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Published OnlineFirst January 27, 2012; DOI: 10.1158/0008-5472.CAN-11-3292
Cancer
Research
Review
Regulation of Cancer Progression by b-Endorphin Neuron
Dipak K. Sarkar, Sengottuvelan Murugan, Changqing Zhang, and Nadka Boyadjieva
Abstract
It is becoming increasingly clear that stressful life events can affect cancer growth and metastasis by modulating
nervous, endocrine, and immune systems. The purpose of this review is to briefly describe the process by which stress
may potentiate carcinogenesis and how reducing body stress may prevent cancer growth and progression. The
opioid peptide b-endorphin plays a critical role in bringing the stress axis to a state of homeostasis. We have recently
shown that enhancement of endogenous levels of b-endorphin in the hypothalamus via b-endorphin neuron
transplantation suppresses stress response, promotes immune function, and reduces the incidence of cancer in rat
models of prostate and breast cancers. The cancer-preventive effect of b-endorphin is mediated through the
suppression of sympathetic neuronal function, which results in increased peripheral natural killer cell and macrophage activities, elevated levels of anti-inflammatory cytokines, and reduced levels of inflammatory cytokines.
b-endorphin inhibition of tumor progression also involves alteration in the tumor microenvironment, possibly
because of suppression of catecholamine and inflammatory cytokine production, which are known to alter DNA
repair, cell-matrix attachments, angiogenic process, and epithelial–mesenchymal transition. Thus, b-endorphin cell
therapy may offer some therapeutic value in cancer prevention. Cancer Res; 72(4); 836–40. 2012 AACR.
Introduction
Neuroendocrine Response to Stress
Emerging evidence suggests that chronic neurobehavioral
stress can promote growth and progression of various cancers.
Psychologic factors may alter immune and endocrine functions, and it has long been hypothesized that, through this
pathway, stress may affect tumor growth and spread. On the
other hand, it has long been known that relieving the stress of
cancer often leads to faster recovery and general well-being in
patients who are undergoing chemotherapy or radiotherapy
(1). Recent work with animal models suggests that the body's
neuroendocrine response (release of hormones in circulation)
following psychosocial or physical stress can significantly
affect many aspects of the body's immune systems (2) and
can also, directly or via immune surveillance, alter important
processes of cells that help to protect against the formation of
cancer, such as DNA repair and the regulation of cell growth
(3–5). Therefore, controlling the body's stress response may be
beneficial to immunity against cancer. Hence, in this review, we
first briefly describe the process of how stress may affect
immunity and cancer growth and then summarize the data
obtained in animal studies showing how reduction of the stress
response by b-endorphin cell transplantation may prevent
cancer growth and progression.
Environmental and psychosocial stimuli initiate a cascade of
physiologic changes in the central nervous system (CNS) and
periphery, which subsequently trigger the autonomic nervous
system (ANS) and the hypothalamic–pituitary–adrenal axis
(HPA; reviewed in ref. 6). Stressful experiences activate components of the limbic system, including the hypothalamus, the
hippocampus, and the amygdala, which modulate the activity
of hypothalamic and brain-stem structures that control the
HPA and ANS activities. The hypothalamus secretes corticotrophin-releasing hormone (CRH) and arginine vasopressin
from the paraventricular nucleus of the hypothalamus, both of
which activate the pituitary to release hormones of the proopiomelanocortin peptides, such as adrenocorticotropic hormone (ACTH), which stimulate the secretion of glucocorticoids
from the adrenal cortex into the peripheral circulation. Stress
response also involves secretion of adrenaline (epinephrine)
from the chromaffin cells of the adrenal medulla. In addition to
the activation of the HPA axis, stressful stimuli activate the
sympathetic nervous system (SNS), what is often termed the
"fight or flight" response. Like other parts of the nervous
system, the SNS operates through a series of interconnected
neurons, many of which have direct connections with the
neurons of the paraventricular nucleus, which run through
the brain stem and the preganglionic neurons and terminate in
the ganglia near the spinal column. From these ganglia, postganglionic fibers run to the effector organs, including spleen
and many other lymphoid tissues. The main neurotransmitter
of the preganglionic sympathetic fibers is acetylcholine, a
chemical messenger that binds and activates nicotinic acetylcholine receptors on postganglionic neurons. The principal
neurotransmitter released by the postganglionic neurons is
Authors' Affiliation: Rutgers Endocrine Program, Rutgers, The State
University of New Jersey, New Brunswick, New Jersey
Corresponding Author: Dipak K. Sarkar, Rutgers University, 67 Poultry
Farm Lane, New Brunswick, NJ 08901. Phone: 732-932-1529; Fax: 732932-4134; E-mail: [email protected]
