Molecular and neuroendocrine mechanisms of cancer cachexia

Abstract

Cancer and its morbidities, such as cancer cachexia, constitute a major public health problem. Although cancer cachexia has afflicted humanity for centuries, its underlying multifactorial and complex physiopathology mitigates the understanding of its mechanistic aspects. During the last decades we have witnessed a dramatic increase in the knowledge of cancer cachexia pathophysiology. Anorexia, muscle and adipose tissue wasting are the main features of cancer cachexia. These, apparently, independent symptoms have humoral factors secreted by the tumor as a common cause. Importantly, the hypothalamus has emerged as an organ that senses the peripheral signals emanated from the tumoral environment, and not only elicits anorexia but also contributes to the development of muscle and adipose tissue loss. Herein, we review the roles of factors secreted by the tumor and its effects on the hypothalamus, muscle and adipose tissue, as well as underscore key targets that are being exploited for cancer cachexia treatment.

Full text

Molecular and neuroendocrine
mechanisms of cancer cachexia
Maria Carolina S Mendes, Gustavo D Pimentel, Felipe O Costa and Jose
´
B C Carvalheira
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP),
MA: 13083-970 Campinas, Sao Paulo, Brazil
Correspondence
should be addressed
to J B C Carvalheira
Email
carvalheirajbc@uol.com.br
Abstract
Cancer and its morbidities, such as cancer cachexia, constitute a major public health problem.
Although cancer cachexia has afflicted humanity for centuries, its underlying multifactorial
and complex physiopathology has hindered the understanding of its mechanism. During the
last few decades we have witnessed a dramatic increase in the understanding of cancer
cachexia pathophysiology. Anorexia and muscle and adipose tissue wasting are the main
features of cancer cachexia. These apparently independent symptoms have humoral factors
secreted by the tumor as a common cause. Importantly, the hypothalamus has emerged as an
organ that senses the peripheral signals emanating from the tumoral environment, and not
only elicits anorexia but also contributes to the development of muscle and adipose tissue
loss. Herein, we review the roles of factors secreted by the tumor and its effects on the
hypothalamus, muscle and adipose tissue, as well as highlighting the key targets that are
being exploited for cancer cachexia treatment.
Key Words
" hypothalamus
" cancer
" muscle
" neuropeptides
" neuroendocrinology
Journal of Endocrinology
(2015) 226 , R29–R43
Introduction
The earliest report of significant weight loss dates back
to Hippocrates’ School of Medicine (about 460–377 BC).
Since that era, this syndrome has been recognized as a
condition associated with poor prognosis, justifying the
name cachexia, from the Greek kakos (i.e., bad) and hexis
(i.e., condition or appearance), or ‘bad condition’. It is
associated with many chronic or end-stage diseases such as
cancer, cardiac, respiratory, renal or hepatic failure and
infectious diseases, as well as aging (Doehner & Anker
2002). During human history, weight loss has always
been recognized as a marker in the perception of
control and damage in relation to health and disease.
Notably, a fit appearance is associated with willpower and
self-discipline, whilst the perception of potential harm
and loss of control is related to changing body states, such
as the development of obesity and especially cachexia
(Chamberlain 2004).
Patients’ and their families’ perception of muscle
wasting makes the disease visible and represents an
indication that death is closer (Hopkinson et al. 2006).
As cachexia goes on, wasting of skeletal muscle tissue
diminishes mobility and lethargy impairs concentration,
leading patients towards isolation and depression (Wata-
nabe & Bruera 1996, Stewart et al. 2006). Importantly,
cachexia not only affects the patient, but also their families,
caregivers, and healthcare professionals, who often experi-
ence emotions of fright and hopelessness as they try to
palliate symptoms by feeding the patients (Reid et al. 2009).
The emotional distress experienced by healthcare pro-
fessionals and nihilism regarding the effectiveness of
cachexia treatment frequently block conversation about
weight loss, which makes even the discussion of cachexia a
taboo (Booth et al. 1996, Parle et al. 1997, Churm et al.
2009). In this review, we will highlight the mechanistic
Journal of Endocrinology
Review
M C S MENDES and others Mechanisms of cancer cachexia
226:3 R29–R43
http://joe.endocrinology-journals.org Ñ 2015 Society for Endocrinology
DOI: 10.1530/JOE-15-0170 Printed in Great Britain
Published by Bioscientifica Ltd.

foundation of cancer cachexia, the knowledge of which
has started to change the current nihilistic therapeutic
approach to this devastating condition.
Cancer cachexia
Cancer cachexia is defined as a multifactorial syndrome,
characterized by anorexia as well as diminished body
weight, loss of skeletal muscle, and atrophy of adipose
tissue (Fearon et al. 2011). Specifically, weight loss of
more than 5% in previously healthy individuals or more
than 2% in subjects with depletion of current body
weight (BMI less than 20 kg/m
2
) or in individuals with
reduced appendicular muscle index (males less than
7.26 kg/m
2
and females less than 5.45 kg/m
2
) constitute
the diagnosis of cancer cachexia (Fearon et al. 2011).
