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The role neuropeptides play in cancer
initiation, progression, metastasis, and
therapeutic resistance is poorly under-
stood. Studies have indicated paradoxical
roles for diverse neuropeptides in cancer
processes, raising the question of whether
they serve primarily pro- or anticancer
functions. How neuropeptide expression
and their functions change during cancer
progression, and how their ectopic expres-
sion may influence caner-associated
behavioral changes are discussed.
Y. Wu, A. Berisha,
J. C. Borniger* ........................... 2200111
Neuropeptides in Cancer: Friend and
Foe?
Review
2200111 (1 of 20) © 2022 Wiley-VCH GmbH
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Review
Neuropeptides in Cancer: Friend and Foe?
Yue Wu, Adrian Berisha, and Jeremy C. Borniger*
DOI: 10.1002/adbi.202200111
highly dynamic network of various cell
types (e.g., cancer cells, endothelial cells,
immune cells, fibroblasts) that exert dier-
ential eects on neuronal activity within
the local environment. Thus, complex
signaling between cancer and stromal cells
in the TME results in altered firing rates
of local nerves. Reciprocally, increased
neuronal activity and subsequent release
of classical neurotransmitters and/or
neuropeptides within the TME results in
enhanced cancer progression and sub-
sequent metastasis in various preclinical
models and clinical studies.[–]
Nerves interact with multiple stromal
cells in the TME where they indirectly
promote tumor growth, progression, and
subsequent metastasis.[] Several studies
have demonstrated that sympathetic nerve
innervation and subsequent release of the
neurotransmitter norepinephrine (NE) is
increased in breast tumors.[,,] However,
recent work has demonstrated that there
is an inverse relationship between tumor
weight and norepinephrine content (i.e.,
larger the size of the tumor, the lower
the levels of NE), despite increased innervation of sympathetic
nerves within the TME.[] These findings may be attributed
to a relatively unexplored phenomenon: neuropeptide release
within the TME. Neuropeptides are molecular messengers that
regulate a variety of functions in the central and peripheral
nervous systems via binding G-protein-coupled receptors
(GPCRs) on target cells. One of the many functions of neuro-
peptides is serving as growth factors for normal cells via the
activation of the heterotrimeric G protein Gq and subsequent
synthesis of second messengers and engagement of tyrosine
phosphorylation cascades. Neuropeptides act as neuromodu-
lators, in that they can alter the response of neurons to neu-
rotransmitters and other circulating signals, such as leptin,
ghrelin, glucose, and insulin—all of which are aected during
cancer progression.[–] For example, both neuropeptide Y
(NPY) and hypocretin/orexin neurons appear to mediate some
of the orexigenic eects of centrally administered ghrelin as
administration of NPY receptor antagonists attenuated ghrelin-
induced feeding. Similarly, ghrelin-induced feeding was sup-
pressed in orexin knockout mice, indicating that ghrelin may
stimulate feeding through both the orexin and NPY systems.[]
However, neuropeptide signaling is exploited within cancer
cells and many studies demonstrate the contribution of neuro-
peptides in tumor cell proliferation and migration,[] with many
major neuropeptides also potentially contributing to cancer
processes (see Table 1). Additionally, neuropeptides exert direct
Neuropeptides are small regulatory molecules found throughout the body,
most notably in the nervous, cardiovascular, and gastrointestinal systems.
They serve as neurotransmitters or hormones in the regulation of diverse
physiological processes. Cancer cells escape normal growth control mecha-
nisms by altering their expression of growth factors, receptors, or intracel-
lular signals, and neuropeptides have recently been recognized as mitogens
in cancer growth and development. Many neuropeptides and their receptors
exist in multiple subtypes, coupling with dierent downstream signaling
pathways and playing distinct roles in cancer progression. The consideration
of neuropeptide/receptor systems as anticancer targets is already leading to
new biological and diagnostic knowledge that has the potential to enhance
the understanding and treatment of cancer. In this review, recent discoveries
regarding neuropeptides in a wide range of cancers, emphasizing their
mechanisms of action, signaling cascades, regulation, and therapeutic
potential are discussed. Current technologies used to manipulate and analyze
neuropeptides/receptors are described. Applications of neuropeptide analogs
and their receptor inhibitors in translational studies and radio-oncology are
rapidly increasing, and the possibility for their integration into therapeutic
trials and clinical treatment appears promising.
Y. Wu, A. Berisha, J. C. Borniger
Cold Spring Harbor Laboratory
One Bungtown Rd, Cold Spring Harbor, NY 11724, USA
E-mail: bornige@cshl.edu
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/adbi.202200111.
1. Introduction
Cancer cells often co-opt neural pathways in the early stages
of tumorigenesis resulting in enhanced pro-tumor signaling
(e.g., survival pathways, resistance to apoptosis). Further, the
invasion of cancer cells in or around pre-existing and/or newly
emerging nerves provides an additional route by which cancer
cells can metastasize even in the absence of lymphatic and vas-
cular invasion.[,] Subsequently, the invasion of cancer cells
along nerves and/or within dierent nerve layers (i.e., endoneu-
rium, perineurium, epineurium), termed perineural invasion
(PNI), often precipitates cancer associated-pain observed in
various types of malignancies.[–] These changes within the
tumor microenvironment (TME) drive hypersensitivity of sen-
sory neurons that reside in dorsal root ganglia (DRGs) which
are primarily responsible for relaying nociceptive sensation to
upstream brain regions. In addition, the TME encompasses a
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eects on cells that comprise the TME including endothelial
cells and immune cells.[–] Neuropeptide action on immune
cells results in immune cell-derived cytokine release with far-
reaching systemic neuroendocrine and metabolic changes via
interactions with the central nervous system and peripheral
organs. An example of this is demonstrated when discussing
the immunomodulatory eects of the endogenous neuropep-
tide vasoactive intestinal peptide (VIP). For example, VIP and
other neuropeptides can reduce the production of inflamma-
tory cytokines and chemokines while stimulating the produc-
tion of anti-inflammatory cytokines (e.g., IL-, IL-Ra).[]
VIP also down regulates the expression of other inflammatory
mediators such as inducible nitric oxide synthase and cycloox-
ygenase (COX) and subsequent release of nitric oxide and
prostaglandin E by macrophages, dendritic cells (DCs), and
microglia.[,] VIP also functions as a macrophage-deactivating
factor as VIP has been shown to inhibit in vitro and in vivo
production of the proinflammatory cytokines tumor necrosis
factor alpha (TNF alpha), interleukin- (IL-), interleukin-
(IL-), and of nitric oxide (NO) and stimulates the production
of the anti-inflammatory cytokine interleukin- (IL-).[,]
Additionally, several neuropeptides (e.g., substance P and
neuropeptide Y) are implicated in inflammation, develop-
ment, and tissue repair-common pathways exploited during
the initial stages of tumorigenesis.[] Interestingly, several
neuropeptides are ectopically expressed within various
clinically aggressive solid tumors including breast, pancreatic,
lung, and gastrointestinal cancers.[,–] Several nonpituitary
tumors (e.g., small cell lung carcinomas, carcinoid tumors,
medullary thyroid carcinomas, breast, kidney, colon, prostate)
also ectopically express and secrete the neuropeptide adreno-
corticotropic hormone (ACTH) resulting in the onset and
subsequent diagnosis of ectopic ACTH syndrome observed in
≈–% of cases of Cushing’s syndrome (CS).[,] The eleva-
tion in ACTH is attributed to cancer-induced amplification of
its precursor peptide [i.e., proopiomelanocortin (POMC)] that
is normally present within the cells from which the cancer
originated.[] This observation demonstrates the ability of
cancer cells to ectopically express neuropeptides and increase
the concentration of neuropeptides that are normally present
within a narrow window in the cells that undergo transfor-
mation. Therefore, neuropeptides in the TME may originate
from nerves themselves or from several dierent forms of
tumors that ectopically express neuropeptides. Interestingly,
Table 1. Major neuropeptides with potential roles in cancer processes.
Neuropeptide and
receptors
Abundant regions Coreleased
neurotransmitters
Physiological functions Ref.
Neuropeptide Y
(NPY, 36 aa); Y1, Y2, Y4,
Y5, y6 receptors
CNS: hypothalamus, amygdala, hippocampus,
nucleus of the solitary tract, locus coeruleus,
nucleus accumbens, cerebral cortex
PNS: adrenal medulla, liver, heart, spleen,
vascular endothelial cells
Norepinephrine,
epinephrine,
GABA, serotonin
CNS: food intake, energy homeostasis,
circadian rhythm, cognition, stress response
PNS: vasoconstrictor
[39–42]
Substance P (SP, 11 aa);
NK1 receptor
CNS: dorsal horn, hypothalamus, Amygdala
PNS: vascular endothelial cells, muscle cells,
immune cells, gastrointestinal and genitourinary
tracts, lung, thyroid gland, tumor cells
Serotonin,
dopamine,
norepinephrine,
acetylcholine,
GABA, glutamate,
epinephrine
CNS: pain, stress, anxiety, neurogenic inflammation,
neuronal survival, and degeneration
PNS: vomiting reflex, defensive behavior,
cardiovascular system, salivary secretion, smooth
muscle contraction, vasodilation, chronic
inflammation
[42–45]
Neurotensin (NTS, 13
aa); NTS1-3 receptors
CNS: spinal cord, trigeminal nucleus, central
amygdaloid nucleus, anterior pituitary, median
eminence, preoptic, and basal hypothalamic areas
PNS: gastrointestinal tract, heart, adrenals,
pancreas, respiratory tract
Dopamine, glycine,
acetylcholine,
norepinephrine
CNS: sensory and motor functions, temperature
regulation, neuroendocrine control of the pituitary,
blood flow, and blood pressure
PNS: modulation of vascular smooth muscle
activity, gastrointestinal motility, and
pancreaticobiliary secretions
[46–49]
Orexin/Hypocretin
(OX, 33 aa/ 28 aa);
OX1/2 receptors
CNS: perifornical, lateral, and posterior hypothalamus
PNS: gastrointestinal tract, kidney, adrenal gland,
pancreas, placenta, stomach, ileum, colon,
colorectal epithelial cells
Glutamate,
dynorphin
CNS: maintain the wakefulness, food consumption,
energy homeostasis, reward seeking, stress,
motivation, drug addictions
PNS: blood pressure, heart rate, gut mobility,
hormone secretion, lipolysis, reproduction
[50–52]
Somatostatin (SST, 14
aa/ 28 aa); SSTR1-5
receptors
CNS: cortex, hypothalamus, brainstem, spinal cord
PNS: gastrointestinal tract, lung, pancreas,
nerves of the heart, thyroid, skin, eye, and thymus
Acetylcholine,
norepinephrine
CNS: control of pituitary hormone secretion,
regulation of locomotor activity and cognitive
functions
PNS: inhibition of intestinal
motility and absorption, vascular contractility,
cell proliferation
[53–55]
Vasoactive intestinal
peptide (VIP, 28 aa);
VPAC1/2 receptors
CNS: suprachiasmatic nuclei of the hypothalamus,
hippocampus, cortex
PNS: gastrointestinal tract, respiratory tract,
pancreas, urinary tract, immune, and endocrine cells
Acetylcholine,
serotonin
CNS: neuroprotective eects
PNS: regulation of intestinal motility
[56–58]
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the first evidence for the production of VIP by cells of the
immune system was identified in rat peritoneal, intestinal, and
lung mast cells using radioimmunoassay and immunohisto-
chemical studies.[] Additionally, immune cells also produce
neuropeptides (e.g., VIP) in response to antigenic and inflam-
matory signals and can act in an autocrine/paracrine manner
via specific receptors expressed on immune cells.[,] Thus, it
is likely that neuropeptides play a key role in this context (i.e.,
low or high neurotransmitter release) where they can alter
the response of neurons to cancer derived signals. Addition-
ally, it is possible that the increase in tumor volume, despite
a reduction in neurotransmitter release, is achieved because
of the actions of local neuropeptides. A reduction in neuro-
transmitter release and corresponding increases in neuropep-
tide release may be employed by local nerves as a strategy to
optimize eciency in the TME. Important questions remain,
for instance, what are the relative ratios of neurotransmitters
and neuropeptides within the TME? Do neurotransmitters and
neuropeptides work synergistically or antagonistically within
tumors? What are the major sources of neuropeptides in the
TME? Below, we discuss current evidence for the role neuro-
peptides play in local crosstalk within the TME, as well as distal
eects this signaling may have on systemic physiological and
behavioral processes.
