Clinical studies indicate that stress, chronic
depression, social support and other psycho-
logical factors might influence cancer onset
and progression1–5. 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 activity7.
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 systems8. 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-
tems8. 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 disorder9,10.
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-
lamines11. These changes are manifested
by deleterious health consequences such
as increased risk for cardiac disease, slower
wound healing and increased risk from
infections11. In the past decade, it has become
increasingly clear that chronic alterations
in neuroendocrine dynamics can also alter
multiple physiological processes involved in
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 spouse5.
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 years16. A third study
found that the combination of extreme
stress and low social support was related to a
ninefold increase in breast cancer incidence4.
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 progression2. By contrast,
positive factors such as social support and
optimism have predicted longer survival17,18.
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 risk19.
Recent experimental studies have begun to
elucidate the mechanisms underlying these
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
The influence of bio-behavioural
factors on tumour biology: pathways
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.
240 | MARCH 2006 | VOLUME 6
© 2006 Nature Publishing Group
incidence and rate of tumour growth20.
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 cells21–24. 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 lung24,25 and a similar
increase in the number of lung metastases
counted 3 weeks later24–26. 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 metastasis21–24.
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 metastasis27.
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 exchanges28 as well as lower
activity of metaphase nucleolar organizer
regions in bone marrow cells29. 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 activity31.
VEGF also interferes with the development
of T cells and the functional maturation of
dendritic cells32,33, 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
cancer34. 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 cancer35.
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) pathway36,37. 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 βARs36,37.
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-blockers38. 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 cells12,13. In both
of these studies, β2AR 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 cAMP39. In mammary
tumours, activation of βARs has been linked
to accelerated tumour growth13–15. The
protein is an important transcription factor
that is activated by multiple signal-transduc-
tion pathways in response to external stimuli,
including stress hormones40,41. Several studies
have shown a role for the CREB family of pro-
teins in tumour cell proliferation, migration,
angiogenesis and inhibition of apoptosis40–42,
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 PKA43. For example,
βAR-mediated activation of cAMP promotes
ovarian cancer cell adhesion through the
EPAC–RAP1 pathway44. 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 lymphocytes45,
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
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 models46,47. 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 accumulation48. 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 stress49,50, and oxytocin and
dopamine, which decrease with stress51.
Prolactin can promote cell growth and
survival in breast tumour and other tumour
cells52. 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
tumours53. 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
antagonist54. Dopamine, which is known
to inhibit the growth of several types of
malignant tumours55, blocks VEGF-induced
angiogenesis both in vitro and in vivo,
primarily by inducing endocytosis of VEGF
receptor 2 in endothelial cells56.
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 cancer57,58. Data from separate lines of
investigation show that stress can disrupt cir-
cadian glucocorticoid rhythms57,59 and favour
tumour initiation and progression57,58,60.
Night-time shift work, a condition that is
known to disrupt endocrine rhythms, is a
risk factor for breast and colorectal cancer61.
Mice with circadian disruption owing to Per1
(period 1) or Per2 gene mutations are prone
to tumour development and early death62,63.
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-growing64. 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.
Negative life events
Autonomic nervous system
• Other neuropeptides
↓ Immune response
↑ Migration and invasion
↑ Proteases (MMPs)
• Altered DNA repair
cytokines (VEGF, IL-6)
↑ Oncogene transcription
↑ Viral replication
↑ Host-cell cycling
242 | MARCH 2006 | VOLUME 6
© 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 rhythms60. 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 survival58,65.
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 SCN60, and circadian
genes, including Per1, regulate tumour
suppression, cellular response to DNA
damage, and apoptosis63. Glucocorticoid
rhythms that are driven by the SCN62 are
linked to both enumerative and functional
immunity66. 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 patients67.
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-
teins69,70. Taken together, these data indicate a
potentially important role of circadian regula-
tion in cancer defence and treatment62.
Influences on viral oncogenesis
The first experimental demonstration that
bio-behavioural factors could promote
cancer came from animal studies of tumour
viruses71. 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 crowding72,73.
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 response74–76. The evidence for
a viral contribution to human cancer has
grown77 (BOX 1), and stress hormones have
Table 1 | Effects of stress and stress-associated hormones on cancer
AnimalBiological effect Tumour typeEffect on tumour
Increased metastasis of
tumour cells to the lung
Increased metastasis of
tumour cells to the lung
Fewer lung metastasis
Restraint stress RatsDecreased numbers of T cellsMammary144
High versus low
Decreased natural-killer-cell activity
Decreased natural-killer-cell activity
RatsDecreased angiogenesis with high
MiceDecreased angiogenesis; decreased VEGF–
VEGFR2 binding and phosphorylation
Decreased macrophage activity
Decreased IL-12, IFNγ, CCL27 (also known as
CTACK) and numbers of infiltrating T cells;
increased numbers of suppressor cells
Skin and squamous cell
number, size and
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
• 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).
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© 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 stress78,79. In these
studies HPA activity increased in parallel
with reactivation of EBV79,80, and gluco-
corticoid hormones were subsequently
found to increase EBV gene expression
in vitro80,81. High-risk human papilloma
viruses (HPVs), which contribute to cervi-
cal and rectal carcinomas, also respond to
glucocorticoids by activating gene expres-
sion82–84, interacting with cellular proto-
oncogenes such as HRAS85, and evading
cellular immune responses by downregu-
lating the expression of tumour MHC-I
(major histocompatibility complex class I)
molecules86. Clinical studies have identi-
fied stressful life events as a risk factor for
increased progression of cervical dysplasia
in HPV-positive women87,88. Furthermore,
glucocorticoid antagonists can inhibit HPV
activity in vitro89–91, 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
viruses90,92–94. These dynamics are so pro-
nounced that glucocorticoids are employed
clinically to activate hepatitis B and C
viruses for eradication by replication-
dependent antiviral drugs93,95.