doi: 10.1158/0008-5472.CAN-11-3292
2012 American Association for Cancer Research.
836
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b-Endorphin Neuron and Cancer Prevention
noradrenaline (norepinephrine). The other division of the ANS
is the parasympathetic nervous system, which is responsible
for stimulation of "rest and digest" activities that occur when
the body is at rest and normally functioning, in opposition to
the sympathetic neurons. The main neurotransmitter of the
parasympathetic fibers is acetylcholine. Acetylcholine acts on 2
types of receptors, the nicotinic cholinergic (at postganglionic
neurons) and muscarinic (at the target organ).
The so-called "fight or flight" response can also be seen as an
energy redirection program, and the "rest and digest" activities
can be seen as an energy storage program (7). During these
body responses, hormones and neurotransmitters that provide
energy-rich fuels to stores and those that provide energy-rich
substrates are being released. Additionally, altered production
and secretion of various proinflammatory cytokines, such as
TNF-a, interleukins-1b (IL-1b) and -6 (IL-6), and circulating
activated immune cells, are being imposed. Many of these
conditions contribute to the metabolic syndromes that often
co-occur with cancer.
Neuroendocrine–Neuroimmune Pathways of
Cancer
Recently, the results of various studies on animals and
humans point to the fact that the body's psychophysiologic
reactions during stress are associated with a greater likelihood
of incidence or relapse of cancer (5, 8). At cellular and molecular levels, psychologic stress-associated increase in production of epinephrine, norepinephrine, and cortisol cause an
upregulation of DNA damage sensors Chk1 and Chk2 and the
protooncogene CDC25A, which is involved in cell-cycle delay
following DNA damage, resulting in increased cell transformation and/or tumorigenicity (9). The findings of transgenic,
knockout, and in vitro models suggest that a dysregulated
stress response downregulates tumor suppressor genes, such
as PTEN, or DNA repair genes, such as BRCA1 (10). Animal
studies have shown that activation of the SNS (which happens
during various stresses) increased lung tumor metastases,
whereas pretreatment of animals with b-adrenergic antagonists (to block the activity of SNS activation) and indomethacin
(to block inflammation) synergistically blocked the effects of
behavioral stress on lung tumor metastasis. Consistent with
these findings are recent data showing that b-adrenergic
antagonists promote ovarian cancer cell spreading and adhesion to laminin-5 and enhance the adhesion to a fibronectin
matrix (11). Thus, catecholamines may promote cancer cell–
matrix attachments. Norepinephrine and epinephrine can also
promote migration and the invasive potential of ovarian cancer
cells by increasing matrix metalloproteinase 2 (MMP-2), MMP9, and some other MMPs that are important for tumor cell
penetration (12). In addition, it has been found that stress
hormones may promote angiogenic mechanisms in human
tumors by increasing production of VEGF. IL-6, another key
cytokine that plays an important role in tumor progression and
angiogenesis, is also elevated by norepinephrine in various
cancer animal models (13). Thus, chronic stress activates not
only the HPA axis but also production of catecholamine and
several inflammatory cytokines, which may promote cancer
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growth and progression at biochemical and molecular levels
(14).
Studies from human and animal models have also shown
that acute and chronic stressful events have adverse effects on a
variety of immunologic mechanisms, such as trafficking of
neutrophils, macrophages, antigen-presenting cells, natural killer (NK) cells, and T and B lymphocytes (5, 15). Exposure to stress
modulates cell-mediated immunity by suppressing lymphocyte
proliferation and NK activation, lowering the number of CD4þ
cells in the peripheral blood and altering CD4 to CD8 T-cell
ratios (5, 16). Studies have also shown that depression and stress
might have effects on carcinogenesis indirectly through the
poorer destruction or elimination of abnormal cells by reduced
NK cell activity. Decreased NK cell activity is also associated
with growth and progression of a variety of cancers in animals
and humans, because NK cells seem to represent a first line of
defense against the metastatic spread of tumor cells (17).