2. Characteristic Features of Neuropeptides
Changes in the properties of local nerves within the TME may
have long-lasting implications on subsequent release of neu-
ropeptides. Secretory organelles that undergo exocytosis are
often categorized into two general categories based on size:
the large dense-cored vesicles (LDVs) > nm in diameter
and the smaller vesicles in the range of –nm, classically
referred to as “synaptic vesicles.”[] Classic small molecule
neurotransmitters (e.g., acetylcholine, GABA, glutamate) exert
rapid and short-lasting eects on target tissues, whereas neu-
ropeptides exert a response of longer duration, in a similar
fashion to circulating peptide hormones (e.g., altered gene
expression on the order of minutes to hours). Therefore, both
neuropeptides and peptide hormones can act as autocrine,
paracrine, and endocrine signals in the body.[] However, the
key distinguishing feature between neuropeptides and peptide
hormones—at “normal” physiological conditions—is that neu-
ropeptides are synthesized and secreted by neurons, whereas
peptide hormones are synthesized and secreted from endo-
crine cells. In addition, neuropeptides act on neural substrates,
whereas peptide hormones act on a variety of target organs
and glands. Although neuropeptides and neurotransmitters
are often colocalized in synaptic vesicles, this is not always the
case. Smaller synaptic vesicles contain classical neurotransmit-
ters exclusively, whereas the LDVs contain both neuropeptides
and neurotransmitters.
2.1. Frequency-Dependent Release and Calcium Dynamics
A discussion on how the firing rates (i.e., frequency of
action potentials) of dierent neurons impacts the release
of neuropeptides and neurotransmitters is highly relevant to
our discussion on cancer as the LDVs containing both neuro-
peptides and neurotransmitters require higher firing rates or
“bursting activity” to become “active” (i.e., release neuropep-
tides).[–] In addition, neuropeptides released in the local
environment in response to increased neuronal discharge have
long-lasting eects on nearby neurons, such as increased excit-
ability,[] which may further drive cancer progression. Thus,
the principle of frequency-dependent release is highly impor-
tant in the context of cancer cells because the same neuro-
peptides that are released in response to tumorigenesis and
subsequent PNI may not be released—or released at very low
levels—under steady-state conditions.[] This phenomenon
becomes more evident when looking at two classical examples
of physiological and pathological conditions that can induce the
release of neuropeptides that are otherwise not released. The
first example assessed the changes in firing rates of a subset
of hypothalamic neurons (i.e., oxytocinergic neurons) at basal
conditions and then during prolonged sucking of maternal
nipples from pups, promoting the subsequent secretion of
milk.[] Oxytocinergic neurons were observed to fire at ≈Hz
(.–. Hz) at baseline with prolonged stimulation by ten
or more pups increasing the firing rates of these neurons to
–Hz followed by strong milk ejection from the mammary
gland within – s.[] Therefore, the release of the neuropep-
tide oxytocin can be modulated by external stimulation. Similarly,
the release of endogenous opioid peptides in response to severe
pain exerts analgesic eects in preclinical models.[] Interest-
ingly, intracranial, or intraspinal electrical stimulation is used
to provide relief for patients suering from chronic pain,[,]
raising the possibility that modulation of neuropeptide release
may be a useful therapeutic intervention. Further expanding
on this concept, increased electrical stimulation of isolated rat
neurohypophyses (i.e., posterior pituitary gland) resulted in
increased neuropeptide release. More specifically, Racke et al.[]
demonstrated that electrical stimulation of the rat neurohypo-
physes with a frequency of Hz caused the release of about
µU vasopressin and µU oxytocin. On the other hand, elec-
trical stimulation of the rat neurohypophyses with a frequency
of Hz caused the release of µU vasopressin and oxytocin,
highlighting the frequency-dependent release of certain neu-
ropeptides. Interestingly, a single burst stimulation with a fre-
quency of Hz resulted in increased vasopressin release from
the rat posterior pituitary gland compared to constant stimula-
tion with a frequency of Hz–indicating that phasic burst
stimulation may be more eective than tonic constant-frequency
stimulation in triggering neuropeptide release.[,]
Given the fundamental role of calcium (Ca+) ions in exocy-
tosis, several studies have provided evidence that the release of
neuropeptides and classical neurotransmitters exhibit dierent
Ca+ dynamics. Neuropeptide release is triggered by small ele-
vations in Ca+ concentrations in the bulk cytoplasm (i.e., con-
tinued firing of neurons) as opposed to the higher elevations of
Ca+ concentrations (i.e., individual action potentials) required
for the secretion of amino acids and classical neurotransmitters
near the active sites.[] These changes in the amount of Ca+
required for exocytosis may be due to the location of LDVs and
synaptic vesicles relative to the site of Ca+ release. Paradoxi-
cally, classical neurotransmitter release is thought to occur very
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close to the site of Ca+ entry despite the higher levels of Ca+
required for exocytosis, whereas neuropeptide release occurs at
a distal location from the site of Ca+ entry despite the lower
levels of Ca+ needed for neuropeptide release (see Figure 1).[]
In accordance with these findings, Huang and Neher[] dem-
onstrated that Ca+ dependent exocytosis of LDVs can occur
at Ca+ concentrations that are at least ten times lower than
those required for neurotransmitter and amino acid release
from nerve terminals, indicating that neurotransmitters and
neuropeptides are not necessarily released in response to the
same stimuli despite their colocalization. For example, several
studies indicate that the ratio of neurotransmitters to neuro-
peptides may further dier in response to certain stimuli. A
study by Franck et al.[] demonstrated that the release of the
neuropeptide substance P (SP) from rat spinal cord slices was
increased by electrical stimulation of frequencies in the range
of – Hz. Additionally, the release of the classical small-
molecule neurotransmitter -hydroxytyptamine (-HT; sero-
tonin) per pulse remained constant, indicating that coexisting
neurotransmitters and neuropeptides may be released in dif-
ferent proportions depending on the stimulation frequency.
Therefore, it is likely that repeated stimulation of neurons
at higher frequencies is required for neuropeptide release,
whereas individual action potentials are not sucient. Thus, it
is essential to discern the dierential release of neuropeptides
and neurotransmitters during the early stages of cancer initia-
tion and progression as this will provide additional insight into
the molecular and cellular changes sustaining cancer progres-
sion and may provide further therapeutic targets for various
malignancies.
This phenomenon of cancer cells altering the recruitment
and organization of nerves within the TME has been widely
investigated. Cancer cells often co-opt neuronal programs
through the release of growth factors [e.g., nerve growth factor
(NGF), brain-derived neurotrophic factor (BDNF)] that pro-
mote innervation of the TME.[–] Similar to neuropeptides,
growth factors (e.g., neurotrophins) are proteinaceous signaling
molecules that are produced and secreted by cells, including
neurons. Although growth factors are synthesized, expressed,
and released by neurons they are not generally considered
neuropeptides.[] However, several growth factors may fulfill
the criteria of neuropeptides (e.g., BDNF).[] Studies inves-
tigating the direct impact of cancer cells on the electrophysi-
ological properties of local nerves is, to a large extent, lacking.
This is largely due to an absence of electrophysiological tech-
niques that can detect changes in electrophysiological proper-
ties at single-cell resolution within co-culture in vitro assays,
and especially in vivo. In addition, a lack of understanding
of the cancer cell-neuron connections in the periphery (i.e.,
chemical or electrical in nature) contributes to this absence of
experimental evidence. Despite these limitations, recent work
by Kovacs and Vermeer[] demonstrated that high-grade serous
ovarian carcinoma (HGSOC)—densely innervated by TRPV+
sensory nerves—are more electrically conductive and exhibit
a higher mean spike amplitude than benign/normal ovarian
tissue. These findings are consistent with the hypothesis that
nerves within the TME increase their electrical activity and may
reflect increased numbers of sensory nerves within the TME
of HGSOC. As we alluded to previously, neuropeptide release
is frequency dependent; nerves with higher firing rates release
an abundance of neuropeptides when compared to nerves that
exhibit lower firing rates. Thus, combining the principle of
frequency-dependent release of neuropeptides with the experi-
mental observation that malignant tissues are more electrically
conductive than benign/normal ovarian tissue, it is likely that
neuropeptides are aberrantly released within the TME during
cancer progression as the local nerves may not exhibit the firing
rates required to elicit the release of neuropeptides during
normal, steady-state conditions. However, the study by Kovacs
and Vermeer[] did not measure the change in the firing rates
of neurons when cocultured with cancer cells. They specifi-
cally measured the changes in mean spike amplitude which can
dier independent of changes to the firing rates of neurons
(i.e., higher spike amplitude may not correspond to increased
firing rates of neurons). Additionally, the electrical activity of
malignant, benign, and normal tissues was measured using a
multielectrode array consisting of a × electrode grid (i.e.,
electrodes) which may not provide high enough spatial reso-
lution to measure the changes in the firing rates of individual
neurons. Building on these findings, future studies will need
to assess the changes in the firing rates of neurons that are
cocultured with cancer cells, and expand these approaches in
vivo. Although logical reasoning and emerging evidence sug-
gests that cancer cells increase the activity of local nerves within
the TME, more studies need to be conducted across various
malignancies to fully establish this phenomenon as a potential
mechanism by which nerves and cancer cells communicate.
