WORKSHOP

Cancer Anorexia and Cachexia

Michael J. Tisdale, DSc
From the Pharmaceutical Sciences Research Institute, Aston University, Birmingham,
United Kingdom
Patients with cancer cachexia experience a profound wasting of adipose tissue and lean body mass.
Anorexia, although often present, is insufficient to account for tissue wasting because 1) cachexia involves
massive depletion of skeletal muscle that does not occur during anorexia, 2) nutritional supplementation
cannot replenish the loss of lean body mass, 3) cachexia can occur without anorexia, and 4) food intake
might be normal for the lower weight of the cancer patient. Anorexia can arise from 1) decreased taste
and smell of food, 2) early satiety, 3) dysfunctional hypothalamic membrane adenylate cyclase, 4)
increased brain tryptophan, and 5) cytokine production. Appetite stimulants such as cyproheptadine,
medroxyprogesterone acetate, and megestrol acetate do not significantly improve lean body mass. Tumor
products might be more important in the development of cachexia. Cachectic patients excrete in their
urine a lipid-mobilizing factor that directly stimulates lipolysis in a cyclic AMP– dependent manner and
increases energy expenditure. Loss of skeletal muscle in cachexia is caused by upregulation of the
ubiquitin–proteasome catabolic pathway. Cachexia-inducing tumors elaborate a sulfated glycoprotein,
which directly initiates protein catabolism in skeletal muscle. The action of this proteolysis-inducing
factor is attenuated by the polyunsaturated fatty acid eicosapentaenoic acid, which is also effective in
preventing loss of skeletal muscle in cancer patients. Antagonists of tumor catabolic factors will provide
important new agents in the treatment of cancer cachexia. Nutrition 2001;17:438 – 442. ©Elsevier
Science Inc. 2001

KEY WORDS: cachexia, anorexia, lipid-mobilizing factor, proteolysis-inducing factor, eicosapentaenoic

acid

INTRODUCTION that leads to weakness and immobility of the cancer patient and
eventually to death through impairment of respiratory muscle
Cachexia can be defined as the effects of the tumor on the host function.
other than those resulting from mechanical interference with vital Second, the measured food intake does not correspond with the
organs. Cachexia involves weight loss, particularly from skeletal degree of malnutrition,4 and attempts to increase dietary intake
muscle and adipose tissue, anemia, electrolyte and water abnor- through dietary counseling or nutritional supplementation cannot
malities, and is often accompanied by anorexia. Anorexia, defined halt the wasting process, even though the nutritional intake should
as the loss of appetite and early satiety, is present in up to one-half be sufficient to meet the metabolic demands of the patient in terms
of newly diagnosed cancer patients.1 Treatment of cancer, partic- of resting energy expenditure. Any weight gain is transient and
ularly with chemotherapy, causes nausea and vomiting, leading to comprises fat and water and not lean body mass.5 A similar
anorexia and weight loss. Weight loss in this case should be situation is seen in patients with HIV6 or sepsis,7 suggesting that
distinguished from cancer cachexia and will require different ther- weight loss under these conditions results from complex metabolic
apeutic interventions. Although anorexia is commonly associated events rather than simple nutritional insufficiency.
with cachexia, it is unlikely that the weight loss in cancer arises Third, in rats and humans, loss of muscle and adipose tissue
primarily from the reduction in food intake. often precedes a decrease in food intake.8 In mice and humans,
First, the body composition change in cachexia differs from cachexia can occur, even without anorexia.9
that found in anorexia. During starvation, glucose utilization by the Fourth, there are some indications that anorexia is more appar-
brain is replaced by ketone bodies derived from fat. This leads to ent than real: although cancer patients with weight loss showed
decreased gluconeogenesis from amino acids by the liver and decreased food intake per kilogram of their usual body weights, it
conservation of muscle mass. Body composition analysis of pa- was normal for their current weights.1 These results suggest that
tients with anorexia nervosa has shown that most of the weight loss tumor-induced weight loss occurs first and that food intake then
arises from fat and only a small amount from muscle.2 In contrast, decreases to match the lowered body weight. Although anorexia
lung cancer patients, who had lost 30% of their preillness stable might be a phenomenon separate from cachexia, it is important to
weight, showed an 85% decrease in total body fat and a 75% understand the mechanism because it might be treatable by
decrease in skeletal muscle protein mass; non-muscle protein was protein-calorie supplementation.
conserved.3 In anorexia nervosa, loss of visceral mass occurs in
proportion to loss of muscle mass. It is this loss of skeletal muscle
CAUSES OF ANOREXIA

