatory or suppressor T-cell num-
bers within the tumours and in the circula-
tion were also increased
110
. Studies in mice
of the immune response to transplanted
syngeneic tumours showed that noradrena-
line
111
and adrenaline
112,113
directly inhibited
the generation of anti-tumour cytotoxic
T cells through β-adrenergic signalling
mechanisms. Chronic stress has been shown
to modulate lymphocyte apoptosis through
Table 2 | Neuroendocrine influences on tumour viruses
Human tumour virus Malignancy Sensitivity*
Human papilloma viruses 16 and 33 Cervical and head/neck cancer HPA
Hepatitis B virus Hepatocellular carcinoma HPA
Hepatitis C virus Hepatocellular carcinoma HPA
Epstein–Barr virus Lymphoma, and nasopharygeal
carcinoma
HPA
Human T-cell lymphotropic viruses
1 and 2
Adult T-cell leukaemia/lymphoma ANS
Kaposi sarcoma-associated
herpesvirus
Kaposi sarcoma, and primary
effusion lymphoma
ANS
*Presumptive, based on in vitro studies. ANS, autonomic nervous system; HPA, hypothalamic–pituitary–adrenal
axis. Vaccination is an important primary prevention strategy against viral tumours, and behavioural factors can
influence the efficacy of this approach by modulating vaccine-induced immune responses
102,103
.
Box 2 | Viral oncology
• Viral infections contribute to approximately 15% of human cancers worldwide
77
.
• Pathogenic mechanisms include expression of viral oncogenes (for example, human T-cell
lymphotropic virus
Tax, and Epstein–Barr virus nuclear antigens and latent membrane protein 1),
inhibition of host-cell tumour-suppressors (for example, human papillomavirus E6, which targets
p53 and E7, which targets RB), and genomic damage stemming from immune-mediated cell
turnover (for example, hepatitis B and C viruses)
77,142,143
.
• All major human tumour viruses are sensitive to the intracellular signalling pathways activated by
the hypothalamic–pituitary–adrenal axis and autonomic nervous system. These mediators can
reactivate latent tumour viruses, stimulate oncogene expression and inhibit host-cell antiviral
responses.
PERSPECTIVES
244
|
MARCH 2006
|
VOLUME 6 www.nature.com/reviews/cancer
© 2006 Nature Publishing Group

an increase in FAS (also known as CD95 or
APO1) expression. It has been hypothesized
that such lymphocyte reduction might result
in an increase in the incidence of oncogenic
viral infections and DNA damage
114
.
Compromised natural killer (NK)-cell
function has been shown in both animal
and clinical studies of surgical stress
22,115
.
High levels of psychological distress have
been linked to reduced cellular immunity in
patients with breast
116
and ovarian cancer
117
.
More specifically, distress measured by self-
report was correlated with low NK-cell cyto-
toxicity in tumour-infiltrating lymphocytes
from human ovarian cancers
117
. Low
peripheral NK-cell counts are prognostic for
early breast cancer mortality, and reduced
NK-cell cytotoxicity is predictive of a poor
clinical outcome in patients with breast
carcinoma
58
. Positive psycho-social factors
such as social support have been associated
with increased levels of NK-cell cytotoxic-
ity in patients with breast
118
and ovarian
cancer
117
. The relationship of increased
NK-cell cytotoxicity with social support was
not limited to the periphery; it was also seen
in tumour-infiltrating lymphocytes isolated
from human ovarian cancers, reflecting pos-
sible psycho-social influences on the tumour
microenvironment
117
. Patients with breast
cancer who reported increased psychological
growth through participation in a cognitive
behavioural intervention programme dem-
onstrated increased levels of cellular immune
function
119
. Preliminary studies have found
that the expression of spirituality was related
to increased numbers of circulating T cells
in patients with breast cancer
120
, and that the
use of humour as a coping mechanism was
associated with increased NK-cell activity in
cancer patients
121
.
Clinical opportunities and challenges
Our understanding of the biological and
clinical significance of psycho-social and bio-
behavioural influences on cancer pathogen-
esis is expanding. As described in this review,
factors such as chronic stress, depression and
social support have been linked to tumour
biology, viral oncogenesis and cell-mediated
immunity
(FIG. 3). Although the molecular
pathways have not been completely deline-
ated, observations to date indicate a need for
novel therapeutic paradigms that integrate a
bio-behavioural perspective.
It is plausible that successful manage-
ment of factors such as stress and negative
mood might have a salubrious effect on the
neuroendocrine regulation of oncogenesis,
tumour growth and metastasis, and cancer
immunoediting processes. Psycho-social
interventions such as relaxation and
cognitive behavioural techniques that alter
negative mood seem to modulate ANS and
HPA hormonal activity
122–124
. Moreover,
such interventions can potentially be used
in conjunction with conventional therapies
to maximize treatment efficacy
125,126
. Stress-
management interventions that dampen
chronic-stress-related physiological changes
might facilitate immune system ‘recovery’
and thereby increase immune surveillance
during the active treatment of cancer
119,124
.
Group-based psycho-social interventions
that combine relaxation with cognitive
behavioural techniques, such as cognitive
behavioural stress management (CBSM),
have been shown to increase indicators
Figure 3 | Integrated model of bio-behavioural influences on cancer
pathogenesis through neuroendocrine pathways. In this model, bio-
behavioural factors such as life stress, psychological processes and
health behaviours (blue panel) influence tumour-related processes
(green panel) through the neuroendocrine regulation of hormones,
including adrenaline, noradrenaline and glucocorticoids (red panel).