Further studies will need to investigate the specific neuropep-
tides that are dierentially expressed and secreted from nerves
Figure 1. Eects of neuropeptides in the tumor microenvironment (TME).
(1) Cancer cells release axon guidance cues, growth factors, and proin-
flammatory cytokines into the TME. The actions of the axon guidance
cues and growth factors results in the (2) recruitment of local nerves and/
or emergence of new nerves into the TME. Once nerves integrate into the
TME, the interaction between cancer cells and local nerves results in an
increase in the firing rates of these nerves with subsequent (4) small ele-
vations in cytoplasmic calcium concentrations required for the (5) release
of neuropeptides from local nerves. Newly released neuropeptides, in
turn, signal back onto cancer cells, driving (6) tumor progression and
initiating the early stages of (7) perineural invasion and (8) subsequent
metastasis along nerve fibers.
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in malignant and normal/benign tissues. Moreover, it is likely
that the mode or speed of transportation of these neuropeptides
along axons is impacted during cancer progression which may
contribute to ectopic release of these neuropeptides within the
TME.
2.2. Recruitment, Docking, and Fusion of Neuropeptides
In addition to the physical dierences and frequency-
dependent release of these two classes of vesicles, they also
dier in their recruitment, docking, and fusion to the plasma
membrane.[] For example, synaptic vesicles are often found in
clusters restricted to small sections of the presynaptic plasma
membrane termed the “active zone,” which lies at the inter-
face between the presynaptic terminal and the synaptic cleft.
These active zones contain evolutionarily conserved protein
complexes that primarily function to dock synaptic vesicles for
exocytosis and recruit voltage-gated Ca+ channels to the pre-
synaptic membrane.[] However, LDVs are not located at these
active zones but are instead scattered diusely around the nerve
terminal (i.e., axons) and are found in the soma and dendritic
compartments as well.[–] Huang and Neher demonstrated
that LDVs are also located at ectopic sites outside of the active
zones, where neuropeptides are released extrasynaptically at
the somata of dorsal root ganglion (DRG) neurons.[] The dif-
ferences in the location of release between neuropeptides (i.e.,
soma, dendrites) and neurotransmitters (i.e., nerve endings,
synapses) may be partly due to the fact that neuropeptides are
exclusively produced in the cell soma without local synthesis
in nerve endings— in contrast to the classical neurotransmit-
ters which are synthesized within the soma and locally in nerve
endings. As a result of this extra synaptic release of neuropep-
tides, neuropeptides diuse over short distances within the
local environment and longer distances where they can act
as hormones in dierent brain regions—in sharp contrast to
the spatially restricted actions of neurotransmitters.[,] The
ability of neuropeptides to persist in extracellular fluid and dif-
fuse over long distances is largely due to absence of any known
reuptake mechanisms for neuropeptides. On the other hand,
neurotransmitters often have various reuptake mechanisms
which explains why their eects are primarily short-term and
spatially limited. Interestingly, local release of neuropeptides
within the TME sustain the proliferation of solid tumors via
autocrine/paracrine loops.[,,,] In addition, it is possible
that the long-distance eects of these TME-derived neuropep-
tides on distinct brain regions contribute to many of the cancer-
related neurological disorders often observed in patients (e.g.,
cognitive impairment, sleep disruption, depression, and pain).
2.3. Plasticity in Neuropeptide Expression
Neuropeptides are capable of modulating neurotransmitter
release, and reciprocally, neurotransmitters can also aect
the synthesis and subsequent release of neuropeptides. For
example, somatostatin (also known as somatotropin-release
inhibiting factor (SRIF)—a neuropeptide whose expression
is widely distributed in the central and peripheral nervous
systems—increases the release of certain neurotransmitters
such as - hydroxytryptamine (-HT; serotonin) and dopamine
but can also decrease the release of gamma-aminobutyric acid
(GABA) and norepinephrine.[,] Reciprocally, the release of
SRIF is aected by -HT and GABA, suggesting that neuro-
transmitter release also aects the release of neuropeptides.[]
Neuropeptides exhibit additional plasticity in their expression.
Some neuropeptides are abundantly expressed under steady-
state circumstances which indicates that these subsets of neu-
ropeptides are functionally available at any time. The second
type are neuropeptides that are normally expressed at low
levels and are only elevated in response to stimuli (e.g., nerve
injury, inflammation, tumorigenesis), such as adrenocortico-
tropic hormone (ACTH). Neuropeptides that are expressed
early during development are often downregulated postna-
tally.[] This phenomenon constitutes the third type of neuro-
peptide plasticity and is relevant as cancer cells co-opt many of
the neural pathways that are active during development (e.g.,
nerve regeneration, tissue repair), indicating that some of the
same neuropeptides that are expressed during development are
potentially expressed during the early stages of tumorigenesis.
One example highlighting this phenomenon is demonstrated
by Cohen et al.[] when investigating neuropeptide Y (NPY)
expression in the adrenal gland. NPY is expressed in a subset of
cells within the adrenal medulla, the inner part of the adrenal
gland. Cohen et al.[] demonstrated that there is a biphasic
pattern of expression of NPY mRNA during development of
the human adrenal medulla. More specifically, NPY mRNA
is detectable between . weeks of gestational age through
weeks of gestational age and is then not detectable until
months after birth. However, when analyzing NPY mRNA
expression in neuroblastoma tumors—which often arise in
the adrenal medulla—/ (≈%) neuroblastoma tumors
expressed NPY mRNA.[] Thus, this study demonstrates that
certain neuropeptides present during embryonic development
(e.g., NPY) also play a role in the development of tumors from
the same cell of origin (e.g., neuroblastomas). Therefore, tumor
cells may retain the molecular mechanisms that mediate dier-
entiation of the embryonal cells from which they arise.
A major stimulus that promotes neuropeptide release are
cytokines (e.g., induced by nerve injury). Although controlled,
regulated release of these cytokines is beneficial and impor-
tant for remodeling after injury, chronic release is adverse. For
example, proinflammatory cytokines [e.g., interleukin (IL)-,
-, - and TNF-a] are expressed during the first phase of nerve
injury[] and regulate the inflammatory response through the
recruitment of macrophages.[] However, chronic release of
TNF-a has been demonstrated to reproduce the nociceptive
behaviors and endoneurial pathology found following experi-
mental nerve injuries, implicating TNF-a in the pathologies
of neuropathic pain.[–] Cytokines are widely known for
their eects on various solid tumors where they stimulate
neurotransmitter and neuropeptide synthesis and subsequent
release in the TME. A study by Freidin etal.[] demonstrates
the role of cytokines in regulating neuropeptide expression in
sympathetic neurons—which are commonly associated with
aggressive cancers (e.g., breast, prostate, pancreatic), increased
mortality, and disease recurrence.[] Specifically, exposure of cul-
tured explants of the rat superior cervical ganglion—harboring
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sympathetic nerve cell bodies—to the proinflammatory cytokine
interleukin-β (IL-β) increased the release of the neuropeptide
SP by sympathetic neurons. IL-β and other proinflammatory
cytokines are elevated within tumors where they predominantly
exert pro-tumor eects.[] IL-β is produced and secreted by
various cells that comprise the TME including immune cells,
fibroblasts, and cancer cells.[] Thus, it is likely that a portion
of the SP synthesized and released within tumors (e.g., breast)
is induced by IL-β, which itself is derived from the stromal
cells that encompass the TME and subsequent binding to its
receptors on sympathetic nerves. Increased expression of SP
within the TME is important because SP expression has been
shown to promote cancer initiation, progression, and mediate
perineural invasion in pancreatic cancer.[–] Thus, this
interplay between SP and IL-β and plasticity in neuropeptide
expression in the TME is highly relevant to our discussion on
cancer and should be investigated further to provide insight
into the role of neuropeptides in the TME.
3. Neuropeptides and Their Receptors in Cancer
3.1. Neuropeptide Y
NPY is one of the most prevalent peptides in the mammalian
central and peripheral nervous systems. It is composed of
amino acids, exerting context-dependent neurotransmitter and
neuromodulator functions throughout the human body. In
addition to NPY, peptide YY (PYY), and pancreatic polypeptide
(PP) are also native ligands of the NPY receptor family, medi-
ating their eects via corresponding receptors with dierent
potencies. NPY receptors are monomer proteins that belong to
the class A G-protein coupled receptors (GPCRs) coupled with
Gi/o. So far, seven Y receptors have been discovered in verte-
brates,[,] of which five (Y, Y, Y, Y, and Y) are present
in mammals and four (Y, Y, Y, and Y) are functional in
humans.[] The Y receptor, on the other hand, is active in rab-
bits and mice.[] NPY and its receptors (Y, Y, Y) contribute
to a wide range of physiological activities as a multiligand/
receptor system that is broadly distributed throughout the body.
In the CNS, they are located in the spinal cord and many brain
regions responsible for food intake, energy homeostasis, circa-
dian rhythms, cognition, and stress responses, among other
functions.[] In the periphery, NPY is mostly expressed in the
sympathetic nervous system, where it regulates cardiovascular
and other processes in conjunction with norepinephrine and
adenosine triphosphate (ATP).
NPY receptors have recently received substantial interest due
to their over-expression in a variety of human malignancies,
including breast carcinomas,[] neuroblastomas,[] Ewing sar-
comas,[] renal cell carcinomas, ovarian cancers, nephroblas-
toma, and gastrointestinal stromal tumors,[] among others.