Stress is also associated with altered inflammatory and antiinflammatory cytokine ratios in systemic circulation. It increases
expression of IL-1b and TNF-a and reduces expression of IL-2
and IFN-g (18). Sustained elevation of TNF-a is known to inhibit
the activity of protein tyrosine phosphatase, causing reduced
production of the MHC class I antigen of the cell surface and
leading to malignant cells escaping immune surveillance (8).
Although many specific details remain to be delineated, it is
becoming increasingly clear that stressful life events can affect
cancer growth, progression, and metastasis by modulating
nervous, endocrine, and immune systems of the body.
The Endogenous Opioid Peptide b-Endorphin
Reduces the Body's Stress Response, Increases
Innate Immune Functions, and Prevents Cancer
Growth and Progression
b-Endorphin, an endogenous opioid polypeptide primarily
produced by the hypothalamus and the pituitary gland, is known
to have the ability to inhibit stress hormone production and
produce analgesia and a feeling of well-being (19). b-endorphin
is a cleavage product of pro-opiomelanocortin, which is also the
precursor hormone for ACTH and a-melanocyte–stimulating
hormone (a-MSH). In the hypothalamus, the primary products
of pro-opiomelanocortin are b-endorphin and a-MSH, whereas
in the pituitary, pro-opiomelanocortin produces all 3 products
(b-endorphin, a-MSH, and ACTH). b-endorphin neuronal cell
bodies are primarily localized in the arcuate nuclei of the
hypothalamus, and its terminals are distributed throughout the
CNS, including the paraventricular nucleus of the hypothalamus
(20). In the paraventricular nucleus, these neurons innervate
CRH neurons and inhibit CRH release (21), whereas a m-opioid
receptor antagonist increases it (22). During stress, secretion of
CRH and catecholamine stimulates secretion of hypothalamic
b-endorphin and other pro-opiomelanocortin-derived peptides,
which in turn inhibit the activity of the HPA axis (23). b-Endorphin is known to bind to d- and m-opioid receptors to modulate
the neurotransmission in neurons of the ANS via neuronal
circuitry within the paraventricular nucleus. b-Endorphin peptides, produced from the pituitary pro-opiomelanocortin that
circulates in the periphery, are primarily regulated by CRH and
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Sarkar et al.
Figure 1. b-Endorphin neuronal cells in the hypothalamus control the neoplastic growth and progression of tumor cells, likely by modulating one or more of the
factors indicated. Effects include the activation of parasympathetic nervous system control of lymphoid organs, causing activation of innate immune cells
(macrophages and NK cells) and an increase in anti-inflammatory cytokine levels in the circulation. The HPA axis and subsequent stress hormones released
from the adrenal gland and sympathetic nerve terminals (glucocorticoids and catecholamines) may also be suppressed. In a tumor microenvironment,
these hormonal and cytokine changes downregulate inflammation-mediated epithelial–mesenchymal transition (EMT) and, thereby, suppress cancer
progression. Collectively, these effects create an unfavorable environment for tumor initiation, growth, and progression.
arginine vasopressin and may have less control over the ANS
function.
In the CNS, the opioid peptide b-endorphin is reported to
have rewarding and reinforcing properties and to be involved
in stress response. Additionally, a low level of central b-endor-
838
Cancer Res; 72(4) February 15, 2012
phin is connected with the process of stress-related psychiatric
disorders, depression, and posttraumatic stress disorder (24,
25). Abnormalities in b-endorphin neuronal function are correlated with a higher incidence of cancers and infections in
patients with schizophrenia, depression, fetal alcohol
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b-Endorphin Neuron and Cancer Prevention
syndrome, and obesity (reviewed in ref. 26). Despite this
evidence, the role of the neuronal b-endorphin in these
diseases is not well studied, because long-term peripheral
administrations of this opioid-like peptide, or its agonist
analogue, induce tolerance and dependence in animals and
make it difficult to study its action on chronic disease, like
cancer, in animals. Furthermore, peripheral b-endorphin
may not act like central b-endorphin, and therefore, data
from b-endorphin knockout or transgenic mice on the
neuroendocrine–immune axis are often difficult to interpret.