Recently, it has been recognized that weight loss alone is
insufficient to express the complexity of cachexia, and two
other clinical characteristics have been incorporated into
its definition: It cannot be fully reversed by conventional
nutritional support and it leads to functional impairment
(Muscaritoli et al. 2010, Fearon et al. 2011). Its incidence
varies according to tumor type, from 31% in patients with
good-risk non-Hodgkin’s lymphoma to 87% in those
with gastric cancer in some series (Dewys et al. 1980,
Teunissen et al. 2007). Importantly, since cachexia is
accompanied by the incapacity for improvement of
nutritional status through supplements, it leads to frailty
and ultimately accounts for approximately 20% of cancer
deaths (Dewys et al. 1980, Ross et al. 2004, Bachmann et al.
2008, Fearon et al. 2011, 2013). The cachexia-mediated
increased mortality is probably due to lower response to
chemotherapy and worse toxicity in anti-cancer
treatment, besides higher susceptibility to infections and
other clinical complications (Costa & Donaldson 1979,
Andreyev et al.1998, Nitenberg & Raynard 2000,
Arrieta et al. 2010).
It is well known that anorexia alone is not able to
cause cachexia. This is one of the main characteristics
that distinguishes cachexia from starvation. In the
former, both adipose tissue and skeletal muscle mass are
depleted, while muscle mass is preserved during starvation
(Fearon 2011). It is noteworthy that starvation in
cancer patients, may be associated with upper digestive
obstruction or fistula, particularly in head and neck,
esophageal, gastric and pancreatic cancer patients, or
peritoneal carcinomatosis-induced multi-level abdominal
obstruction (Dechaphunkul et al. 2013). However, the
great majority of advanced-cancer patients, mainly those
with lung, hepatic or bone metastasis and lung, cervical or
head and neck primary cancers, present a hypermetabolic
state that is characteristic of cachexia.
The physiopathology of cancer cachexia remains
unclear. Several cancer-related metabolic pathways induce
weight loss, muscle and adipose tissue wasting, anorexia,
anemia, and asthenia. The apparent causes of these
symptoms are energy imbalance (increased energy expen-
diture rate), negative protein balance (increased proteol-
ysis and decreased protein synthesis), and increased
lipolysis. Mechanistically, several factors such as increased
levels of hormones, cytokines and factors secreted by the
tumor as well as deregulation of control by the hypo-
thalamus of energy expenditure and hunger/satiety
promote cancer cachexia (Fig. 1).
In fact, cancer cachexia is characterized by maladap-
tive maintenance of inflammation. In contrast, acute
activation of the immune system in response to tissue
stress or infection serves as an adaptive response that is
essential to host survival (Ramos et al.2004). These
responses include fever, headache, changes in the sleep–
wake cycle, anorexia, fatigue, and nausea referred to as
‘sickness behavior’ (Hart 1988, Elmquist et al. 1997). The
organismal advantages of these actions are demonstrated
by their wide expression among vertebrates and also
partial expression in some invertebrates (Kluger 1991).
For instance, force-feeding acutely infected animals is
associated with higher mortality, signifying short-term
anorexia as a host defense mechanism in infection and
tissue injury (Murray & Murray 1979). Additionally,
somnolence and fatigue diminish energy expenditure
during periods of caloric intake restriction (Hart 1988,
Saper & Breder 1992, 1994).
Molecular mechanisms of skeletal muscle
wasting
Cachexia-induced muscle atrophy occurs as a result of
both reduced protein synthesis at initiation and elonga-
tion steps and increased protein degradation. Muscle
wasting is the main cause of poor prognosis and low
quality of life. Skeletal muscle protein degradation
is promoted by ubiquitin–proteasome and autophagy–
lysosomal pathways, as well as the calcium-dependent
enzymes (calpains), which can be activated by the
proteolysis-inducing factor (PIF), myostatin, activin A
(ActA), and cytokines (Matzuk et al. 1994, Tisdale 2009,
Zhou et al. 2010, Johns et al. 2013).
PIF, a glycoprotein first isolated from the MAC16
tumor, has been detected in the urine of cancer patients
with cachexia (Todorov et al. 1996, Cariuk et al. 1997).
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Specifically, patients bearing a vast range of cancers, such
as pancreatic, breast, ovary, lung, and colon and rectum,
present increased circulating levels of PIF (Cariuk et al.
1997). Importantly, the isolation of this protein and
subsequent injection into mice induced severe and
prompt body-weight loss (Tisdale 2003). In striking
contrast, it has been reported that PIF is not related to
either survival or muscle wasting in patients with
advanced cancers (Wieland et al. 2007). Mechanistically,
PIF not only promotes protein degradation by increasing
mRNA levels of ubiquitin-carrier protein and proteasome
subunits (Tisdale 2003), but also inhibits protein synthesis
through activation of the RNA-dependent protein kinase
(PKR) (Eley & Tisdale 2007). The latter effect is dependent
on eukaryotic initiation factor 2 alpha-subunit (eIF2a)
phosphorylation, which suppresses protein synthesis by
the eIF2 complex (Eley & Tisdale 2007, Eley et al. 2010).