Reubi et al. used autoradiography to identify NPY receptor
expression in human breast carcinomas, providing initial evi-
dence that NPY may play a role in human cancer.[] In this
study, they discovered that the Y receptor was significantly
overexpressed in % primary breast carcinomas and % of
lymph node metastases, whereas normal breast tissues pref-
erentially expressed the Y receptor subtype. Other studies
have also shown that the NPY receptor subtypes exhibit a
dierentiation-specific expression pattern,[] with expression
shifting from Y to Y in breast tissue undergoing neoplastic
transformation.[] Glioblastomas, a deadly form of brain
cancer, not only produce Y at a high frequency but also have
extraordinarily high Y densities. Moreover, all major glioma
types tested were infiltrated with intratumoral nerve fibers
containing NPY.[] Therefore, Y receptors in tumor cells are
activated by endogenous NPY, triggering functional alterations
to tumor growth.[] Aside from Y and Y, the Y receptor
subtype seems to be critical for cell motility via RhoA activa-
tion.[] Strongly inducible Y expression was found in migra-
tory cells of neuroblastoma[] and liver cancer.[] Together,
it appears that NPY receptors follow four general principles:
) NPY receptors are mainly expressed in specific endocrine
tumors, epithelial malignancies, and embryonal tumors[];
) tumor cells express predominantly Y and/or Y subtypes[];
) Y receptors are mainly involved in the modulation of cancer
cell proliferation, whereas Y receptor activation appears to pro-
mote angiogenesis[]; and ) Y receptors regulate cell prolifer-
ation,[] chemotactic migration, invasion,[,] and contribute
to chemoresistance.[] These properties make NPY receptors
particularly appealing as potential targets for cancer imaging
and treatment.
In most cases, NPY and its receptors serve a pro-oncogenic
role, particularly in neuroendocrine tumors, breast and pros-
tate cancers. However, this eect is not universal, as NPY can
exert tumor suppressive eects in cholangiocarcinoma[] and
hepatocellular carcinoma,[] and it can dramatically inhibit
estrogen-induced cell proliferation via the Y receptor in the
human breast cancer cell line MCF-.[] Generally, NPY pro-
motes or inhibits tumor growth through paracrine,[] auto-
crine, and endocrine[] mechanisms. NPY is primarily
generated in nerve fibers and neuroendocrine cells, then trans-
ported to intratumor nerve fibers or secreted by tumor cells
themselves to activate tumoral NPY receptors. Released NPY
can bind to NPY receptors on tumor cells and tumor blood ves-
sels, thus triggering paracrine and autocrine eects on tumor
cell metabolism and tumoral blood supply. Due to rapid deg-
radation of NPY in the blood stream, endocrine stimulation of
NPY receptors by circulating NPY appears less likely to have
a general function in tumors.[] Furthermore, NPY and par-
ticular Y receptors are expressed in a variety of cell types in the
tumor microenvironment (TME), including immune cells[]
and epithelial cells of tumor-associated blood vessels.[] Addi-
tionally, NPY is engaged in the activation of cancer-associated
fibroblasts (CAFs).[,] Upon paracrine and autocrine regu-
lation, NPY/Y receptors can promote cell proliferation,[,]
mitogenesis, extracellular matrix invasion, migration,[]
and angiogenesis[] in the TME by interacting with multiple
signaling pathways. Calcium/calmodulin-dependent kinase
II (CaMKII), protein kinase C (PKC), and mitogen-activated
protein kinase (MEK/)[,] are major pathways involved,
as illustrated in Figure 2. For example, when NPY binds to
its receptor, the small G-protein Ras is activated. In turn, Ras
recruits and promotes Raf, a serine/threonine protein kinase
that activates MEK, which phosphorylates the MAPK ERK/.
This ERK/MAPK signaling pathway plays a crucial role in
tumor survival and development.[]
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3.2. Substance P
Substance P (SP) is one of the most important members of the
tachykinins (TKs), which includes an evolutionarily conserved
family of small bio-active peptides. TKs are broadly distrib-
uted in mammalian central and peripheral nervous systems,
participating in the regulation of various physiological pro-
cesses including pain, stress, inflammation, wound healing,
leukocyte tracking, microvasculature permeability, cell sur-
vival, and degeneration,[,] among other processes. Recent
studies demonstrate that TKs play a role in dierent steps of
carcinogenesis, such as mitogenesis, angiogenesis, cell migra-
tion, metastasis, and other growth-related events.[] Three G
protein-coupled receptors (GPCRs), termed NK-, NK- and
NK-, mediate the biological actions of three native ligands: SP,
neurokinin A and neurokinin B. SP is a more potent agonist at
neurokinin- receptors (NKRs) than the other two ligands.[]
Both SP and NKR are overexpressed in multiple cancer types
including breast, ovarian, pancreas, prostate, head and neck
cancers, gliomas, and astrocytomas.[,,–] Specifically,
SP is expressed in many cells of the TME, including epithelial
cells, immune cells, cancer stem cells, and fibroblasts.[] Based
on current evidence, SP expression and distribution in cancer
cells can be characterized as: ) having higher expression of
SP in malignant cells than in normal cells within the same
tissue[,]; ) SP is found both in the cytoplasm and is even
more strongly expressed in the nuclei,[] suggesting its poten-
tial role as a genetic neuromodulator or epigenetic factor (dis-
cussed in Section .)[,,]; ) SP and its interaction with
the NKR have a critical role in the tumor microenvironment.
In a large majority of tumors, NKR are found in the intra- and
peritumoral blood vessels,[] where the SP is released from
sensory nerve terminals. SP/NKR activation enhances the pro-
liferation of cultured endothelial cells in vitro and the growth
of capillary vessels in vivo, which in turn facilitates angiogen-
esis during tumor progression; ) SP is also located in dierent
body fluid compartments, such as blood, cerebrospinal fluid,
and breast milk, likely because SP can form a complex with
fibronectin to protect it from peptidase digestion and increase
its half-life.[]
More recently, information on the underlying mechanisms
of SP/NKR complex function in cancer cell proliferation,
migration, angiogenesis, and maintenance of a favorable TME
has become available. In general, SP promotes tumor growth
and development mainly through four mechanisms: ) via
an autocrine pathway, by which SP is released from primary
tumors[]; ) through the paracrine pathway, where SP is
secreted from tumor cells targeting surrounding stromal cells
and epithelial cells of intratumor blood vessels; ) by means of
the peripheral nervous system, in which direct interactions are
provoked between sensory nerve terminals and tumor cells[];
and ) via an endocrine mechanism, related to the organism’s
emotional state, by which SP reaches the whole body through
the bloodstream.[,] Upon SP binding to NKR, multiple
Figure 2. Primary signaling pathways activated by neuropeptides and their receptors involved in cancer progression. The interaction of neuropeptides
with their GPCRs regulates the Ras/MEK, PI3K/Akt, intracellular Ca2+ mobilization, and NF-kB pathways for cell survival and proliferation; cAMP/
PKA/CREB pathway for invasion and drug resistance; Src/ROCK and JAK/STAT pathways for angiogenesis and metastasis; Wnt/ β-catenin pathway
for cancer cell stemness and malignant progression. As a result, neuropeptides may stimulate or inhibit these signaling cascades, causing cancer cell
proliferation, migration, or apoptosis.
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signaling pathways such as phosphoinositide -kinase (PIK)
and mitogen-activated protein kinases (MAPKs) will be acti-
vated, followed by a variety of downstream eectors involved
in protein synthesis, cell cycle progression, gene transcription,
and expression (see Figure).
Tumor progression mediated by SP/NKR occurs primarily
through four major signaling pathways: Wnt/β-catenin, MAPK,
PIK/Akt, and mTOR.[] ) The Wnt signaling cascade is a
crucial transduction pathway that regulates cell survival, pro-
liferation, migration, dierentiation, and organelle dynamics
through the activation of β-catenin.[] Tumorigenesis, TME
remodeling and epithelial-mesenchymal transition (EMT) are
enhanced by Wnt signaling pathway through fine crosstalk
between the tumor and infiltrating immune cells.[] Several
studies demonstrate that pharmacological inhibition of NKR
by antagonists results in suppression of canonical Wnt sign-
aling in colon cancer[,] and hepatoblastoma cell lines.[]
This, in turn, downregulates Wnt-associated protein activity,
including cyclin D, VEGF, c-Myc, and LEF-, thereby leading
to cell cycle arrest, apoptosis, and reduced angiogenesis and
invasion of cancer cells. ) The MAPK signaling pathway is
another key transduction cascade module regulating essential
cellular processes, such as proliferation, dierentiation, migra-
tion, development, inflammation, and apoptosis.[] As two
major components in the MAPK family, phosphorylated ERK
and p have been reported to participate in cancer progression
and invasion.[,] In human astrocytoma cells, SP induces
the accumulation of IL-, IL-, and expression of c-Myc or Src
via p and ERK/ signaling. NKR antagonists can attenuate
this process by reducing SP-induced proinflammatory cytokine
synthesis.[–] SP further activates inflammatory pathways
in macrophages and fibroblasts via ERK/p MAPK-mediated
NF-kB activation, further enhancing EMT and MMP release,
a process critical for cancer invasion and metastasis.[] Addi-
tionally, SP triggers MMP- and MMP- overexpression via
activation of ERK/, JNK, and Akt pathways, leading to cell
proliferation and ECM invasion in breast cancer cells.[,]
) The PIK/AKT signaling pathway plays a crucial role in
cell proliferation and apoptosis resistance by interacting with
the p tumor-suppressor pathway in malignant cells.[]
SP can additionally induce “M-like” macrophage polariza-
tion via PIK/Akt/mTOR signaling, subsequently stimulating
angiogenesis and cell proliferation.[] Building on these find-
ings, Javid et al. reported anticancer activity of the only FDA
approved NKR antagonist, aprepitant, in an esophageal squa-
mous cancer cell line. Aprepitant has eective potency in
inhibiting malignant cell proliferation, inducing apoptosis and
suppressing activation of the PIK/Akt axis and its downstream
eectors (e.g., NF-κB).[] ) Aberrant mTOR signaling caused
by genetic alterations from dierent signaling cascades is also
commonly observed in various types of cancer, regulating cell
proliferation, immune cell dierentiation, and tumor metabo-
lism.[] Rapamycin is a specific inhibitor of mTOR pathway,
inhibiting mTOR function by blocking the cell cycle at the
G/S phase. Several studies have shown that SP/NKR can
activate mTOR in cancer cells. Mayordomo et al. treated breast
cancer cells with a neutralizing anti-SP antibody and observed
cell cycle blockade and inhibition of mTOR signaling as well
as decreased Her and EGFR expression.[] Together, these
studies demonstrate a pleiotropic role for SP in cancer initia-
tion, progression, metastasis, and resistance to treatment.