Central control of peripheral endocrine function also allows social,
environmental and behavioural processes to interact with biological
risk factors such as genetic background, carcinogens and viral infections
to systemically modulate malignant potential (red panel). Direct
pathways of influence include effects of catecholamines and
glucocorticoids on tumour-cell expression of genes that control cell
proliferation, invasion, angiogenesis, metastasis and immune evasion
(green panel). Stress-responsive neuroendocrine mediators can also
influence malignant potential indirectly through their effects on
oncogenic viruses and the cellular immune system (red panel). These
pleiotropic hormonal influences induce a mutually reinforcing system
of cellular signals that collectively support the initiation and progression
of malignant cell growth (green panel). Furthermore, neuroendocrine
deregulation can influence the response to conventional therapies such
as surgery, chemotherapy and immunotherapy (green panel). In addition
to explaining bio-behavioural risk factors for cancer, this model
suggests novel targets for pharmacological or behavioural intervention.
CTL, cytotoxic T lymphocytes; IL, interleukin; MRD, minimal residual
disease; NKC, natural killer cell; TGFβ, transforming growth factor-β;
TNFα, tumour-necrosis factor-α; TSH, thyroid-stimulating hormone.
Life stress
• Cumulative burden
• Trauma
• Socio-economic status
• Early-life experience
Psychological processes
• Depression
• Social support
• Appraisal and coping
Health behaviour
• Sleep
• Physical activity
• Diet
• Sexual behaviour
Biological cancer-risk factors
•Genetic/hereditary
• Carcinogen exposure
• Ageing
•Co-morbid diseases
• Viral infection
• Circadian clocks
Neuroendocrine regulation
•Adrenaline/noradrenaline
•Glucocorticoids
•Oestrogen, androgen, dopamine,
serotonin, TSH, growth hormone,
prolactin, oxytocin and melatonin
Immune response
•Cellular (NKC, CTL and T-cell
activity) and humoral
•T
H
1/T
H
2 cytokines, macrophages,
IL-1, IL-6, TNFα and TGFβ
•Cell recruitment, signalling and
chemokines
Initiation
•Mutation
• Viral oncogenes
• Cell proliferation
• DNA repair
Therapy
• Surgery
• Chemotherapy
• Radiation
• Targeted molecules
• Immunotherapy
• Endocrine therapy
Metastasis
• Embolism
• Attachment
• Establish microenvironment
• Proliferation
• Angiogenesis
• Invasion
• Migration
Remission/progression
• Growth support for MRD
• Immune surveillance
Tumour growth
• Apoptosis
• Angiogenesis
• Invasion
• Immunological escape
PERSPECTIVES
NATURE REVIEWS
|
CANCER VOLUME 6
|
MARCH 2006
|
245
© 2006 Nature Publishing Group

of immune responses against potentially
oncogenic viral infections, such as EBV
127
.
Such alterations are paralleled by decreased
expression levels of cortisol in the serum, a
reduced depressive mood, increased social
support and enhanced relaxation skills
122
.
In HIV-infected individuals, who as a
group are at risk for multiple opportunistic
cancers, CBSM seems to accelerate recon-
stitution of naive T-lymphocytes, increase
CD8
+
cytotoxic T-cell numbers and decrease
the viral load of HIV over time
122,128
. These
changes are pre-dated by decreases in nega-
tive mood and decreases in urinary cortisol
and noradrenaline output
122,129
. It is plausible
that CBSM might also help decrease the
replication and function of other oncogenic
viruses such as HPV and improve immune
defences against them. Psycho-social inter-
ventions in cancer patients have resulted in
alterations in neuroendocrine regulation and
immunological functions
124,130,131
that are rel-
evant for monitoring neoplastic cell changes.
For example, two recent randomized clinical
trials have documented increases in lym-
phocyte proliferation in patients with breast
cancer following psycho-social interven-
tions
119,124
, and post-intervention changes
in NK-cell activity have also been shown
in patients with malignant melanoma
131
.
Collectively, this work indicates that stress
management can modify neuroendocrine
deregulation and immunological functions
that potentially have implications for tumour
progression. This might be particularly
important among vulnerable populations
such as older adults because ageing is
associated with a suppression of the immune
response.
Clinical studies of psycho-social inter-
ventions with cancer survival as an outcome
have been methodologically flawed or have
failed to confirm a survival advantage in
the treatment group
1,126,132–134
. Similar to
most medical interventions for cancer, the
effectiveness of psycho-social interventions
is likely to vary with the type and stage of
cancer, characteristics of the patient (for
example, age, gender, education, co-morbid
medical conditions, and health behaviours
such as tobacco use, alcohol consumption
and physical activity) and the type and
delivery of the intervention. Nevertheless,
epidemiological evidence correlating psy-
chological and social factors (for example,
chronic depression, hopelessness, marital
disruption and social support) with cancer
incidence, progression and survival give cre-
dence to examining the biological signalling
pathways and mechanisms that underlie
these observations.
Pharmacological interventions can
potentially be used to ameliorate stress-
associated influences on cancer develop-
ment and progression. As discussed above,
β-blockers have been shown to block many
of the deleterious effects of stress. In a large
case–control study of patients with prostate
cancer who were taking anti-hypertensive
medication, only β-blockers were associated
with a reduction of cancer risk
135
. A cohort
study of cardiovascular patients showed that
the use of β-blockers, relative to never-using,
resulted in a 49% decrease in cancer risk,
with a 6% decrease in risk for every year of
use
136
. Large population-based case–control
studies have not confirmed alterations in
risk for invasive breast carcinoma with
β-blocker use
137,138
. The use of antidepressant
medications might be promising, owing to
a concomitant suppression of an inflamma-
tory response that has been associated with
certain types of cancer
139
. For example, lith-
ium inhibits prostaglandin E1, and tricyclic
antidepressants antagonize thromboxanes
140
.
Some monoamine oxidase inhibitors exert a
more potent anti-prostaglandin effect than
indomethacin
140
. Whether these agents can
be used to reduce cancer risk through bio-
behavioural-related mechanisms remains
to be determined, but these studies indicate
that further inquiry is warranted.
Conclusion
Despite significant progress in the past
decade, further research is needed to define
the mechanisms underlying the complex
circuits involving the HPA and ANS axes
and their effects on the processes involved
in cancer development and progression.