Interestingly, PKR also induces muscle protein
degradation by activating the transcription factor nuclear
factor kB(NF-kB). Nuclear accumulation of NF-kB
increases the expression of the muscle-specific ubiquitin
E3 ligases, and RING-finger protein 1 (MuRF1) as well as
some proteasome subunits upregulating the ubiquitin–
proteasome proteolytic mechanism and therefore
promoting skeletal muscle breakdown (Bodine et al.
2001, Argile
´
s et al. 2014). PIF also induces transitory
formation of reactive oxygen species (ROS) through
activation of NADPH oxidase by protein kinase C
(Fan et al. 1990, Smith et al. 2004). Since ROS induce
NF-kB nuclear translocation (Schreck et al. 1991), this
pathway also contributes to increasing the expression of
MuRF1 in skeletal muscle (Li et al. 2003, Cai et al. 2004,
Yu et al. 2008).
Myostatin and activins are members of the transform-
ing growth factor B family, which promote muscle wasting
in certain models of cachexia, including cancer cachexia
(Carlson et al. 1999, Ma et al. 2003, Zhou et al
. 2010, Chen
et al. 2014). Transgenic mice that lack myostatin, as well as
cattle with mutations that reduce the expression of
myostatin, show an increased muscle mass phenotype
(McPherron & Lee 1997, McPherron et al. 1997), whilst
recombinant viral overexpression of activins results in
muscle wasting and fibrosis (Chen et al . 2014). Myostatin
and activins share the same receptor, activin type 2
Figure 1
Tumor-secreted factors promote central- and peripheral-mediated cancer
cachexia. Tumor growth results in the secretion of pro-inflammatory
factors that promote cachexia by signaling anorexia, muscle wasting, and
white adipose tissue (WAT) atrophy. In par ticular, treatment with ghrelin
and parathyroid hormone-related protein (PTHrP) alleviates anorexia in
the hypothalamus. Tumors also secrete both the proteolysis-inducing factor
(PIF) and activin, whi ch leads to skeletal muscle degradation and
sarcopenia. Tumor-secreted zinc-alpha2-glycoprotein (ZAG) induces
lipid oxidation and WAT loss. IFN, interferon; IL, interleukin;
TNF, tumor necrosis factor.
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receptor B (ActR2B), whose antagonism potently reverses
cancer-induced cachexia (Xia & Schneyer 2009, Zhou et al.
2010). Interestingly, circulating serum levels of ActA,
which has been demonstrated to be secreted by cancer
cells, are elevated in cancer cachectic patients (Zhou et al.
2010, Loumaye et al. 2015). Mechanistically, myostatin
and activins trigger skeletal muscle protein breakdown
by upregulating MuRF1 and MAFbx/Atrogin1, as well as
decreasing protein synthesis via inhibition of the Akt/
mTOR pathway (Chen et al. 2014, Gallot et al. 2014).
Activation of this pathway inhibits the activity of the
transcriptional factor Forkhead box O (FoxO), which
is a major regulator of MuRF1 and MAFbx/Atrogin1
expression. Accordingly, the use of a RNA oligonucleotide
to block FoxO1 or dominant-negative FoxO3 attenuates
loss of skeletal muscle mass in a model of cachexia by
suppressing MAFbx/Atrogin1 transcription (Sandri et al.
2004, 2006).
Increasing evidence indicates that cytokines play a
pivotal role in promoting skeletal muscle atrophy. It is
well established that tumor necrosis factor (TNF) is a key
cytokine that induces skeletal muscle wasting. For
instance, CHO cells that overexpress TNF promote
muscle wasting in mice (Oliff et al. 1987, Acharyya et al.
2004). In contrast, inhibition of TNF with a chimeric TNF
receptor prevented muscle wasting in mice bearing a
TNF-producing tumor (Teng et al. 1993). More recently,
TNF-induced atrophy was demonstrated to be mediated
by the induction of MAFbx/Atrogin1 in muscle by the
attenuation of FoxO activation (Wang et al. 2014) as well
as by increasing MuRF1 (Sishi & Engelbrecht 2011). TNF
also suppresses the PI3K/Akt pathway (Sishi & Engelbrecht
2011). Interestingly, inhibitor of nuclear factor kappa B
kinase subunit beta (IKKb) conditional knockout mice
present hyperphosphorylation of Akt. Conversely, Akt
inhibition leads to muscle atrophy, indicating the
existence of crosstalk between the IKKb/NF-kBand
PI3K/Akt pathways, which control muscle degradation
(Mourkioti et al. 2006). Recently, a new member of the
TNF superfamily has been described, TNF-like weak
inducer of apoptosis (TWEAK), which promotes cachexia
by a mechanism similar to that of TNF, i.e., by activating
NF-kB and promoting augmented expression of MuRF1,
which targets components of the thick filaments (Dogra
et al. 2007, Mittal et al. 2010, Kumar et al. 2012).