3.3. Neurotensin (NTS)
NTS is a tridecapeptide located primarily in the brain and intes-
tine, where it functions as both a neuropeptide and an endo-
crine hormone, respectively. Centrally, it is secreted by neurons
and acts as a signaling molecule to neighboring cells, control-
ling body temperature, sensory and motor functions, pituitary
neuroendocrine functions, blood flow and pressure, sleep,
and other homeostatic functions. In the periphery, NTS is
released by endocrine cells in the gastrointestinal tract, where
it acts as a local hormone for the digestive system. Besides its
canonical role in neural regulation and gut motility, emerging
studies support a new role for NTS in a variety of malignancies,
including pituitary adenoma, glioma, head and neck tumors,
pancreatic, colon, prostate, lung, and breast cancers.[] NTS
function is mediated by neurotensin receptors, which are com-
prised of three subtypes (NTSR, , ). NTSR and NTSR are
typical (with seven transmembrane domains) GPCRs, whereas
NTR is a single transmembrane receptor belonging to the
Sortilin family. NTSR has mainly been identified in the CNS
and has a lower anity for NTS, while NTSR and NTSR are
found in a variety of human peripheral tissues and cancer cells.
Interestingly, in some cases, these three receptors can interact
with each other by forming functional heterodimers to finely
adjust their downstream functions.[,]
NTS is produced by multiple cancers, and expression of
NTSRs is also very common (e.g., in % of breast cancer,
% of small-cell lung cancer, –% of pancreatic cancer,
–% melanoma).[] Of note, there may be significant dier-
ences between NTSR expression due to dierent cancer types/
stages and detection methods, such as RT-qPCR, western blot,
northern blot, and autoradiography.[] Generally, NTS may
influence tumors in a conventional endocrine manner, with
endogenous NTS production leading to enhanced tumor devel-
opment via NTR signaling. Furthermore, some tumors have
been found to not only contain NTS receptors but also generate
NTS peptide, resulting in autocrine and/or paracrine actions.
Based on current studies, NTS/NTSRs functions will be dis-
cussed in two types of malignancies: neuroendocrine tumors
and epithelial-derived tumors.
. Neuroendocrine tumors arise in the pituitary, prostate, gas-
trointestinal tract, lung, and thyroid gland, containing spe-
cialized cells with both characteristics of endocrine cells and
nerves. In the androgen-dependent human prostate cancer
cell line LNCap, for example, NTS secretion and NTSR over-
expression were observed under androgen deprivation, fol-
lowed by enhanced neuroendocrine dierentiation, cell pro-
liferation, and invasion.[] Androgen-dependent PC cells
are not able to produce NTS, however NTSR expression sig-
nificantly increased when cells were supplemented with very
low concentrations of NTS (.–n, near physiologic post-
prandial blood concentrations).[] Peripheral activated B lym-
phocytes may be a possible source of circulating NTS.[,]
These results support an endocrine, autocrine/paracrine
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role for NTS/NTSR activation. Similar autocrine/paracrine
eects also occur in small-cell lung cancer[] and pituitary
adenoma.[] In both cell culture and xenograft models,
higher amounts of NTS secretion and NTSR expression
were characteristic of malignant rather than normal cells,
while NTS-induced cell proliferation and migration can
be dramatically attenuated by SR (an FDA-approved
selective antagonist to NTSR).[] Furthermore, NTS ex-
pression (not NTSR) is associated with significantly worse
survival in melanoma patients.[] Together, NTS, NTSR,
and NTSR are found in neuroendocrine tumor cells, where
they contribute to tumor development via autocrine/parac-
rine or endocrine pathways.
. NTS/NTSR overexpression and a typical autocrine/paracrine
stimulation are also observed in epithelial-derived cancers.
In breast and colon cancers, for instance, NTS appears in
neoplastic cells and induces NTSR overexpression, which
promotes tumor growth and invasion, a process that can be
inhibited by the NTSR antagonist SR.[,] Moreover,
both NTSR and NTSR are found in pancreatic cancers in
the presence of NTS,[,] activating mitogenic signaling
pathways to promote cancer initiation and development.
Interestingly, NTS-induced cell migratory ability depends
on dierent ECM environments; intrinsic cell mobility is
increased, while collective cell migration is reduced.[] In
conclusion, NTS and NTSRs are typically observed in epithe-
lial-derived malignancies, where they promote cancer pro-
gression primarily via autocrine/paracrine pathways.
The influence of NTS/NTSR signaling on cancer progres-
sion can be loosely organized into four stages[] (Figure 3).
) Premalignancy is the first stage, in which various inflam-
matory cytokines, MMPs and ROS are induced under chronic
inflammation. As a result, NTS can act here as a proinflam-
matory neuropeptide, and NTSR is significantly upregulated
during chronic inflammation.[] Within this microenviron-
ment, DNA damage leads to mutations, putatively promoting
carcinogenesis via genomic instability.[] This genomic
damage may result in morphological lesions that are known to
be precursors to certain malignancies. ) Genetic disturbances
and carcinogen stimulation cause epithelial disruption and
facilitate a transition to the malignant state. In this stage, cells
grow uncontrollably, but the cancerous carcinoma is still small
and only localized to one area. Autocrine/paracrine/endocrine-
activated NTSR and NTSR participate in cell survival and
proliferation through the PKC/MAPK/ERK and Ras/PIK/AKT
pathways.[] ) When the tumor is larger, the stroma is altered
due to the loss of the epithelial barrier (i.e., basement mem-
brane), resulting in an invasive state. More signaling cascades
are involved in progression of the malignancy toward a more
aggressive state, such as small RhoGTPases, IL-/CXCR, and
JAK/STAT pathways.[] These can induce stromal damage
and cancer cell infiltration into adjacent tissues or lymph
nodes. ) Enhancers from multiple signaling pathways induce
angiogenesis and further contribute to distant metastasis.
This happens when cancer cells break o a tumor and move
through the body in the bloodstream or lymph system. In the
last two stages, cancer cells in the tumor core are undergoing
hypoxia and are surrounded by a very acidic microenvironment.
NTSR signaling promotes a metastatic phenotype in pancre-
atic cancer cells by inducing localized extracellular acidifica-
tion in normoxic cells, preceding acidosis caused by hypoxia,
and switching to glycolysis. Intriguingly, an NTS analog Lys-
ψ-LysNT exhibits rapid and robust alkalinization to counteract
the acidic microenvironment via activating sodium/proton
exchanger activity.[] Despite advances in understanding
Figure 3. Neurotensin system (NTS/NTSR) influences on cancer progression. Chronic inflammation generates cytokines, MMPs, and ROS, which
cause genomic damage and promote a premalignant state. Gene dysregulation and carcinogens stimulate NTS/NTSR signaling pathway, causing
epithelial damage and facilitating the transition to a malignant state. Loss of the epithelial barrier alters the stroma, giving rise to an invasive state.
NTS/NTSR system might be further activated through autocrine, paracrine, or endocrine pathways, leading to tumor microenvironment remodeling
and angiogenesis typical of the highly invasive stage. Cellular enhancers, an acidic environment, and hypoxia all contribute to tumor development and
distal metastasis.
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of the NTS/NTSR system in cancer over the last two decades,
further findings are needed for the development of targeted
therapeutics.
3.4. Orexins/Hypocretins
The orexins/hypocretins (Orexin-A/B, also known as Hypo-
cretin-/) are hypothalamic neuropeptides that regulate sleep/
arousal, food intake, energy homeostasis, stress, reward, and
drug addiction, among other functions. However, orexins are
not limited to the central nervous system, a small fraction is
also produced by the enteric nervous system and secretory tis-
sues in periphery, where they participate in the regulation of
blood pressure, heart rate, gut motility, and hormone secretion.
The two subtypes of orexin (OX), orexin-A (OxA), and orexin-B
(OxB), orchestrate their diverse functions by binding and acti-
vating two GPCRs, OXR, and OXR. OxA has a greater anity
binding to OXR, whereas both OxA and OxB have a similar
anity to OXR. Although orexin-expressing neurons project
widely throughout the CNS, these two receptors are distributed
in dierent brain regions,[] reflecting their dierential physi-
ological functions. Recently, another exciting aspect of orexins
and their receptors has emerged, which is their potential roles
in inflammation and cancer.
Although multiple studies have demonstrated that orexins
induce apoptosis resulting in significant reduction in cancer
cell growth, their proliferative or inhibitory eects are highly
cell-type dependent. On one hand, both orexin isoforms (OxA
and OxB) were found to consistently promote apoptosis and
suppress cell growth in multiple colon cancer cell lines.[]
OXR was only expressed in malignant (and not adjacent
normal) cells as revealed by RT-qPCR and immunohistochem-
istry.[,] In most of the colon cancer cell lines expressing
both receptors, orexin treatment significantly induces apop-
tosis and inhibits growth. Only HCT- cells, which do not
express OXR, did not undergo apoptosis upon treatment
with OxA.[] Similar results were obtained from in vivo colon
tumor xenografts, where dramatic reductions in tumor sizes
were observed for all cell lines upon OxA treatment, excepting
HCT- cells.[] Another study from Wen et al. indicates that
OxA can also reduce cell viability and promote apoptosis in
HCT- cells, but the cells subsequently upregulate autophagy
processes to resist apoptosis,[] likely attenuating the eects of
orexin on cell death. Additionally, dramatic reductions in cell
viability was found in OxA treated rat glioma cells with an IC
in the nanomolar range. These results reflect an overall anti-
cancer eect mediated by OXR.
On the other hand, treatment of gastric cancer cells with
OxA leads to overexpression of OXR, but paradoxically results
in enhanced cell survival and proliferation through activa-
tion of Akt signaling and inhibition of caspase- activity via
ERK/.[,] The same proliferative eects from orexin has
additionally appeared in adrenal cancers.[,] Despite the rel-
atively consistent negative or positive influences in the above
malignancies, orexins have a mixed eect in prostate cancer.