The body of data outlined above supports
a model in which bio-behavioural factors
influence multiple aspects of tumorigenesis
through their impact on neuroendocrine
function
(FIG. 3). These effects include direct
promotion of tumour growth by affecting
steps in the metastatic cascade and viral
oncogenesis. Furthermore, the interplay
between behavioural processes and cellular
immune factors also supports a favourable
physiological environment for tumour
establishment and growth. In the context of
this ‘systems biology’ perspective, pharma-
cological and behavioural interventions that
address neuroendocrine dysfunction could
have a clinically significant role in avoiding
these deleterious effects on tumour growth.
Although stress per se does not cause cancer,
the clinical and experimental data outlined
above indicate that factors such as mood,
coping mechanisms and social support can
significantly influence the underlying
cellular and molecular processes that facili-
tate malignant cell growth. As cancer treat-
ment evolves towards a more patient-specific
approach, consideration of the influence
of bio-behavioural factors provides a novel
perspective for mechanistic studies and new
therapeutic targets.
Michael H. Antoni is at the Departments of Psychology,
Psychiatry, and Behavioural Sciences and the
Sylvestor Cancer Center, University of Miami,
P.O. Box 248185, Coral Gables, Florida 33124, USA.
Susan K. Lutgendorf is at the Departments of
Psychology and Obstetrics and Gynecology and The
Holden Comprehensive Cancer Center, University of
Iowa, E11 Seashore Hall, Iowa City, Iowa 52242, USA.
Steven W. Cole is at the Division of Hematology–
Oncology, University of California, Los Angeles School
of Medicine 11-934 Factor Building, Los Angeles,
California 90095-1678, USA.
Firdaus S. Dhabhar is at the Department of Psychiatry
and Behavioral Sciences, Stanford University School of
Medicine, 401 Quarry Road, Office 2325, Stanford,
California 94305, USA.
Sandra E. Sephton is at the Department of
Psychological and Brain Sciences, James Graham
Brown Cancer Center, University of Louisville,
2301 South 3rd Street, Room 317, Louisville,
Kentucky 40202, USA.
Paige Green McDonald and Michael Stefanek are at
the Basic and Biobehavioural Research Branch,
Behavioural Research Program, Division of Cancer
Control and Population Sciences, National Cancer
Institute, National Institutes of Health,
6130 Executive Boulevard, MSC 7363, Bethesda,
Maryland 20892, USA.
Anil K. Sood is at the Departments of Gynecologic
Oncology and Cancer Biology, University of Texas M.
D. Anderson Cancer Center, Unit 1362, P.O.
Box 301439, Houston, Texas 77230-1439, USA.
Correspondence to P.G.M.
e-mail: pm252v@nih.gov
doi:10.1038/nrc1820
1. Stefanek, M. & McDonald, P. G. in Handbook of
Behavioral Science and Cancer (eds Miller, S. M.,
Bowen, D. J., Croyle, R. T. & Rowland, J.) (American
Psychological Association, Washington DC) (in the
press).
2. Reiche, E. M., Nunes, S. O. & Morimoto, H. K. Stress,
depression, the immune system, and cancer. Lancet
Oncol. 5, 617–625 (2004).
3. Spiegel, D. & Giese-Davis, J. Depression and cancer:
mechanisms and disease progression. Biol. Psychiatry
54, 269–282 (2003).
4. Price, M. A. et al. The role of psychosocial factors in
the development of breast carcinoma: part I. The
cancer prone personality. Cancer 91, 679–685
(2001).
5. Lillberg, K. et al. Stressful life events and risk of breast
cancer in 10,808 women: a cohort study. Am. J.
Epidemiol. 157, 415–423 (2003).
6. Glaser, R. & Kiecolt-Glaser, J. K. Stress-induced
immune dysfunction: implications for health. Nature
Rev. Immunol. 5, 243–251 (2005).
7. Chrousos, G. P. & Gold, P. W. The concepts of stress
and stress system disorders. Overview of physical and
behavioral homeostasis. JAMA 267, 1244–1252
(1992).
8. Charmandari, E., Tsigos, C. & Chrousos, G. P.
Endocrinology of the stress response. Annu. Rev.
Physiol. 67, 259–284 (2005).
9. McEwen, B. S. Allostasis and allostatic load:
implications for neuropsychopharmacology.
Neuropsychopharmacology 22, 108–124
(2000).
PERSPECTIVES
246
|
MARCH 2006
|
VOLUME 6 www.nature.com/reviews/cancer
© 2006 Nature Publishing Group

10. Kiecolt-Glaser, J. K., McGuire, L., Robles, T. F. &
Glaser, R. Emotions, morbidity, and mortality: new
perspectives from psychoneuroimmunology.
Annu. Rev. Psychol. 53, 83–107 (2002).
11. McEwen, B. S. Sex, stress and the hippocampus:
allostasis, allostatic load and the aging process.
Neurobiol. Aging 23, 921–939 (2002).
12. Sood, A. K. et al. Stress hormone mediated invasion of
ovarian cancer cells. Clin. Cancer Res. 12, 369–375
(2006).
13. Badino, G. R., Novelli, A., Girardi, C. & Di Carlo, F.
Evidence for functional β-adrenoceptor subtypes in CG-
5 breast cancer cell. Pharm. Res. 33, 255–260 (1996).
14. Vandewalle, B., Revillion, F. & Lefebvre, J. Functional
β-adrenergic receptors in breast cancer cells. J. Cancer
Res. Clin. Oncol. 11 6 , 303–306 (1990).
15. Marchetti, B., Spinola, P. G., Pelletier, G. & Labrie, F.
A potential role for catecholamines in the development
and progression of carcinogen-induced mammary
tumors: hormonal control of β-adrenergic receptors
and correlation with tumor growth. J. Steroid
Biochem. Mol. Biol. 38, 307–320 (1991).
16. Penninx, B. W. et al. Chronically depressed mood and
cancer risk in older persons. J. Natl Cancer Inst. 90,
1888–1893 (1998).