Increasing levels of interleukin 6 (IL6) also correlate
with development of cachexia. Accordingly, treatment
with an IL6 receptor antagonist, or MABs to murine IL6,
was able to suppress key cachexia parameters (Strassmann
et al. 1992, Enomoto et al. 2004, Zaki et al. 2004).
However, IL6 alone is not enough to promote cachexia
syndrome (Soda et al. 1994, 1995). Interestingly, increased
IL6 levels are correlated with poor prognosis in patients
with advanced cancer (Suh et al. 2013), and are associated
with increased weight loss, morbidity, and mortality in
patients with lung cancer (Bayliss et al. 2011). Despite the
absence of solid results in cancer cachectic patients,
interferon gamma MAB reversed wasting syndrome in a
cachexia animal model, indicating a role for this cytokine
in cachexia syndrome (Matthys et al. 1991).
Molecular mechanisms of adipose tissue loss
Although the mechanisms behind muscle wasting have
been extensively studied, much less is known about factors
that promote adipose tissue loss in cancer cachectic
patients. The fact that viable cancer cells do not induce
weight loss, particularly adipose tissue wasting, indicates
that tumor-secreted factors could be the cause of fat
atrophy (Costa & Holland 1962). The search for these
factors led to the discovery of a lipid-mobilizing factor,
which was purified from the urine of cachectic individuals
(Masuno et al. 1981, 1984, Taylor et al. 1992, McDevitt
et al. 1995).
Over the last decade, zinc-alpha2-glycoprotein (ZAG)
has been characterized as an adipokine, which induces
lipid mobilization and is upregulated in cancer cachexia
(Bing et al. 2004, 2010, Bao et al. 2005). Mechanistically,
the lipolytic effect of ZAG is mediated by activation of
B3-adrenoceptors (Russell et al. 2002), which, through
AMPc pathway activation in a GTP-dependent manner,
leads to hormone sensitive lipase (HSL) activation and
glycerol release (Hirai et al. 1998). Accordingly, both
genetically-obese (ob/ob) mice and outbred NMRI mice
treated with human ZAG display decreased body weight,
with pronounced carcass fat loss, without change in
body water or nonfat mass, and neither changes in
food nor water intake (Hirai et al. 1998, Russell et al.
2004). Moreover, mice bearing xenografts of a tumor cell
line that overexpress ZAG display dramatic weight loss
(Hale 2002). ZAG also induces lipid utilization, increasing
fat oxidation (Russell & Tisdale 2002, 2010), due to
upregulation of mitochondrial uncoupling protein 1
(UCP1) mRNA in brown adipose tissue (BAT) (Bing et al.
2002, Russell et al . 2004), mediated by ZAG binding and
activation of B3-adrenoreceptor in adipocytes (Russell
et al. 2002).
In addition to tumor-derived ZAG effects, inflam-
matory mediators, such as TNF, modulate white adipose
tissue (WAT) homeostasis. Importantly, TNF inhibits
Journal of Endocrinology
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DOI: 10.1530/JOE-15-0170 Printed in Great Britain
Published by Bioscientifica Ltd.

lipoprotein lipase activity (Price et al. 1986), and increases
HSL mRNA expression (Tisdale 2004, Agustsson et al .
2007). Additionally, TNF has been shown to inhibit
glucose transport, by reducing glucose transporter 4
protein and mRNA levels, decreasing substrates for
lipogenesis (Hauner et al. 1995). TNF-induced lipolysis is
mediated by activation of MAPK kinase, ERK and elevation
of intracellular AMPc by decreasing the expression of
cyclic-nucleotide phosphodiesterase 3B (Zhang et al.
2002). MAPK and JNK activation lead to peroxisome
proliferator-activated receptor gamma (PPARY) phos-
phorylation, inhibiting pre-adipocyte differentiation
(Hu et al. 1996). It has also been observed that TNF
decreases the protein levels of perilipins A and B at the
surface of lipid droplets in 3T3L1 adipocytes, inducing
lipolysis. Furthermore, overexpression of perilipins by
adenovirus infection blocks this effect (Souza et al. 1998).
In cancer cachexia, TNF increases monocyte chemoat-
tractant protein 1 expression in adipocytes, attracting
monocytes to the adipose tissue, resulting in inflam-
mation (Machado et al. 2004). The infiltrating macro-
phages are responsible for increasing TNF production,
and also IL6 and IL1 beta, generating a vicious cycle of
macrophage recruitment and cytokine production.
Neuroendocrine regulation of food intake and
anorexia
The hypothalamus is the master key for the control of
energy homeostasis. Importantly, it is in this CNS area that
hundreds of signals converge, including hormones,
nutrients, and cytokines, to integrate the complex
energy expenditure/food intake balance physiology
(Schwartz et al. 2000, Laviano et al. 2008, 2012, Blanco
Martı
´
nez de Morentin et al. 2011, Pimentel et al. 2014).