OXR was upregulated upon orexin supplement both in cell
cultures[,] and clinical samples,[] however this was also
associated with increased cell growth in nondierentiated cells
and apoptosis in dierentiated cells. This indicates that there
might be a transformational regulation of orexin receptor
expression during malignancy, and therapeutic treatment
windows may need to take into account receptor expression
dynamics in early versus late-stage prostate cancers.[]
Theoretically, orexins may exert their actions via autocrine,
paracrine, and/or endocrine pathways in order to regulate phys-
iological functions.[] However, it is notable that OxA has never
been detected in tumors,[] suggesting that OXR present in
tumoral tissue was not activated by endogenous OxA. In other
words, the orexin system does not exert its functions via an
autocrine mode based on current studies. Also, the endocrine
pathway is also less plausible as the concentration of circulating
orexins is about p, which is too low to activate OXR in
tumors. Therefore, both endogenous orexins and OXR have
no impact on tumor growth, and they can only aect malig-
nancy in the presence of exogenous orexins.[] Despite the lack
of orexins within tumors, OxA expression can be detected in
“fiber-like” stroma surrounding prostate tumors and follicular
exocrine epithelia,[] indicating a possible impact on tumor
growth through stromal cells within the TME. Therefore, the
orexin/OXR system probably acts through paracrine eects on
cancerous cells. As described above, their activation can trigger
multiple signaling pathways for the modulation of cell survival,
proliferation, and apoptosis, including cAMP, JNK, p/MAPK,
ERK/, and PIK/Akt. Generally, the cAMP pathway activates
relevant enzymes and regulates gene expression, JNK, ERK/,
and PIK/Akt activation triggers cell proliferation, cell cycle
progression, and apoptosis suppression, while p/MAPK par-
ticipates in programmed cell death.[,] More recently, Voisin
et al. revealed that the orexin/OXR system induced a mito-
chondrial apoptosis response, which is driven by a new sign-
aling pathway including immunoreceptor tyrosine-based motifs
(ITIM) and the tyrosine-protein phosphatase nonreceptor type
(SHP) both in Chinese hamster ovary (CHO) cells and colon
cancer cells.[] In conclusion, recent studies on orexin sign-
aling provides a wide range of possibilities in the treatment of
certain cancers; however, we are still at an early stage in this
novel field and much future work is required.
3.5. Other Neuropeptides
Multiple other neuropeptides, including bombesin-like pep-
tides, gastrin, cholecystokinin (CCK), arginine vasopressin
(AVP), somatostatin (SST), vasoactive intestinal polypeptide
(VIP), and others have also been implicated in cancer growth
and metastasis.[] For unclear reasons, several of them failed
to attract further research interest beyond initial reports, as the
goal of neuropeptide research shifted from basic to clinical.
SST and VIP are two with potentially significant therapeutic
opportunities.
SST, also known as SRIF, is a family of cyclic peptides
mainly produced by normal endocrine, immune, and neuronal
cells, and by certain tumors.[,] SSTs have broad inhibitory
eects on both endocrine and exocrine secretion. SST recep-
tors (SSTR) are widely distributed in healthy tissues and are
involved in various processes, such as inhibiting hormone
secretion, reducing cell proliferation, and promoting apoptosis,
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which implies a potential inhibitory role for these peptides in
cancer growth. Indeed, preclinical studies showed that SST–
SSTR interactions have tumor-suppressor activity in certain
cancers.[] Direct antitumoral activity is mediated through
receptors on tumor cells. SSTRs are connected with G proteins,
and through them somatostatin inhibits adenyl cyclase (Gi),
activates potassium/calcium channels, stimulates protein phos-
phatases, and intracellular tyrosine phosphatase. In addition,
somatostatin has an indirect antiproliferative eect on tumors
by the inhibition of growth factors and angiogenesis.[,]
Vasoactive intestinal peptide (VIP) is a neuropeptide con-
sisting of amino acids, which is widely produced in both the
central and peripheral nervous system, as well as in endocrine
and immune cells.[] Besides its canonical neurotransmitter
and neurotrophic eects, VIP also acts as neuroprotective factor
in the CNS via a cAMP-dependent direct pathway, or indi-
rectly via the actions of astrocytes/Treg cells.[] Three types of
VIP receptors (VIPRs) (i.e., VPAC, VPAC, and PAC) have
been identified, all of which belong to the Class B G protein-
coupled receptors. VIPRs are ubiquitously expressed in human
malignancies, where VIP/VIPRs function in an autocrine
fashion where the tumor both possesses VIPRs and secretes
VIP. VPAC is specifically overexpressed in most epithelial
malignancies, including colon, breast, lung, prostate cancers,
as well as in brain tumors like gliomas, while VPAC recep-
tors are only found in some leiomyomas and gastrointestinal
stromal tumors.[,] However, their eects on cancer growth
are bidirectional. In some tumors, activation of these receptors
has growth and invasion stimulatory eects through activation
of NF-kB signaling, increasing expression of cyclin D, MMPs,
VEGF, and decreasing cell adhesion.[,] Their growth inhibi-
tory eects were also reported in glioma cells,[] renal cancer
cells,[] retinoblastoma,[] and human small-cell lung cancer
in vitro and in vivo.[,] These opposing eects are caused by
dierent receptor subtypes coupling to dierent signaling path-
ways,[,,] specific in vitro cell culture settings with calorie
restriction,[] or via unknown mechanisms.[]
Table 2 summarizes the roles of the above-mentioned neuro-
peptides and receptors in cancer, as well as their mechanisms
of action and related signaling networks. The following sections
discuss potential regulatory mechanisms of neuropeptide/
receptor systems, especially their epigenetic regulation using
SST and VIP as examples, as well as their possible therapeutic
applications in cancer.
4. Neuropeptides in Cancer-Associated Behavioral
Problems
Acting as endocrine hormones, neuromodulators, or neuro-
transmitters, neuropeptides regulate a wide variety of physi-
ological processes and behaviors in neurons and non-neuronal
tissues, such as growth, learning and memory, food intake, tem-
perature management, and autonomic responses.[] Therefore,
Table 2. Functions, action modes, and signaling pathways of neuropeptides and their receptors in cancer.
Neuropeptide/
receptor(s)
Cancer types Functions in cancer Action modes in cancer Signaling pathways Ref.
Neuropeptide Y NPY/
Y1R, Y2R
Breast, ovarian, prostate
cancers, pituitary tumor,
adrenocortical lesions,
pheocromocytoma,
neuroblastoma,
gastroenteropancreatic tumors
Cell proliferation, mitogenesis,
matrix invasion, migration,
angiogenesis
Promotion/Suppression of
cancer growth through
autocrine and paracrine
mechanisms
MAPK/ERK, PI3K/Akt [115, 122, 124,
128, 134, 136]
Substance P SP/NK1R Breast, ovarian, pancreas, thyroid,
prostate, lung, oral, head, and
neck cancers, glioma/
astrocytoma, melanoma,
leukemia, retinoblastoma,
larynx carcinoma
Cell proliferation, antiapoptosis,
migration (invasion, infiltration
and metastasis), chronic
inflammation, neoangiogenesis
Promotion of cancer
development through
autocrine, paracrine, endocrine
pathways, or peripheral
nervous system
Wnt/β-catenin, MAPK/
ERK, PI3K/Akt, mTOR
[105, 108, 140,
144]
Neurotensin NTS/
NTR1, NTR3
Pancreatic, colon, prostate, lung,
liver, breast cancers, pituitary
adenoma, glioma, head, and
neck tumors
Cell proliferation, survival,
EMT, migration, invasion,
neoangiogenesis
Stimulation of cancer growth
via endocrine, autocrine, and
paracrine pathways
MAPK/ERK, PI3K/Akt,
FAK/Src, Ca2+
mobilization, JAK/STAT3
[174, 192, 227,
228]
Orexin/Hypocretin
OX/OX1R, OX2R
Colon, pancreas, prostate, gastric
cancers, neuroblastoma
Induction of apoptosis and
inflammation, increased
cell proliferation
Inhibition/Promotion of cancer
growth via paracrine pathway
cAMP, JNK, p38/MAPK,
ERK1/2 ITIM/SHP2
[209, 229–231]
Somatostatin SST/
SST1R-5R
Breast, colon, prostate,
gastrointestinal, small cell lung
cancers
Inhibition of hormone
secretion and cell proliferation,
cell-cycle arrest, induction of
apoptosis, tumor-imaging
Inhibition of cancer growth via
autocrine, paracrine, endocrine
and exocrine pathways
MAPK/ERK, PI3K/Akt [215, 232–234]
Vasoactive Intestinal
Polypeptide VIP/
VPAC1R, VPAC2R
Breast, lung, prostate, pancreas
cancers, glioma, astrocytoma
Activation (common)/
inhibition (less common) of
tumor growth, angiogenesis,
tumor-imaging
Stimulation/Inhibition of
cancer growth via endocrine,
autocrine, and paracrine
pathways
cAMP/PKA/ERK, PI3K/
Akt, PLC/Ca2+,CREB,
NF-κB,
[221, 235, 236]
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it is critical that we understand how neuropeptides can integrate
the functions of the brain and the systems of the body. Major
advances in the last years have identified the importance of
neuropeptides such as those released by hypothalamic neurons.
The hypothalamus is a phylogenetically conserved and impor-
tant brain regions responsible for many basic behavioral and
physiological functions including feeding and digestion, fluid
and electrolyte balance, energy metabolism, metabolic control,
reproduction, thermoregulation, and sleep-wake cycles.[,]
As such, the hypothalamus is a critical component of the neu-
roendocrine system in which hypothalamic neurons control
the secretion of hormones in the anterior pituitary gland and
consequently in its target endocrine organs in the periphery.
Peripheral endocrine secretions, in turn, influence neuronal
function in the central nervous system in a predominantly neg-
ative feedback loop. This principle is important because most
hypothalamic and pituitary hormones are neuropeptides, high-
lighting how neuropeptides can integrate the functions of the
brain and the systems of the body.
In addition to normal neuroendocrine secretion, neuropep-
tides can also be produced by tumor cells and this may result
in direct and indirect cancer-associated disorders beyond their
actions within the TME (see Figure4). A brief understanding of
how the brain and body are integrated via the neuroendocrine
system and how tumor-derived neuropeptides are relevant to
this discussion can be achieved through examining the eects
of the pituitary peptide adrenocorticotropic hormone (ACTH).