17. Reynolds, P. & Kaplan, G. A. Social connections and
risk for cancer: prospective evidence from the Alameda
County Study. Behav. Med. 16, 101–110 (1990).
18. Allison, P. J., Guichard, C., Fung, K. & Gilain, L.
Dispositional optimism predicts survival status 1 year
after diagnosis in head and neck cancer patients.
J. Clin. Oncol. 21, 543–548 (2003).
19. Gotay, C. C. Behavior and cancer prevention. J. Clin.
Oncol. 23, 301–310 (2005).
20. Laconi, E. et al. Early exposure to restraint stress
enhances chemical carcinogenesis in rat liver. Cancer
Lett. 161, 215–220 (2000).
21. Ben-Eliyahu, S., Yirmiya, R., Liebeskind, J. C., Taylor,
A. N. & Gale, R. P. Stress increases metastatic spread
of a mammary tumor in rats: evidence for mediation
by the immune system. Brain Behav. Immun. 5,
193–205 (1991).
22. Ben-Eliyahu, S., Page, G. G., Yirmiya, R. & Shakhar, G.
Evidence that stress and surgical interventions
promote tumor development by suppressing natural
killer cell activity. Int. J. Cancer 80, 880–888 (1999).
23. Page, G. G. & Ben-Eliyahu, S. A role for NK cells in
greater susceptibility of young rats to metastatic
formation. Dev. Comp. Immunol. 23, 87–96 (1999).
24. Page, G. G., Ben-Eliyahu, S., Yirmiya, R. & Liebeskind,
J. C. Morphine attenuates surgery-induced
enhancement of metastatic colonization in rats. Pain
54, 21–28 (1993).
25. Stefanski, V. & Ben-Eliyahu, S. Social confrontation
and tumor metastasis in rats: defeat and β-adrenergic
mechanisms. Physiol. Behav. 60, 277–282 (1996).
26. Ben-Eliyahu, S. et al. The NMDA receptor antagonist
MK-801 blocks nonopioid stress induced analgesia
and decreases tumor metastasis in the rat. Proc.
West. Pharmacol. Soc. 36, 293–298 (1993).
27. Melamed, R. et al. Marginating pulmonary-NK activity
and resistance to experimental tumor metastasis:
suppression by surgery and the prophylactic use of a
β-adrenergic antagonist and a prostaglandin synthesis
inhibitor. Brain Behav. Immun. 19, 114–126 (2005).
28. Fischman, H. K., Pero, R. W. & Kelly, D. D. Psychogenic
stress induces chromosomal and DNA damage. Int. J.
Neurosci. 84, 219–227 (1996).
29. Sacharczuk, M., Jaszczak, K. & Sadowski, B.
Chromosomal NOR activity in mice selected for high
and low swim stress-induced analgesia. Behav. Genet.
33, 435–441 (2003).
30. Thaker, P. H. et al. in The 36th Annual Meeting of the
Society of Gynecologic Oncologists 30 (Miami,
Florida, 2005).
31. Ferrara, N. & Davis-Smyth, T. The biology of vascular
endothelial growth factor. Endocr. Rev. 18, 4–25 (1997).
32. Ohm, J. E. et al. VEGF inhibits T-cell development and
may contribute to tumor-induced immune
suppression. Blood 101, 4878–4886 (2003).
33. Gabrilovich, D. I. et al. Production of vascular
endothelial growth factor by human tumors inhibits
the functional maturation of dendritic cells. Nature
Med. 2, 1096–1103 (1996).
34. Lutgendorf, S. K. et al. Vascular endothelial growth
factor and social support in patients with ovarian
carcinoma. Cancer 95, 808–815 (2002).
35. Costanzo, E. S. et al. Psychosocial factors and
interleukin-6 among women with advanced ovarian
cancer. Cancer 104, 305–313 (2005).
36. Fredriksson, J. M., Lindquist, J. M., Bronnikov, G. E. &
Nedergaard, J. Norepinephrine induces vascular
endothelial growth factor gene expression in brown
adipocytes through a β-adrenoreceptor–cAMP–
protein kinase A pathway involving Src but
independently of Erk1/2. J. Biol. Chem. 275,
13802–13811 (2000).
37. Lutgendorf, S. K. et al. Stress-related mediators
stimulate vascular endothelial growth factor secretion
by two ovarian cancer cell lines. Clin. Cancer Res. 9,
4514–4521 (2003).
38. Masur, K., Niggemann, B., Zanker, K. S. &
Entschladen, F. Norepinephrine-induced migration of
SW 480 colon carcinoma cells is inhibited by β-
blockers. Cancer Res. 61, 2866–2869 (2001).
39. McDonald, P. H. & Lefkowitz, R. J. β-Arrestins: new
roles in regulating heptahelical receptors’ functions.
Cell Signal. 13, 683–689 (2001).
40. Abramovitch, R. et al. A pivotal role of cyclic AMP-
responsive element binding protein in tumor
progression. Cancer Res. 64, 1338–1346 (2004).
41. Lang, K. et al. Induction of a metastatogenic tumor
cell type by neurotransmitters and its pharmacological
inhibition by established drugs. Int. J. Cancer 112,
231–238 (2004).
42. Jean, D. & Bar-Eli, M. Regulation of tumor growth and
metastasis of human melanoma by the CREB
transcription factor family. Mol. Cell. Biochem. 212,
19–28 (2000).
43. de Rooij, J. et al. Epac is a Rap1 guanine-nucleotide-
exchange factor directly activated by cyclic AMP.
Nature 396, 474–477 (1998).
44. Enserink, J. M. et al. The cAMP–Epac–Rap1 pathway
regulates cell spreading and cell adhesion to laminin-
5 through the α
3
β
1
integrin but not the α
6
β
4
integrin.
J. Biol. Chem. 279, 44889–44896 (2004).
45. Distelhorst, C. W. Recent insights into the mechanism
of glucocorticosteroid-induced apoptosis. Cell Death
Differ. 9, 6–19 (2002).