We have recently circumvented this problem by using
b-endorphin cell transplantation, in which pure b-endorphin
neurons are differentiated from neuronal stem cells in vitro
and then transplanted in the paraventricular nucleus at a
site where endogenous b-endorphin neurons make synaptic
contact with both CRH and neuronal populations connected
with the ANS (27). With this approach, it was feasible to
increase the influence of this opioid on 3 important components of body stress regulation: the HPA axis, sympathetic
neurons, and parasympathetic neurons. As they do in vivo, in
vitro–differentiated b-endorphin cells, when transplanted
into the paraventricular nucleus of the hypothalamus of
stress hyperresponsive and immune-deficient fetal alcohol–exposed rats, reduced plasma levels of corticosterone
and improved NK-cell cytolytic function in these rats (23).
b-endorphin transplantation also suppressed plasma corticosterone and increased NK cell activity in control rats.
We have previously shown that the neural stem cell–derived
b-endorphin neurons, when injected into the paraventricular
nucleus, remained viable at the site of transplantation for a
long period and suppressed carcinogen-induced prostate cancer development in rats (27). Additionally, we showed that
supplementation of b-endorphin neurons through transplants
prevented carcinogen-induced mammary tumorigenesis and
tumor metastasis (26). Importantly, when the b-endorphin
transplants were given at the early stage of tumor development, many tumors were destroyed, possibly because of
increased innate immune activity, and the surviving tumors
lost their ability to progress to high-grade cancer owing to
b-endorphin cells' suppressive effects on epithelial–mesenchymal transition regulators. Another remarkable effect of the
b-endorphin transplantation was that it promoted the activation of the innate immune (NK cells and macrophages) activity,
following tumor cell invasion, to such an extent that tumor cell
migration to another site was completely halted. NK cells and
macrophages are critical components of the innate immune
system and play a vital role in host defense against tumor cells
(28, 29). Hence, the increased level of innate immunity may
have caused unfavorable conditions for cancer cell survival. In
the b-endorphin cell–treated animals, the lower inflammatory
milieu that was achieved by the higher level of anti-inflammatory cytokines and the lower level of inflammatory cytokines may have also been involved in inhibiting cancer growth
and transformation. Several studies have identified the involvement and roles of inflammatory cytokines in breast malignancy (30). The cancer-preventive and inflammatory cytokine
suppression effects of the b-endorphin neuronal transplant
could be reversed by treatment with a b-receptor agonist or by
a nicotine acetylcholine receptor antagonist. This finding
suggests that the suppression of sympathetic neuronal function and the stimulation of parasympathetic neuronal activity
are the processes that b-endorphin neurons engage to activate
peripheral immunity and anti-inflammatory cytokines to control tumor growth and progression (Fig. 1).
Concluding Remarks
Neurobehavioral stress has been shown to promote tumor
growth and progression, possibly by altering the production of
hormones, catecholamine, and inflammatory cytokines.
Although the cellular mechanisms of stress-activated chemicals on tumor growth and progression are not apparent, it has
been found that these chemicals decrease immune surveillance
and alter the tumor microenvironment, including cell-matrix
attachments, cell migration, invasive potential, and angiogenic
mechanisms. Reduction of body stress via b-endorphin neural
transplants in the brain decreases cancer growth and progression in animal models of breast and prostate cancers, possibly
by altering ANS functioning, leading to activation of innate
immunity and reduction in systemic levels of inflammatory
and anti-inflammatory cytokine ratios. Thus, it is apparent that
stress prevention by b-endorphin cell therapy might be beneficial in controlling breast, prostate, and possibly other
cancers.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Grant Support
This work was partly supported by NIH grant R37AA08757.
Received September 30, 2011; revised October 25, 2011; accepted October 30,
2011; published OnlineFirst January 27, 2012.
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Cancer Research
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Regulation of Cancer Progression by β-Endorphin Neuron
Dipak K. Sarkar, Sengottuvelan Murugan, Changqing Zhang, et al.
Cancer Res 2012;72:836-840. Published OnlineFirst January 27, 2012.
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