The hypothalamus is subdivided into functional areas
that fine tune the energy balance by sending signals that
coordinately increase food intake and suppress energy
expenditure or vice versa. Historically, it was loss-of-
function experiments, performed in the 1930’s, that
provided the proof of concept that the CNS is crucial to
the regulation of energy balance. The results of these
initial studies revealed that different cerebral regions could
control energy balance, in particular it was verified that
CNS lesions performed in macaques and cats lead to
deregulation of food intake and loss of thermogenesis
control (Ranson et al. 1938). However, it was only in
the 1950’s that the hypothalamus was established as a
crucial organ for this control. Specifically, lesions in
the ventromedial region of the hypothalamus of rats
induce hyperphagia, while lateral hypothalamus lesions
promote anorexia (Anand & Brobeck 1951, Miller 1957,
Hervey 1959).
The hypothalamus is constituted by neurons that
coordinately secrete anorexigenic (cocaine- and
amphetamine-regulated transcript (CART) and pro-opio-
melanocortin (POMC)) or orexigenic (agouti-related
protein (AgRP) and neuropeptide Y (NPY)) NPs to control
food intake. These NPs are produced mainly in the arcuate
(ARC) nucleus and paraventricular nucleus (PVN), but also
in the ventromedial hypothalamus (VMH) (Schwartz et al.
2000, Lage et al. 2008, Pimentel et al. 2013). The VMH
contains neurons that promote increased energy expendi-
ture (Schwartz et al. 2000, Blanco Martı
´
nez de Morentin
et al. 2011, Pimentel et al. 2013, Martı
´
nez et al. 2014).
Consistent with a VMH tonic pro-anorexigenic effect,
VMH-specific injection of colchicine (a neuronal blocker)
into anorectic rats increased food intake (
Varma et al. 2000,
Laviano et al. 2002). Moreover, certain areas of the brain,
such as the nucleus of the solitary tract (NST) have also been
implicated in the control of appetite. Accordingly, there is
an increase in NST neuron c-Fos activity after i.c.v. IL1B
injection (DeBoer et al. 2009).
Several lines of evidence indicate that the melano-
cortin system has a key role in hypothalamus dysfunction
in cancer cachexia. This system is mainly composed
of POMC neurons that secrete aMSH and exert their
anorexigenic effects on neurons that contain the melano-
cortin 4 receptor (MC4R; Balthasar et al. 2005, Cone 2005,
Silva et al.2014). It is noteworthy that mouse
neuronal cells express both POMC and CART in the
same neurons, while CART is not found in perikarya and
axons of human POMC neurons (Menyhe
´
rt et al. 2007).
Interestingly, MC4R-, but not MC3R-knockout mice, are
resistant to cachexia (Marks et al. 2001, 2003). Accor-
dingly, the administration of MC4R antagonists directly
to the hypothalamus ameliorates cancer-associated
and chronic-kidney-disease-associated cachexia and
attenuates the anorexigenic actions of the sphingosine 1
phosphate (Wisse et al. 2001, Markison et al. 2005, Cheung
et al. 2007, DeBoer et al. 2008, Silva et al. 2014).
MC4R is also expressed in orexigenic neurons and
these neurons are inhibited by a MSH decreasing
NPY/AgRP release (Laviano et al. 2008). Injection of a
melanocortin receptor antagonist attenuates radiation-
mediated anorexia and cachexia, when compared with
non-irradiated mice, in an AgRP-dependent manner
(Joppa et al. 2007). Interestingly, treatment with megestrol
acetate (MA), a drug approved by the FDA for cancer
cachexia, alleviates anorexia due to increased
Journal of Endocrinology
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M C S MENDES and others Mechanisms of cancer cachexia
226:3 R33
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DOI: 10.1530/JOE-15-0170 Printed in Great Britain
Published by Bioscientifica Ltd.

hypothalamic NPY expression (McCarthy et al. 1994),
which is decreased in anorectic cancer patients (Jatoi et al.
2001). Taken together, these findings indicate that
decreased activity of NPY/AgRP neurons occurs synergis-
tically to the hyperstimulation of POMC neuronal cells
and that the melanocortin system is critical for neuro-
endocrine-axis-mediated cancer cachexia.
In addition to the melanocortin system, other
neuronal circuits have been found to be dysfunctional in
cancer cachexia. Among these, hypothalamic serotoni-
nergic and dopaminergic systems are the most studied.
Consistent with an anorexigenic effect of the serotoniner-
gic system, 5HT1B-receptor is upregulated in PVN and
supraoptic nuclei of tumor-bearing rats (Makarenko et al.
2005) and VMH-specific serotoninergic system blockade
ameliorates appetite in anorexic rats (Laviano et al. 1996).
On the other hand, consistent with a dual effect of the
dopaminergic system in cancer cachexia, VMH-specific
dopamine 1 receptor antagonist leads to decreased
appetite and, in contrast, dopamine 2 receptor antagonist
administration increases food intake in tumor-bearing
rodents (Sato et al. 2001). Much less is known about the
glutamatergic neural circuit in the genesis of cancer
cachexia, but the increased activity of this system is
associated with anorexia. Consistent with this, a reduction
of vagal/glutamatergic neurotransmission with metabo-
tropic glutamate receptor antagonist (I(C)-AP3) alleviates
inflammation-LPS-driven anorexia, cachexia and febrile
states (Weiland et al. 2006).