46. Herr, I. et al. Glucocorticoid cotreatment induces
apoptosis resistance toward cancer therapy in
carcinomas. Cancer Res. 63, 3112–3120 (2003).
47. Wu, W. et al. Microarray analysis reveals
glucocorticoid-regulated survival genes that are
associated with inhibition of apoptosis in breast
epithelial cells. Cancer Res. 64, 1757–1764 (2004).
48. Nakane, T. et al. Effects of IL-1 and cortisol on β-
adrenergic receptors, cell proliferation, and
differentiation in cultured human A549 lung tumor
cells. J. Immunol. 145, 260–266 (1990).
49. Dave, J. R. et al. Chronic sustained stress increases
levels of anterior pituitary prolactin mRNA.
Pharmacol. Biochem. Behav. 67, 423–431 (2000).
50. Almeida, S. A., Petenusci, S. O., Franci, J. A., Rosa e
Silva, A. A. & Carvalho, T. L. Chronic immobilization-
induced stress increases plasma testosterone and
delays testicular maturation in pubertal rats.
Andrologia 32, 7–11 (2000).
51. Young, W. S. 3rd & Lightman, S. L. Chronic stress
elevates enkephalin expression in the rat
paraventricular and supraoptic nuclei. Brain Res. Mol.
Brain Res. 13, 111–117 (1992).
52. Clevenger, C. V., Furth, P. A., Hankinson, S. E. &
Schuler, L. A. The role of prolactin in mammary
carcinoma. Endocr. Rev. 24, 1–27 (2003).
53. Pequeux, C. et al. Oxytocin- and vasopressin-
induced growth of human small-cell lung cancer is
mediated by the mitogen-activated protein kinase
pathway. Endocr. Relat. Cancer 11, 871–885
(2004).
54. Pequeux, C. et al. Oxytocin synthesis and oxytocin
receptor expression by cell lines of human small cell
carcinoma of the lung stimulate tumor growth through
autocrine/paracrine signaling. Cancer Res. 62,
4623–4629 (2002).
55. Chakroborty, D. et al. Depleted dopamine in gastric
cancer tissues: dopamine treatment retards growth of
gastric cancer by inhibiting angiogenesis. Clin. Cancer
Res. 10, 4349–4356 (2004).
56. Basu, S. et al. The neurotransmitter dopamine inhibits
angiogenesis induced by vascular permeability factor/
vascular endothelial growth factor. Nature Med. 7,
569–574 (2001).
57. Sephton, S. & Spiegel, D. Circadian disruption in
cancer: a neuroendocrine-immune pathway from stress
to disease? Brain Behav. Immun. 17, 321–328
(2003).
58. Sephton, S. E., Sapolsky, R. M., Kraemer, H. C. &
Spiegel, D. Diurnal cortisol rhythm as a predictor of
breast cancer survival. J. Natl Cancer Inst. 92,
994–1000 (2000).
59. Chrousos, G. P. & Gold, P. W. A healthy body in a
healthy mind — and vice versa — the damaging power
of ‘‘uncontrollable’’ stress. J. Clin. Endocrinol. Metab.
83, 1842–1845 (1998).
60. Filipski, E. et al. Host circadian clock as a control point
in tumor progression. J. Natl Cancer Inst. 94,
690–697 (2002).
61. Schernhammer, E. S. et al. Night-shift work and risk of
colorectal cancer in the nurses’ health study. J. Natl
Cancer Inst. 95, 825–828 (2003).
62. Fu, L. & Lee, C. C. The circadian clock: pacemaker and
tumour suppressor. Nature Rev. Cancer 3, 350–361
(2003).
63. Fu, L., Pelicano, H., Liu, J., Huang, P. & Lee, C. The
circadian gene Period2 plays an important role in
tumor suppression and DNA damage response in vivo.
Cell 111, 41–50 (2002).
64. Mormont, M. C. & Levi, F. Circadian-system alterations
during cancer processes: a review. Int. J. Cancer 70,
241–247 (1997).
65. Mormont, M. C. et al. Marked 24-h-rest–activity
rhythms are associated with better quality of life,
better response, and longer survival in patients with
metastatic colorectal cancer and good performance
status. Clin. Cancer Res. 6, 3038–3045 (2000).
66. Kronfol, Z., Nair, M., Zhang, Q., Hill, E. E. & Brown,
M. B. Circadian immune measures in healthy volunteers:
relationship to hypothalamic–pituitary–adrenal axis
hormones and sympathetic neurotransmitters.
Psychosom. Med. 59, 42–50 (1997).
67. Rich, T.
et al. Elevated serum cytokines correlated with
altered behavior, serum cortisol rhythm, and
dampened 24-hour rest–activity patterns in patients
with metastatic colorectal cancer. Clin. Cancer Res. 11,
1757–1764 (2005).
68. Balkwill, F. & Mantovani, A. Inflammation and cancer:
back to Virchow? Lancet 357, 539–545 (2001).
69. Blask, D. E., Sauer, L. A. & Dauchy, R. T. Melatonin as
a chronobiotic/anticancer agent: cellular, biochemical,
and molecular mechanisms of action and their
implications for circadian-based cancer therapy. Curr.
Top. Med. Chem. 2, 113–132 (2002).
70. Sanchez-Barcelo, E. J., Cos, S., Fernandez, R. &
Mediavilla, M. D. Melatonin and mammary cancer: a
short review. Endocr. Relat. Cancer 10, 153–159
(2003).
71. Jensen, M. M. The influence of stress on murine
leukemia virus infection. Proc. Soc. Exp. Biol. Med.
127, 610–614 (1968).
72. Justice, A. Review of the effects of stress on cancer in
laboratory animals: importance of time of stress
application and type of tumor. Psychol. Bull. 98,
108–138 (1985).
73. Riley, V. Psychoneuroendocrine influences on
immunocompetence and neoplasia. Science 212,
1100–1109 (1981).