As part of the hypothalamic-pituitary-adrenal (HPA) axis, ACTH
acts downstream corticotropin-releasing hormone (CRH) on the
adrenal cortex to control the subsequent release of glucocorti-
coids (e.g., cortisol, corticosterone). Glucocorticoid release in
turn exerts a multitude of eects on host physiology (e.g., immu-
nosuppression, integrated stress responses, hyperglycemia) but
importantly, also results in feedback inhibition on the hypothal-
amus and pituitary gland to regulate the magnitude and dura-
tion of glucocorticoid release. Although cortisol is essential to
life, chronically high concentrations of cortisol can damage the
various tissues throughout the body. Common manifestations
include diabetes, hypertension, sudden mood changes, muscle
weakness, and irregular menstrual cycles. The main causes of
Cushing’s syndrome (i.e., chronically elevated cortisol levels)
are ACTH-dependent (when the body makes too much ACTH,
which in turn increases cortisol production), ACTH-independent
(when the adrenal is making too much cortisol and ACTH is
therefore low), and iatrogenic (when the patient is taking long-
term administration of corticosteroid drugs) in nature. Pituitary
adenomas are the most prevalent type of ACTH-dependent dis-
ease, accounting for over % of all occurrences. In this condi-
tion, a small tumor causes increased ACTH production. Ectopic
ACTH-producing tumors comprise the other type of ACTH-
dependent disease. In this rare condition, tumors outside of the
pituitary are generating too much ACTH, most commonly in the
Figure 4. Indirect and direct eects of TME-derived neuropeptides on cognition relevant to cancer. A) Physiological and psychological stress induced
by the presence of a peripheral tumor results in the engagement of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent ACTH release by
the anterior pituitary gland. In addition, ectopic ACTH expression by cancer cells may contribute to increased systemic ACTH levels and subsequent
elevations in systemic cortisol. The consequences include a deregulated negative feedback loop on the HPA axis and subsequent cognitive impairment
attributed mainly to elevated cortisol. These changes can also result in indirect eects on functional capacity, organ function, and mobility. B) Tumor-
derived substance P is secreted by cancer cells in the TME where it enters systemic circulation and eventually the brain parenchyma where it binds its
receptors (e.g., NK-1) which are abundant in the limbic system. Activation of these receptors in the limbic system engages neuronal circuits that result
in behavioral changes including depression, stress, and anxiety. These changes in behavioral states result in enhanced production of substance P by the
limbic system which enter systemic circulation via circumventricular organs and influence the TME in a way that putatively favors tumor progression
(i.e., tumor cell proliferation, angiogenesis, metastasis).
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lung and thymus gland, but have also been found in the thyroid,
ovary, adrenal gland, and liver. In the ACTH-independent cases,
either both adrenal glands are hyperactive or there is an adrenal
tumor that is making too much cortisol (about %). Although
most of these tumors are benign, they can rarely progress into
adrenal cancers.
However, ACTH also influences complex behavioral pro-
cesses including learning and memory,[–] highlighting
the ability of neuropeptides to travel long-distances within the
CNS where they have direct eects on neurons that are inte-
grated within distinct neuronal circuits. Interestingly, a study
by Heesen et al. demonstrates that hyperactivation of the HPA
axis is related to increased cognitive impairment in multiple
sclerosis.[] Given that cancer patients experience excess levels
of stress, it is conceivable that a similar alteration in the HPA
axis is present in cancer patients. Classic work on frog sympa-
thetic ganglia also demonstrates this ability of neuropeptides
to act on cells micrometers away from their release site–which
may or may not be released at the synaptic site (i.e., they are
ectopically expressed).[] Additionally, ACTH is produced by
other brain regions and peripheral tissues (e.g., gastrointestinal
tract, lymphocytes), where if present in abundant concentra-
tions, can travel to the brain parenchyma and engage in “short-
loop” negative feedback on the hypothalamus with downstream
consequences on systemic physiology and behavior.[,–]
As alluded to previously, neuropeptides influence cognitive
function due to their actions in cortical and subcortical brain
regions.[] Furthering our discussion using the neuropep-
tide ACTH as an example, several seminal papers have dem-
onstrated the role of ACTH in adaptive behavior in preclinical
models.[–] Many of these behavioral deficits induced by
removal of the anterior pituitary gland can be corrected by
administration of ACTH, highlighting its dramatic eects on
cognitive function. Similarly, administration of CRH directly
into the ventricular system in the brain also results in behav-
ioral activation including anxiety and stress responses due to
elevated plasma norepinephrine (NE) and epinephrine.[–]
This demonstrates that neuropeptide eects in the CNS can
extend to the periphery aecting a myriad of physiological out-
puts (e.g., functional capacity, organ function, mobility). Impor-
tantly, the eects of neuropeptides on distinct neuronal circuits
within the CNS is largely due to the ability of neuropeptides
to diuse long distances within the extracellular compartment
and cerebrospinal fluid.[]
Aside from tumor-released neuropeptides, the TME is another
significant source of neuropeptide synthesis. Similarly, it is con-
ceivable that TME-derived neuropeptides (e.g., NPY, SP) have
this same capacity to exert eects on neuronal circuitry directly
or indirectly through altering the actions of other host factors.
Interestingly, SP itself, whose expression is increased in breast
cancer cells, has been shown to directly result in blood brain bar-
rier (BBB) impairment.[] The disruption in the BBB is mainly
achieved through SP-mediated changes in the tight junction pro-
teins ZO- and claudin- in brain microvascular endothelial cells.
The ability of neuropeptides to infiltrate the brain parenchyma
where they exert eects on neuronal circuitry is largely attributed
to the ability of neuropeptides to bypass the BBB via circum-
ventricular organs-regions of the brain that are characterized by
the lack of a BBB and therefore allow for direct communication
between the brain and circulatory system.[] Additionally, these
circumventricular organs (e.g., median eminence) permit hypo-
thalamic neuropeptides to leave the brain without disrupting
the BBB where they can influence systemic physiology.[] In
addition, the presence of peripheral tumors has been shown to
disrupt the integrity of the BBB during cancer progression, pre-
senting an additional route by which TME-derived neuropeptides
can exert eects on neuronal circuitry.[,]
Additionally, SP is also highly relevant to the discussion of
cancer-induced neurological dysfunction (e.g., depression,
stress, anxiety). It is widely recognized that cancer and depres-
sion frequently accompany one another, and depressive symp-
toms can be exacerbated by disease severity and other cancer
associated symptoms (e.g., pain, fatigue). The limbic system
is a brain structure that includes the hypothalamus, amygdala,
and hippocampus. As a result, the limbic system is involved
in the processing of emotion, memory and behavior through
the coordinated activity of interconnected cortical and subcor-
tical brain structures. SP and its receptor NK- are expressed in
the limbic system and their involvement has been implicated
in neurological disorders including depression, stress, and
anxiety.[–] Interestingly, the NK- receptors expressed in the
limbic system are similar to the NK- receptors overexpressed
in human cancer cells and patient tissue samples.[] As men-
tioned previously, SP is also highly expressed in several tumors
including breast. Within the TME, SP is released by nerves and
can enter the systemic circulation to influence systemic physi-
ology including CNS function. SP can enter the brain paren-
chyma, via the aforementioned routes, where it exerts its eects
on neuronal circuits and influences subsequent behavior rel-
evant to cancer (i.e., depression, anxiety, stress) see Figure .
Additionally, the onset of depression can increase the produc-
tion of substance P from the limbic system, where it can enter
systemic circulation, via circumventricular organs, and influ-
ence the TME with consequences such as increased tumor
progression.[,] Thus, TME-derived neuropeptides (e.g., SP)
may have the capacity to increase tumor progression locally and
influence neuronal function distally in the CNS with eects on
cognition and behavior relevant to cancer.
5. Regulation and Therapeutic Applications of
Neuropeptide/Receptor Systems in Cancer
5.1. Regulation of Neuropeptide/Receptor Systems
Although a few neuropeptide receptors are intrinsically
expressed in both healthy and neoplastic cells for physiological
uses, it is more common that they are only present in malig-
nant tissues under inflammation or after exogenous neuro-
peptide treatment. In some cases, neuropeptide receptors shift
their expression from one subtype to the other. For example,
Swift et al. observed that when prostate cancer cell lines become
more aggressive and less dierentiated, elevated NTR expres-
sion shifts toward NTR.[] The appearance of neuropeptide
receptors indicates the stemness and programmed dierentia-
tion abilities of these cells.
External control of receptor function arises from the addition
of agonists or antagonists similar to endogenous ligands. A broad
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range of neuropeptide mimics and inhibitors have been devel-
oped, with a few already approved and therapeutically accessible
on the market, e.g., the NTS/NTSR antagonist SR; the
SP/NKR antagonist aprepitant. SR (meclinertant) was the
first nonpeptide selective antagonist developed for NTSR. It is
used in scientific research to investigate the interaction between
NTS and other neurotransmitters in the brain, and exhibits anxi-
olytic, antiaddictive, and memory-impairing eects in animal
studies. Aprepitant (Emend, Merck) is the first agent available in
the new drug class of NKR antagonists, clinically used to treat
chemotherapy-induced nausea and vomiting.
Neuropeptide receptor expression is regulated by signal
transduction pathways like the Wnt/β-catenin signaling
pathway, which governs downstream cascades regulating tran-
scriptional control of proliferation and dierentiation. Upon
Wnt signaling, nuclear translocalization of β-catenin activates
the NTSR promoter by creating a complex with transcription
factor Tcf.[] This provides a direct link between develop-
mental and oncogenic processes and neuropeptide function.
Epigenetic modifications are further critical in regulating gene
expression and controlling cancer progression.[] Epigenetic
changes are heritable throughout cell divisions, but they are
reversible since the DNA sequence is not changed. DNA meth-
ylation, histone modifications, and microRNA expression are
common types of epigenetic regulatory mechanisms, resulting in
inaccessible DNA or nascent transcript degradation preventing
the production of mature proteins. A decade ago, DNA meth-
ylation was found in the promoter region of neurotensin gene,
which induces severe reduction of transcription and expres-
sion in the human liver cancer cell line Hep G.[] Expression
of the somatostatin receptor (SSTR) was also downregulated in
neuroendocrine tumors[] and gastric cancer cells[] due to
promoter methylation. The other example is from the pituitary
adenylate cyclase activating polypeptide (PACAP), which belongs
to the VIP/PACAP/secretin family and shares % homology
with VIP. In cervical cancer, PACAP is considered as a methyla-
tion biomarker for early cancer detection.[] In addition to DNA
methylation, histone acetylation is also involved in regulating
SSTR.[] Furthermore, microRNAs can mediate the expression
of some neuropeptide receptors in certain disease models. Jo et al.
demonstrated that SSTR expression was upregulated by
miRNA (miR--p) transfection, and this miRNA enhanced the
SST analog (octreotide)-induced reduction in cell proliferation
in both D/D cultures of neuroendocrine cells.[] In cell-based
models of the chronic bladder pain syndrome, long-term sub-
stance P treatment reduced NKR mRNA levels while increasing
regulatory miR-b and miR-.[] These studies indicate
potential uses of epigenetic drugs (like HATs/HDACs)[]
to modulate the expression of certain neuropeptide receptors and
their therapeutic opportunities.