Cancer cachexia molecular signals that
modulate the hypothalamus
It is beyond the scope of this review to report on the
innumerous signals that control energy homeostasis,
but these associated with cancer cachexia will be covered.
It is well established that pro-inflammatory cytokines
released from tumors promote cancer progression and
anorexia (Laviano et al. 2003, Seruga et al. 2008).
The results of initial studies have revealed that VMH-
specific injection of IL1 receptor antagonist attenuates
anorexia in tumor-bearing rats (Laviano et al. 1995, 2000).
Moreover, s.c. injection of the TNF inhibitor improved
food intake, with increased meal number and size in
anorectic rats (Torelli et al. 1999). Accordingly, tumor-
bearing rodents and cancer patients display higher IL1B
and TNF levels in cerebrospinal fluid (CSF; Opara et al.
1995a,b, Protas et al. 2011).
Mechanistically, cytokines induce anorexia by activat-
ing neuronal cells expressing POMC in the ARC nucleus of
the hypothalamus, which increases the central melanocor-
tin system timbre (Lawrence & Rothwell 2001, Reyes &
Sawchenko 2002, Scarlett et al.2007). Consistent with this
model, the use of a selective antagonist of MC4R was enough
to attenuate the anorexigenic effects of IL1B (Joppa et al.
2005). These data indicate that cytokines are CSF soluble
factors critical to hypothalamus-mediated anorexia.
In addition to pro-inflammatory cytokines, other
molecules have been implicated in cancer cachexia, such as
ghrelin and parathyroid hormone-related protein (PTHrP).
Although cachectic patients present high levels of
circulating ghrelin (Shimizu et al. 2003, Garcia et al. 2005),
treatment with ghrelin (s.c.) improves food consumption
in both rodents (DeBoer et al. 2007, Lage et al. 2008,
Fujitsuka et al. 2011) and cancer patients (Neary et al. 2004).
These findings indicate that hyperghrelinemia is a com-
pensatory mechanism that fails to overcome the cancer-
cachexia-induced decreased ghrelin signaling in the hypo-
thalamus (
Fujitsuka et al. 2011). The orexigenic ghrelin
effects are mediated by the hypothalamus, where this
hormone suppresses the expression of IL1R and POMC, and
increases AgRP and NPY expression (DeBoer et al. 2007).
Ghrelin-mediated attenuation of cachexia is reproduced in
different models, interestingly in fasting, denervation and
chronic-kidney-disease-mediated cachexia, ghrelin treat-
ment attenuated muscle protein degradation due, at least in
part, to the inhibition of actinomyosin cleavage (DeBoer
et al. 2008, Porporato et al. 2013).
The results of recent studies have indicated that
tumors release PTHrP, which not only decreases food
intake but also promotes muscle wasting (Asakawa et al.
2010, Kir et al. 2014). The results of these studies indicate
that blocking PTHrP may be an effective strategy for
treating cancer cachexia. Mechanistically, PTHrP activates
hypothalamic urocortins 2/3 via vagal afferent pathways
and inhibition of gastric emptying (Asakawa et al. 2010).
Importantly, PTPHrP neutralization is enough to suppress
B-adrenergic timbre, which attenuates energy expenditure
and muscle mass loss in anorectic mice (Kir et al. 2014).
Although the intracellular mechanisms that promote
hypothalamic-hormone-mediated anorexia are still
unclear, the activation of hypothalamic AMP-activated
protein kinase (AMPK) is a crucial event. AMPK is a key
mediator of energy balance that modulates food intake
and energy expenditure (Blanco Martı
´
nez de Morentin
et al. 2011, Hardie 2015). The results of recent studies
indicate that AMPK senses a multitude of nutritional and
hormonal signals such as berberine, omega 3 fatty acids,
glucose, alpha lipoic acid and leucine, insulin, leptin,
thyroid hormones, and inflammatory mediators (Kahn
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et al. 2005, Ropelle et al. 2007, 2008a,b, Lage et al. 2008,
Steinberg et al. 2009, Lo
´
pez et al. 2010, Pimentel et al. 2013,
Santos et al. 2013, Zhang et al. 2014). Likewise, activation
of AMPK not only blunts cancer-induced reduction of food
intake, but also attenuates inflammation and prolongs the
survival of tumor-bearing rats (Ropelle et al. 2007).
Neuroendocrine regulation of
cachexia-induced thermogenesis and
skeletal muscle sarcopenia
The hypothalamus not only promotes anorexia but also
contributes to the development of other cancer cachexia
symptoms, such as increased thermogenesis and skeletal
muscle sarcopenia (Fig. 2). Interestingly, cancer-associated
cachexia increases energy expenditure, an effect mainly
mediated by the BAT and coordinated by the hypothalamus
(Brooks et al.1981, Bianchi et al.1989, Tsoli et al.2012,
Kir et al. 2014). This organ senses the increased
levels of TNF, the tyrotropin-releasing hormone, and
the corticotropin-releasing hormone to promote heat
production via a B3-adrenergic neuronal circuit (Arruda
et al.2011).