74. Rowse, G. L., Weinberg, J., Bellward, G. D. &
Emerman, J. T. Endocrine mediation of psychosocial
stressor effects on mouse mammary tumor growth.
Cancer Lett. 65, 85–93 (1992).
75. Romero, L. et al. A possible mechanism by which
stress accelerates growth of virally-derived tumors.
Proc. Natl Acad. Sci. USA 89, 11084–11087 (1992).
76. McGrath, C. M., Prass, W. A., Maloney, T. M. & Jones,
R. F. Induction of endogenous mammary tumor virus
expression during hormonal induction of mammary
adenoacanthomas and carcinomas of BALB/c female
mice. J. Natl Cancer Inst. 67, 841–852 (1981).
77. zur Hausen, H. Viruses in human cancers. Science
254, 1167–1173 (1991).
78. Glaser, R. et al. Stress-related activation of Epstein–
Barr virus. Brain Behav. Immun. 5, 219–232 (1991).
79. Stowe, R. P., Pierson, D. L. & Barrett, D. T. Elevated
stress hormone levels relate to Epstein–Barr Virus
reactivation in astronauts. Psychosom. Med. 63,
891–895 (2001).
80. Cacioppo, J. T. et al.
Autonomic and glucocorticoid
associations with the steady-state expression of latent
Epstein–Barr Virus. Horm. Behav. 42, 32–41 (2002).
81. Glaser, R., Kutz, L. A., MacCallum, R. C. & Malarkey,
W. B. Hormonal modulation of Epstein–Barr virus
replication. Neuroendocrinology 62, 356–361 (1995).
82. Bromberg-White, J. L. & Meyers, C. Comparison of the
basal and glucocorticoid-inducible activities of the
upstream regulatory regions of HPV18 and HPV31 in
multiple epithelial cell lines. Virology 306, 197–202
(2003).
83. Mittal, R., Pater, A. & Pater, M. M. Multiple human
papillomavirus type 16 glucocorticoid response
elements functional for transformation, transient
expression, and DNA–protein interactions. J. Virol.
67, 5656–5659 (1993).
84. Gloss, B. et al. The upstream regulatory region of the
human papilloma virus-16 contains an E2 protein-
independent enhancer which is specific for cervical
carcinoma cells and regulated by glucocorticoid
hormones. EMBO J. 6, 3735–3743 (1987).
85. Pater, M. M., Hughes, G. A., Hyslop, D. E., Nakshatri, H.
& Pater, A. Glucocorticoid-dependent oncogenic
transformation by type 16 but not type 11 human
papilloma virus DNA. Nature 335, 832–835 (1988).
PERSPECTIVES
NATURE REVIEWS
|
CANCER VOLUME 6
|
MARCH 2006
|
247
© 2006 Nature Publishing Group

86. Bartholomew, J. S. et al. Integration of high-risk
human papillomavirus DNA is linked to the down-
regulation of class I human leukocyte antigens by
steroid hormones in cervical tumor cells. Cancer Res.
57, 937–942 (1997).
87. Coker, A. L., Bond, S., Madeleine, M. M., Luchok, K. &
Pirisi, L. Psychosocial stress and cervical neoplasia
risk. Psychosom. Med. 65, 644–651 (2003).
88. Pereira, D. B. et al. Life stress and cervical squamous
intraepithelial lesions in women with human
papillomavirus and human immunodeficiency virus.
Psychosom. Med. 65, 427–434 (2003).
89. Pater, M. M. & Pater, A. RU486 inhibits glucocorticoid
hormone-dependent oncogenesis by human
papillomavirus type 16 DNA. Virology 183, 799–802
(1991).
90. Chou, C. K., Wang, L. H., Lin, H. M. & Chi, C. W.
Glucocorticoid stimulates hepatitis B viral gene
expression in cultured human hepatoma cells.
Hepatology 16, 13–18 (1992).
91. Kamradt, M. C., Mohideen, N. & Vaughan, A. T.
RU486 increases radiosensitivity and restores
apoptosis through modulation of HPV E6/E7 in
dexamethasone-treated cervical carcinoma cells.
Gynecol. Oncol. 77, 177–182 (2000).
92. Tur-Kaspa, R., Burk, R. D., Shaul, Y. & Shafritz, D. A.
Hepatitis B virus DNA contains a glucocorticoid-
responsive element. Proc. Natl Acad. Sci. USA 83,
1627–1631 (1986).
93. Chayama, K. et al. A pilot study of corticosteroid
priming for lymphoblastoid interferon α in patients with
chronic hepatitis C. Hepatology 23, 953–957 (1996).
94. Magy, N. et al. Effects of corticosteroids on HCV
infection. Int. J. Immunopharmacol. 21, 253–261
(1999).
95. Yokosuka, O. Role of steroid priming in the treatment
of chronic hepatitis B. J. Gastroenterol. Hepatol. 15,
E41–E45 (2000).
96. Cole, S. W. et al. Impaired response to HAART in HIV-
infected individuals with high autonomic nervous
system activity. Proc. Natl Acad. Sci. USA 98,
12695–12700 (2001).
97. Cole, S. W., Jamieson, B. D. & Zack, J. A. cAMP
externalizes lymphocyte CXCR4: implications for
chemotaxis and HIV infection. J. Immunol. 162,
1392–1400 (1999).
98.
Cole, S. W., Korin, Y. D., Fahey, J. L. & Zack, J. A.
Norepinephrine accelerates HIV replication via protein
kinase A-dependent effects on cytokine production.
J. Immunol. 161, 610–616 (1998).
99. Killebrew, D. & Shiramizu, B. Pathogenesis of HIV-
associated non-Hodgkin lymphoma. Curr. HIV Res. 2,
215–221 (2004).
100. Chang, M. et al. β Adrenoreceptors reactivate Kaposi’s
Sarcoma-associated Herpesvirus lytic replication via
PKA-dependent control of viral RTA. J. Virol. 79,
13538–13547 (2005).