5.2. Targeting Neuropeptide Receptors for Cancer
Molecular Therapy
Targeted therapies generally take advantage of biological mole-
cules that are uniquely expressed or significantly overexpressed
in tumors. A plausible approach is to target neuropeptides,
growth factors, and the signaling pathways that mediate their
mitogenic eects with antibodies, antagonists, and/or selective
inhibitors. Regarding neuropeptide receptors, the presence of a
distinct cell surface receptor in cancer cells verses their normal
counterparts is a molecular hallmark in targeted therapy. So
far, several of them have been widely used for diagnosis and
therapy, including SST receptors, HER, integrin receptors,
EGFR, and VIP receptors.[] The basic principle is to use neu-
ropeptide analogs targeting certain receptors, improving tumor
visualization or blocking proliferative signaling. We discuss
three types of cancer-specific molecular therapies using neuro-
peptide agonists/antagonists, cytotoxic peptide conjugates, and
radiolabeled ligand conjugates below.
. Agonists/Antagonist-based cancer therapy. Although tumor-in-
hibitory neuropeptides (such as SST and OX) have distinct in-
hibitory eects on tumors, their therapeutic potential is limited
due to their relatively short plasma half-life. Thus, metabolically
stable compounds with native ligand-like properties are ex-
pected to show an improved clinical profile. Metabolic stability
can be accomplished by either shrinking the size to eliminate
catalytic sites, generating cyclic structures, or incorporating
modifications (e.g., D-amino acids or N-methylated amino ac-
ids). A wide variety of agonists/antagonists targeting neuropep-
tide receptors are reviewed recently,[] including NPYR,[,]
NKR,[] SSTR,[,] and VIPR.[]
. Cytotoxic peptide conjugate-based cancer therapy. Conven-
tional tumor chemotherapy is restricted by multidrug resist-
ance, toxicity to normal cells, and a lack of tumor selectivity.
More targeted delivery of chemotherapeutic drugs to cancer
cells can result in higher drug concentrations in tumors, while
lowering toxicity to normal cells. Owing to the high-anity
of peptides and high-expression of receptors on tumor cell
surfaces, tumors can be targeted by cytotoxic neuropeptide
conjugates. VIP-ellipticine conjugates, for example, act as
VPAC receptor agonists, binding to VPAC receptors with
high anity while retaining antiproliferative eect. In one
study, they were absorbed by cancer cells expressing the
VPAC receptor and then catalyzed by proteolytic enzymes,
resulting in ellipticine release and cellular cytotoxicity.[]
. Peptide-receptor radionuclide therapy (PRRT). Radiolabeled-
neuropeptides (e.g., SST and VIP) or analogs are used in
tumor imaging. PRRT is based on the presence of high lev-
els of receptors in tumors and their ability to form ligand–
receptor complexes, allowing radiopharmaceuticals to be
internalized and accumulate inside tumors. Notably, there
are many studies on SSTR-based radiotherapy,[] whereas
reports on VIPR-based radiotherapy for human tumors are
lacking due to inadequate specificity.[,]
In conclusion, these cancer molecular therapy approaches
suggest that neuropeptide receptor-based imaging and treat-
ment will be crucial for early cancer detection and control.
6. Current Research Strategies and
Future Directions
Notable strategies in neuropeptide research can be summa-
rized into three major areas based on structure, location, and
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function[] (see Figure 5). ) Mass spectrometry (MS) and
MALDI-TOF are usually used to determine peptide sequence,
posttranslational modifications, and structural information.
Spectroscopy and nuclear magnetic resonance (NMR) give
information on protein conformations and folding patterns.
X-ray crystallography characterizes structural details with high
spatial resolution. ) Regarding peptide location, antibody-
based assays (e.g., radioimmunoassays, immunohistochem-
istry, immunocytochemistry) and immunoelectron microscopy
are commonly used approaches enabling peptide visualization.
Additionally, in situ hybridization is used for target-specific
expression mapping of neuropeptide coding genes, while
promoter-reporter gene constructs enable transcript detection
in living cells and organisms. Moreover, mass spectrometry
imaging[] is capable of capturing the entire neuropeptidome
without prior knowledge. Bio imaging and microscopy map the
architecture of the nervous system. ) Behavioral studies can
first obtain a general understanding of functions as a judging
potential for disease treatment. Electrophysiology approaches
provide understanding of synaptic mechanisms, followed by
quantitative analyses (e.g., qPCR, western blotting, ELISA,
MS) to imply functions by measuring changes in neuropeptide
levels due to specific behaviors or conditions. Furthermore,
Yulong Li’s group has made significant progress in developing
a number of genetically encoded fluorescent indicators, empha-
sizing how these novel biosensors can be used in uncovering
functional roles of neurotransmitters and neuromodulators in
the nervous system and potentially peripheral malignancies.[]
Neuropeptide/receptor systems are a complicated landscape
that may be brought into better resolution by the combined
eorts of chemists and biologists, as well as a revitalized drive
for drug development. For in vitro screening of potential ago-
nists and antagonists, a combination of recombinant expres-
sion and synthetic biology approaches can be employed for
high-throughput and large-scale synthesis of neuropeptide
analog libraries. Due to the low abundance of neuropeptides
in vivo and their high proteolytic degradation vulnerability,
multiple neuropeptides have been expressed at high levels in
E. coli, e.g., an NPY precursor[] and NTS.[] Additionally,
large-scale peptide production usually relies on solid phase
synthesis, by which diversities of ligands are restricted or time/
cost-consuming to achieve. In such cases, cell-free expression
can be an alternative way to achieve peptide synthesis in large-
scale, high-throughput, and flexible reconstitutions. Compared
to neuropeptides themselves, stable production of their recep-
tors with complete biological functionalities is even more chal-
lenging. As discussed, most neuropeptide receptors are integral
transmembrane GPCRs. GPCRs are one of the most pharma-
cologically successful drug targets, with about % of all com-
mercial drugs and % of newly approved drugs on the market
targeting GPCRs.[] However, their preparation remains dif-
ficult in vitro or in vivo. Many of them are also missing crys-
tallography structure information, which hinders study of the
interactions between peptides and their receptors. Notably, with
the broad application of CRISPR/Cas systems in gene knock-
in/out or creation of transgenic animals, genome-scale CRISPR
interference screening has identified novel determinants of
GPCR-mediated transcriptional signaling. Last year, the launch
of the AlphaFold Protein Structure Database delivered a major
breakthrough in protein structure prediction, which paves a
powerful and rapid supplementary way toward understanding
structure/function relationships other than the traditional
labor-intensive crystallization. Upon noncanonical amino acid
incorporation and click-chemistry conjugation, unbiased nas-
cent peptide labeling became possible both in cell culture and
in animal models, by which newly synthesized peptides can be
visualized through clicking on a fluorophore probe (FUNCAT)
or be pulled down from the endogenous protein pool for fur-
ther analysis though clicking on an anity tag (BONCAT).[]
Targeting the neuropeptide/receptor axis may become a more
widely accepted therapeutic strategy for cancer diagnosis and
therapy in the near future. Monitoring biomarkers for major
tumoral alterations associated with the neuropeptide-receptor
signaling network has great potential and deserves more
investigation.
7. Conclusions
The study of neuropeptides in cancer research is developing
rapidly. Multiple neuropeptides and their receptors are found in
a variety type of cancers, usually exhibiting dierential expres-
sion patterns between malignant and normal cells during
tumor progression. Dierent neuropeptides exert distinct
actions on cancer cells either directly or indirectly through the
tumor microenvironment. These actions are due to receptor
coupling with dierent downstream signaling cascades. Neuro-
peptides may also act in an endocrine fashion to regulate distal
processes in the central nervous system and thereby aect
behaviors. Currently, cancer research on peptides is domi-
nated by two active fields: the first is the search for novel pep-
tide receptors overexpressed in certain cancers; the second is
the discovery of new peptide analogs targeting corresponding
receptors for eective cancer visualization and treatment.
Despite our improved understanding of the mechanisms that
influence neuropeptides and their receptor functions, as well
Figure 5. Typical approaches used in neuropeptide research for deter-
mining structure, localization, and function.
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as our ability to manipulate their expression in cancer cells,
numerous questions remain unanswered. These include: what
causes the disparity across cancer types, as well as the dis-
crepancies between in vitro and in vivo data? Is neuropeptide
receptor subtype and expression levels comparable in primary
tumors and metastases? Can we take advantage of multiple con-
comitant receptor expression in tumors for the use of a thera-
peutic drug cocktail? It is notable that technological advances in
neuropeptide structural elucidation, localization mapping, and
functional understanding have greatly benefited neuropeptide
research, yet no single approach can oer us all the answers we
seek. The combination of various bioanalytical, bioinformatics,
and molecular neuropharmacological tools will drive neuropep-
tide research to new frontiers with likely benefits toward cancer
elimination.
Acknowledgements
This work was supported by a BBRF NARSAD Young Investigator Grant
(No. 28291), an AACR Grant for Transformative Cancer Research (No.
20-20-26-BORN), and a Pershing Square Foundation Innovation Fund
Award to JCB.
Conflict of Interest
The authors declare no conflict of interest.
Keywords
behavior, cancer, neuropeptide, receptor, signaling pathway
Received: April 16, 2022
Revised: May 31, 2022
Published online:
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Y. Wu received her Master’s degree in Pharmaceutical Chemistry from Sun yat-sen University,
China and completed her Ph.D. degree in Synthetic Biology from the University of Queensland,
Australia in 2020. She is currently a postdoctoral fellow at Cold Spring Harbor Laboratory, USA.
Her research interests include exploring interactions between the peripheral nervous system
and cancer, metabolic labeling, detection, and identification of nascent proteome changes in the
nervous system during cancer progression.
A. Berisha was born in Long Island, New York, and is an identical twin and aspiring physician.
Adrian graduated from Stony Brook University with a B.S. in Biology with Honors. He participated
in undergraduate research at the Division of Nephrology and Hypertension at Renaissance School
of Medicine. Adrian is currently employed as a Research Technician in Jeremy Borniger’s lab at
Cold Spring Harbor Laboratory. His primary focus is to investigate the contribution of brainstem
nuclei and the sympathetic nervous system in promoting tumor progression in preclinical models
and identify the neural pathways innervating peripheral tumors.
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