Recently, cachexia has been found to be associated
with the conversion of white adipose cells into beige
cells, a process described as ‘browning’ (Kir et al. 2014,
Nedergaard & Cannon 2014, Petruzzelli et al. 2014). Beige
cells display abundant levels of UCP1, which reduces the
mitochondrial electrochemical gradient to promote
thermogenesis. Mechanistically, it has been suggested
that cancer cachexia-induced browning is also mediated
by an increase in B-adrenergic tonus (Cao et al. 2011, Kir
et al. 2014, Petruzzelli et al. 2014). Unfortunately, it is
not known whether the CNS is implicated in WAT
browning regulation during cancer cachexia. Since several
obesity studies have identified the hypothalamus as an
important regulator of browning (Cao et al . 2011, Baboota
et al. 2014, Beiroa et al. 2014, Owen et al. 2014, Ruan et al.
2014, Dodd et al. 2015), future studies to explore the
role of the hypothalamus in cachexia-induced browning
are encouraged.
Although the influence of the hypothalamus on the
modutation of lean body mass is clear, the mechanisms
are only partially elucidated (Marks et al. 2001, 2003,
Wisse et al. 2001,
Cheung et al. 2008, Braun et al. 2011).
The hypothalamic–pituitary–adrenal axis is an important
Figure 2
The hypothalamus is at the crossroads of cancer cachexia’s main features.
Pro-anorexigenic factors are integrated in discrete nuclei of the
hypothalamus. The ventromedial nucleus (VMH) promotes heat production
in brown adipose tissue (BAT) and may mediate white adipose browning
via the B3 adrenergic system. The paraventricular nucleus (PVN) and
arcuate (ARC) nucleus are the major integrating cente rs of food intake,
modulating the timbre of serotonin (5HT) expression and melanocortin 4
receptor (MC4R) respectively. Interestingly, pro-opiomelanocortin leads to
skeletal muscle break down and sarcopenia. 3V, third ventricle.
Journal of Endocrinology
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M C S MENDES and others Mechanisms of cancer cachexia
226:3 R35
http://joe.endocrinology-journals.org Ñ 2015 Society for Endocrinology
DOI: 10.1530/JOE-15-0170 Printed in Great Britain
Published by Bioscientifica Ltd.

axis that links the CNS to the muscle catabolic program.
Interestingly, brain–IL1B injection leads to muscle wasting
and increases in markers of muscle protein breakdown,
such as MURF and Atrogin1. In accordance with the
existance of an adrenal-mediated effect, adrenalectomy
suppressed IL1B-induced muscle atrophy, whilst gluco-
corticoid treatment was enough to promote muscle
atrophy (Braun et al. 2011). Interestingly, in spite of
muscle wasting induced by cancer, uremia, or LPS, as well
as IL1B-induced anorexia is suppressed by MC4R blockade
(Marks et al. 2001, 2003, Wisse et al. 2001, Cheung et al.
2008, Whitaker & Reyes 2008), MC4R-knockout animals
are not saved from body lean mass loss after central
infusion of IL1B (Braun et al. 2011), these findings indicate
that different neuronal circuits are involved in the CNS
modulation of muscle catabolic programs and that the
hypothalamus is crucial for induction and maintenance of
the main symptoms of cancer cachexia.
Treatment of cancer cachexia
Initial efforts
Although a number of nutritional supplements and drugs,
such as Cannabis (Strasser et al. 2006), eicosapentaenoic
acid (Beck et al. 1991, Barber et al. 1999, Mantovani et al.
2008) and branched-chain amino acids (Eley et al. 2007)
have shown promising results in pre-clinical studies, the
results of phase III clinical trials have failed to demonstrate
a substantial effect of these drugs and nutritional
supplements as treatments for cancer cachexia.
Currently, the only FDA-approved drug for the
treatment of cancer cachexia is medroxyprogesterone.
Medroxyprogesterone acetate and MA are both synthetic
progestins currently used to improve appetite and
promote weight gain in cancer cachexia (Tchekmedyian
et al. 1992). In accordance, the results of recent meta-
analysis indicated that MA is associated with a small effect
on weight gain and increase in appetite (Ruiz et al. 2013).
Although the mechanism of action is unknown, these
drugs reduce pro-inflammatory cytokines and increase
NPY levels in the hypothalamus (Mantovani et al. 2001).
Corticosteroids are alternative orexigenic agents for the
treatment of cancer cachexia (Popiela et al. 1989, Shih &
Jackson 2007). Importantly, dexamethasone treatment
resulted in similar-magnitude effects on weight gain and
increased appetite when compared with MA; however,
this approach was associated with an increased drug
discontinuation rate because of increased collateral effects
(Loprinzi et al. 1999).
New perspectives for the treatment of cancer cachexia
Triggered by better knowledge of the molecular
mechanisms of cachexia, we are observing an increasing
number of cancer cachexia clinical trials. One of the most
promising approaches for cancer cachexia is ghrelin
treatment. A proof of concept study of ghrelin infusion
revealed that this resulted in an increase of energy intake
and in pleasantness of the meal in patients with advanced
incurable cancer in a dose-dependent manner (Neary et al.