101. Turgeman, H. & Aboud, M. Evidence that protein
kinase A activity is required for the basal and tax-
stimulated transcriptional activity of human T-cell
leukemia virus type-I-long terminal repeat. FEBS Lett.
428, 183–187 (1998).
102. Marsland, A. L., Cohen, S., Rabin, B. S. & Manuck, S. B.
Associations between stress, trait negative affect,
acute immune reactivity, and antibody response to
hepatitis B injection in healthy young adults. Health
Psychol. 20, 4–11 (2001).
103. Glaser, R. et al. Stress-induced modulation of the
immune response to recombinant hepatitis B vaccine.
Psychosom. Med. 54, 22–29 (1992).
104. Kinzler, K. W. & Vogelstein, B. The Genetic Basis of
Human Cancer (McGraw–Hill, Toronto, 1998).
105. Dhabhar, F. S. & McEwen, B. S. Acute stress enhances
while chronic stress suppresses cell-mediated immunity
in vivo: a potential role for leukocyte trafficking. Brain
Behav. Immun. 11, 286–306 (1997).
106. Elenkov, I. J. Systemic stress-induced Th2 shift and its
clinical implications. Int. Rev. Neurobiol. 52, 163–186
(2002).
107. Glaser, R. et al. Evidence for a shift in the Th-1 to Th-2
cytokine response associated with chronic stress and
aging. J. Gerontol. A Biol. Sci. Med. Sci. 56,
M477–M482 (2001).
108. Felten, S. & Felten, D. in Psychoneuroimmunology
(eds Ader, R., Felten, D. & Cohen, N.) 27–71
(St. Louis, Montana, 1991).
109. Dhabhar, F. S. & McEwen, B. S. Stress-induced
enhancement of antigen-specific cell-mediated
immunity. J. Immunol. 156, 2608–2615 (1996).
110. Saul, A. N. et al. Chronic stress and susceptibility to
skin cancer. J. Natl Cancer Inst. 97, 1760–1767
(2005).
111. Kalinichenko, V. V., Mokyr, M. B., Graf, L. H. Jr, Cohen,
R. L. & Chambers, D. A. Norepinephrine-mediated
inhibition of antitumor cytotoxic T lymphocyte
generation involves a β-adrenergic receptor
mechanism and decreased TNF-α gene expression.
J. Immunol. 163, 2492–2499 (1999).
112. Cook-Mills, J. M., Cohen, R. L., Perlman, R. L. &
Chambers, D. A. Inhibition of lymphocyte activation by
catecholamines: evidence for a non-classical
mechanism of catecholamine action. Immunology 85,
544–549 (1995).
113. Cook-Mills, J. M., Mokyr, M. B., Cohen, R. L., Perlman,
R. L. & Chambers, D. A. Neurotransmitter suppression
of the in vitro generation of a cytotoxic T lymphocyte
response against the syngeneic MOPC-315
plasmacytoma. Cancer Immunol. Immunother. 40,
79–87 (1995).
114. Shi, Y. et al. Stressed to death: implication of
lymphocyte apoptosis for psychoneuroimmunology.
Brain Behav. Immun. 17 (Suppl.), S18–S26 (2003).
115. Pollock, R. E., Lotzova, E. & Stanford, S. D. Mechanism
of surgical stress impairment of human perioperative
natural killer cell cytotoxicity. Arch. Surg. 126,
338–342 (1991).
116. Andersen, B. L. et al. Stress and immune responses
after surgical treatment for regional breast cancer.
J. Natl Cancer Inst. 90, 30–36 (1998).
117. Lutgendorf, S. K. et al. Social support, distress, and
natural killer cell activity in ovarian cancer patients.
J. Clin. Oncol. 23, 7106–7113 (2005).
118. Levy, S. M. et al. Perceived social support and tumor
estrogen/progesterone receptor status as predictors of
natural killer cell activity in breast cancer patients.
Psychosom. Med. 52, 73–85 (1990).
119. McGregor, B. A. et al. Cognitive-behavioral stress
management increases benefit finding and immune
function among women with early-stage breast cancer.
J. Psychosom. Res. 56, 1–8 (2004).
120. Sephton, S., Koopman, C., Schaal, M., Thoresen, C. &
Spiegel, D. Spiritual expression and immune status in
women with metastatic breast cancer: an exploratory
study. Breast J. 7, 345–353 (2001).
121. Christie, W. & Moore, C. The impact of humor on patients
with cancer. Clin. J. Oncol. Nurs. 9, 211–218 (2005).
122. Antoni, M. H. Stress management effects on
psychological, endocrinological, and immune
functioning in men with HIV infection: empirical
support for a psychoneuroimmunological model.
Stress 6, 173–188 (2003).
123. Carlson, L. E., Speca, M., Patel, K. D. & Goodey, E.
Mindfulness-based stress reduction in relation to
quality of life, mood, symptoms of stress and levels of
cortisol, dehydroepiandrosterone sulfate (DHEAS) and
melatonin in breast and prostate cancer outpatients.
Psychoneuroendocrinology 29, 448–474 (2004).
124. Andersen, B. L. et al. Psychological, behavioral, and
immune changes after a psychological intervention: a
clinical trial. J. Clin. Oncol. 22, 3570–3580 (2004).
125. Lekander, M., Furst, C. J., Rotstein, S., Blomgren, H. &
Fredrikson, M. Social support and immune status
during and after chemotherapy for breast cancer. Acta
Oncol. 35, 31–37 (1996).
126. Fawzy, F. I., Canada, A. L. & Fawzy, N. W. Malignant
melanoma: effects of a brief, structured psychiatric
intervention on survival and recurrence at 10-year
follow-up. Arch. Gen. Psychiatry 60, 100–103 (2003).
127. Esterling, B. A. et al. Psychosocial modulation of
antibody to Epstein–Barr viral capsid antigen and
human herpesvirus type-6 in HIV-1-infected and at-
risk gay men. Psychosom. Med. 54, 354–371 (1992).