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 infection96,97,
activating viral gene transcription96 and
suppressing antiviral cytokines98. People
with heightened ANS activity show an
increased viral load in the plasma and
an impaired response to antiretroviral
therapy96, placing them at increased risk
for AIDS-associated B-cell lymphomas99.
Catecholamines can also activate the
Kaposi sarcoma-associated herpesvirus
(KSHV) through PKA induction of the
viral transcription factor Rta100. Human
T-cell lymphotropic viruses 1 and 2
(HTLV1 and HTLV2, respectively) are
sensitive to PKA-mediated induction of
the oncogenic Tax transcription factor101.
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
relevant102,103. 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 malignancies104 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 function2 such
as antigen presentation, T-cell proliferation,
and humoral and cell-mediated immunity,
mainly through the release of catecholamine
and/or glucocorticoid hormones105–107.
Relevant neuroendocrine and immune sys-
tem interactions include direct synapse-like
connections between sympathetic nerves
and lymphocytes in lymphoid organs108,
neural and endocrine modulation of lym-
phocyte trafficking109, and modulation of
leukocyte function through glucocorticoid
receptors and other receptors70. 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 increased110. Studies in mice
of the immune response to transplanted
syngeneic tumours showed that noradrena-
line111 and adrenaline112,113 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
Human papilloma viruses 16 and 33
Hepatitis B virus
Hepatitis C virus
Cervical and head/neck cancer
Lymphoma, and nasopharygeal
Adult T-cell leukaemia/lymphoma
Human T-cell lymphotropic viruses
1 and 2
Kaposi sarcoma, and primary
*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 responses102,103.
Box 2 | Viral oncology
• Viral infections contribute to approximately 15% of human cancers worldwide77.
• 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
244 | MARCH 2006 | VOLUME 6
© 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 damage114.
Compromised natural killer (NK)-cell
function has been shown in both animal
and clinical studies of surgical stress22,115.
High levels of psychological distress have
been linked to reduced cellular immunity in
patients with breast116 and ovarian cancer117.
More specifically, distress measured by self-
report was correlated with low NK-cell cyto-
toxicity in tumour-infiltrating lymphocytes
from human ovarian cancers117. 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
carcinoma58. Positive psycho-social factors
such as social support have been associated
with increased levels of NK-cell cytotoxic-
ity in patients with breast118 and ovarian
cancer117. 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
microenvironment117. Patients with breast
cancer who reported increased psychological
growth through participation in a cognitive
behavioural intervention programme dem-
onstrated increased levels of cellular immune
function119. Preliminary studies have found
that the expression of spirituality was related
to increased numbers of circulating T cells
in patients with breast cancer120, and that the
use of humour as a coping mechanism was
associated with increased NK-cell activity in
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
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 activity122–124. Moreover,
such interventions can potentially be used
in conjunction with conventional therapies
to maximize treatment efficacy125,126. 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 cancer119,124.
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.
• Cumulative burden
• Socio-economic status
• Early-life experience
• Social support
• Appraisal and coping
• Physical activity
• Sexual behaviour
Biological cancer-risk factors
• Carcinogen exposure
• Viral infection
• Circadian clocks
• Oestrogen, androgen, dopamine,
serotonin, TSH, growth hormone,
prolactin, oxytocin and melatonin
• Cellular (NKC, CTL and T-cell
activity) and humoral
• TH1/TH2 cytokines, macrophages,
IL-1, IL-6, TNFα and TGFβ
• Cell recruitment, signalling and
• Viral oncogenes
• Cell proliferation
• DNA repair
• Targeted molecules
• Endocrine therapy
• Establish microenvironment
• Growth support for MRD
• Immune surveillance
• Immunological escape
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© 2006 Nature Publishing Group
of immune responses against potentially
oncogenic viral infections, such as EBV127.
Such alterations are paralleled by decreased
expression levels of cortisol in the serum, a
reduced depressive mood, increased social
support and enhanced relaxation skills122.
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 time122,128. These
changes are pre-dated by decreases in nega-
tive mood and decreases in urinary cortisol
and noradrenaline output122,129. 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 functions124,130,131 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-
tions119,124, and post-intervention changes
in NK-cell activity have also been shown
in patients with malignant melanoma131.
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
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 group1,126,132–134. 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
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 risk135. 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
use136. Large population-based case–control
studies have not confirmed alterations in
risk for invasive breast carcinoma with
β-blocker use137,138. 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 cancer139. For example, lith-
ium inhibits prostaglandin E1, and tricyclic
antidepressants antagonize thromboxanes140.
Some monoamine oxidase inhibitors exert a
more potent anti-prostaglandin effect than
indomethacin140. 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.
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
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.
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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.
The following terms in this article are linked online to:
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
ACTH | β2AR | EPAC | VEGF
National Cancer Institute: http://www.cancer.gov
breast cancer | lung tumour | ovarian cancer
Anil K. Sood’s web page: http://www.mdanderson.org/
NCI Cancer Control and Population Sciences web site:
Steven Cole’s web page: http://www.cancer.mednet.ucla.
Susan Lutgendorf’s web page: http://www.psychology.
Access to this interactive links box is free online.
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