2004, Strasser et al. 2008, Hiura et al. 2012). More recently,
an oral mimetic of ghrelin (anamorelin) has been tested
and promising results were achieved with 16 cachectic
patients with different types of tumors (Garcia et al. 2013).
Numerous clinical trials to evaluate beneficial effects of
ghrelin and anamorelin in the treatment of cancer
cachexia are active (NCT0933361, NCT00681486,
NCT00225745, and NCT01505764). Although the use of
ghrelin in these patients appears to be safe, more studies
are necessary to confirm its efficacy and safety.
Despite the proven importance of TNF in the
pathogenesis of cancer cachexia, treatment with inflixi-
mab (a MAB to TNF) did not result in improvement in
cachexia cases (Jatoi
et al. 2001, 2010, Wiedenmann et al.
2008). In contrast, cancer cachexia treatment with
thalidomide, a drug with potent anti-inflammatory effects
(Moreira et al. 1993, Fujita et al. 2001, Keifer et al. 2001,
Richardson et al. 2002) presented encouraging preliminary
results (Davis et al. 2012), but we still do not have
sufficient data to recommend this drug in clinical practice
(Reid et al. 2012).
Cancer cachexia promotes insulin resistance, which
not only blunts muscle glucose uptake and liver glucose
production, but also inhibits protein anabolism, contri-
buting to muscle atrophy (Yoshikawa et al. 2001, Winter
et al. 2012). Metformin, the most widely used agent for the
treatment of type 2 diabetes, increases food intake and
prolongs survival in cachectic rats bearing Walker256
tumors (Ropelle et al. 2007). Interestingly, the results of
a clinical trial in individuals with prostate cancer
without cancer cachexia indicated that the association
of metformin, exercise, and low-glycemic-index diet
improved body weight (Nobes et al. 2012). Another insulin
sensitizer, rosiglitazone, a PPAR agonist that improves
insulin sensitivity, prevented weight loss, and helped
avoid muscle protein degradation in an experimental
colon cancer model of cachexia. These effects were
paralleled by a decrease in Atrogin1 and MuRF1 expression
(Asp et al. 2010). Interestingly, emerging evidence has
indicated that insulin resistance-mediated blunted protein
Journal of Endocrinology
Review
M C S MENDES and others Mechanisms of cancer cachexia
226:3 R36
http://joe.endocrinology-journals.org Ñ 2015 Society for Endocrinology
DOI: 10.1530/JOE-15-0170 Printed in Great Britain
Published by Bioscientifica Ltd.

anabolism is not refractory to post-prandial physiological
amino-acid infusion, indicating conventional nutritional
support to be a promising approach for overcoming
anabolic resistance (Winter et al. 2012). As such, insulin
sensitizers are good candidates for the therapeutic
treatment of cancer cachexia, but clinical studies to
confirm experimental data are necessary.
The use of an ActR2B decoy receptor (sActR2B)
prevents muscle wasting and inhibits muscle loss in
different animal models of cachexia (Zhou et al. 2010).
Since the levels of activins are increased in cancer cachectic
patients (Loumaye et al. 2015), a promising approach for
cancer cachexia treatment may be the blockade of ActR2B.
Conclusion
Although cancer cachexia has been a major burden on
our society for centuries, it is only in recent decades that
there has been unprecedented progress in the under-
standing of its molecular basis. A broad concept that
has emerged is that the hypothalamus is a key center for
the control of anorexia and fat loss in cancer cachexia.
Additionally, the results of animal studies have revealed
numerous factors produced by the tumor that act in
muscle, promoting its wasting. Although the potential
therapeutic implications have not yet been fully exploited
in humans, this collective work has already demonstrated
that targeting the hypothalamus and tumor-secreted
factors are attractive therapeutic approaches for alleviating
cancer cachexia.
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of this review.
Funding
J B C C was supported by grants from the Conselho Nacional de
Dese nvolvimento Cientı
´
fico e Tecnolo
´
gico (CNPq; 306821/2010-9) and
the Fundac¸a
˜
o de Amparo a
`
Pesquisa de Sa
˜
o Paulo (2013/07607-8). G D P
was supported by grants from the Fundac¸a
˜
o de Amparo a
`
Pesquisa de
Sa
˜
o Paulo (2014/22347-5).
Author contribution statement
M C S M, G D P, and F O C wrote the initial drafts of the manuscript and
J B C C revised the manuscript.
Acknowledgements
We thank Nicola Conran for reviewing the English.
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Received in final form 12 June 2015
Accepted 22 June 2015
Accepted Preprint published online 25 June 2015
Journal of Endocrinology
Review
M C S MENDES and others Mechanisms of cancer cachexia
226:3 R43
http://joe.endocrinology-journals.org Ñ 2015 Society for Endocrinology
DOI: 10.1530/JOE-15-0170 Printed in Great Britain
Published by Bioscientifica Ltd.