128. Antoni, M. H. et al. Randomized clinical trial of
cognitive behavioral stress management on HIV viral
load in gay men treated with HAART. Psychosom.
Med. (in the press).
129. Antoni, M. H. et al. Increases in a marker of immune
system reconstitution are predated by decreases in
24-hour urinary cortisol output and depressed mood
during a 10-week stress management intervention in
symptomatic gay men. J. Psychosom. Res. 58, 3–13
(2005).
130. Carlson, L. E., Speca, M., Patel, K. D. & Goodey, E.
Mindfulness-based stress reduction in relation to
quality of life, mood, symptoms of stress, and immune
parameters in breast and prostate cancer outpatients.
Psychosom. Med. 65, 571–581 (2003).
131. Fawzy, F. I. et al. A structured psychiatric intervention
for cancer patients. II. Changes over time in
immunological measures. Arch. Gen. Psychiatry 47,
729–735 (1990).
132. Spiegel, D., Bloom, J. R., Kraemer, H. C. & Gottheil, E.
Effect of psychosocial treatment on survival of patients
with metastatic breast cancer. Lancet 2, 888–891
(1989).
133. Goodwin, P. J. et al. The effect of group psychosocial
support on survival in metastatic breast cancer.
N. Engl. J. Med. 345, 1719–1726 (2001).
134. Spiegel, D. Effects of psychotherapy on cancer
survival. Nature Rev. Cancer 2, 383–389 (2002).
135. Perron, L., Bairati, I., Harel, F. & Meyer, F.
Antihypertensive drug use and the risk of prostate
cancer (Canada). Cancer Causes Control 15, 535–541
(2004).
136. Algazi, M., Plu-Bureau, G., Flahault, A., Dondon, M. G.
& Le, M. G. Could treatments with β-blockers be
associated with a reduction in cancer risk? Rev.
Epidemiol. Sante Publique 52, 53–65 (2004) (in
French).
137. Li, C. I. et al. Relation between use of antihypertensive
medications and risk of breast carcinoma among
women ages 65–79 years. Cancer 98, 1504–1513
(2003).
138. Meier, C. R., Derby, L. E., Jick, S. S. & Jick, H.
Angiotensin-converting enzyme inhibitors, calcium
channel blockers, and breast cancer. Arch. Intern.
Med. 160, 349–353 (2000).
139. Coussens, L. M. & Werb, Z. Inflammation and cancer.
Nature 420, 860–867 (2002).
140. Lieb, J. Antidepressants, eicosanoids and the
prevention and treatment of cancer. A review.
Prostaglandins Leukot. Essent. Fatty Acids 65,
233–239 (2001).
141. Sapolsky, R. M. Why Zebras Don’t Get Ulcers: A Guide
to Stress, Stress-Related Diseases, and Coping
(Freeman, New York, 1994).
142. Buchschacher, G. L. J. & Wong-Staal, F. in Cancer:
Principles and Practice of Oncology (eds DeVita, V. T.
J., Hellman, S. & Rosenberg, S. A.) 165–172
(Lippincott Williams & Wilkins, Philadelphia,
2005).
143. Howley, P. M., Ganem, D. & Kieff, E. in Cancer:
Principles and Practice of Oncology (eds DeVita, V. T.
J., Hellman, S. & Rosenberg, S. A.) 173–184
(Lippincott Williams & Wilkins, Philadelphia, 2005).
144. Steplewski, Z., Vogel, W. H., Ehya, H., Poropatich, C.
& Smith, J. M. Effects of restraint stress on
inoculated tumor growth and immune response in
rats. Cancer Res. 45, 5128–5133 (1985).
145. Teunis, M. A. et al. Reduced tumor growth,
experimental metastasis formation, and angiogenesis
in rats with a hyperreactive dopaminergic system.
FASEB J. 16, 1465–1467 (2002).
146. Palermo-Neto, J., de Oliveira Massoco, C. &
Robespierre de Souza, W. Effects of physical and
psychological stressors on behavior, macrophage
activity, and Ehrlich tumor growth. Brain Behav.
Immun. 17, 43–54 (2003).
Acknowledgements
The authors gratefully acknowledge the support of several
Institutes and Centers of the National Institutes of Health;
National Cancer Institute (M.H.A., S.K.L., F.S.D., and
A.K.S.), National Center for Complementary and Alternative
Medicine (S.K.L.), National Institute of Allergy and
Infectious Diseases (S.W.C. and F.S.D.) and National
Institute of Mental Health (M.H.A.). The authors also
acknowledge support received from the Dana Foundation
(F.S.D.), Jonssen Comprehensive Cancer Center (S.W.C.)
and Norman Cousins Center at the University of California,
Los Angeles (S.W.C.). Preparation of this perspective was
facilitated by support from the Division of Cancer Control
and Populations Sciences at the National Cancer Institute.
We are indebted to Wendy Nelson for her editorial review
of the manuscript.
Competing interests statement
The authors declare no competing financial interests.
DATABASES
The following terms in this article are linked online to:
Entrez Gene:
http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
ACTH | β
2
AR | EPAC | VEGF
National Cancer Institute:
http://www.cancer.gov
breast cancer | lung tumour | ovarian cancer
FURTHER INFORMATION
Anil K. Sood’s web page: http://www.mdanderson.org/
departments/gynonc/display.cfm?id=ff562a10-edb5-4561-b
95d6ac0618b5184&method=displayfull&pn=AFADFC5A-
36B0-48EA-B11B71824784D641
NCI Cancer Control and Population Sciences web site:
http://www.cancercontrol.cancer.gov/bimped/
Steven Cole’s web page: http://www.cancer.mednet.ucla.
edu/institution/personnel?personnel%5fid=45359
Susan Lutgendorf’s web page: http://www.psychology.
uiowa.edu/Faculty/Lutgendorf/Lutgendorf.html
Access to this interactive links box is free online.
PERSPECTIVES
248
|
MARCH 2006
|
VOLUME 6 www.nature.com/reviews/cancer
© 2006 Nature Publishing Group