This work has been supported by IACR and the World Cancer Research Patients with cancer frequently present with a decreased taste and
Fund.
smell of food, resulting in increased sweet and decreased bitter
thresholds as well as psychological depression.10
Correspondence to: Michael J. Tisdale, DSc, Pharmaceutical Sciences There might be intractable emesis, bowel obstruction, or dys-
Research Institute, Aston University, Birmingham B4 7ET, United King- phagia. Early satiety is often reported by anorectic cancer patients,
dom such that they feel full after ingestion of a small amount of food.

Nutrition 17:438 – 442, 2001 0899-9007/01/$20.00

©Elsevier Science Inc., 2001. Printed in the United States. All rights reserved. PII S0899-9007(01)00506-8
Nutrition Volume 17, Number 5, 2001 Cancer Anorexia and Cachexia 439

This sensation might result from encroachment of the tumor on the edema, and there was no evidence for an increase in lean body
gastrointestinal tract hindering the passage of food or cause ab- mass and thus no changes in the Karnovsky index,25 a measure of
normalities in the mucosa, resulting in malabsorption.11 Early the performance status of the patient. Even the role of cytokines in
satiety also might result from delayed gastric-emptying times. the anorexia and cachexia of cancer patients may be in doubt
Anorexia in tumor-bearing animals might be caused by a dys- because pentoxifylline, at doses reported to decrease TNF-␣
function in the hypothalamic membrane adenylate cyclase system, mRNA levels in cancer patients, did not show any beneficial effect
as determined by reduced responsiveness to the inhibitory effect of on anorexia or cachexia in a study of 35 patients with lung,
neuropeptide Y and the stimulatory effect of isoprenaline.13 Intra- gastrointestinal, and other tumors.26 These results suggest that
hypothalamic injection of neuropeptide Y stimulated feeding less metabolic alterations induced by tumor products are significant in
potently in rats bearing methylcholanthrene-induced sarcoma than tissue wasting in cachexia.
in controls.14 This was observed before the onset of anorexia and
became more severe as the rats developed anorexia. These results
suggest that the postsynaptic neuropeptide Y–signaling systems FAT METABOLISM IN CACHEXIA
are altered in the hypothalamus of tumor-bearing rats. The level or
release of neuropeptide Y in the paraventricular nucleus and hy- Loss of adipose tissue is a common factor in starvation and cancer
pothalamus is also reduced in tumor-bearing rats but increased in cachexia, which is not surprising because fat comprises 90% of
fasting animals and animals food restricted to match the tumor- adult fuel reserves. Cachectic cancer patients showed increased
bearing animals.15 glycerol and fatty-acid turnover when compared with normal sub-
A number of studies have suggested that enhanced brain avail- jects,27 and fasting plasma glycerol concentrations were higher,
ability of the amino acid tryptophan, a precursor of serotonin, providing evidence for increased lipolysis.28 Although normal
plays a role in the pathogenesis of cancer anorexia by increasing individuals suppress lipid mobilization with glucose administra-
ventromedial hypothalamic serotininergic activity. Tryptophan en- tion, there is impaired suppression in patients with malignant
try into the brain is regulated by a specific transport system shared diseases and continued oxidation of fatty acids.29 Several clinical
by large neutral amino acids (branched-chain amino acids). The studies found increased triacylglycerol hydrolysis before weight
incidence of anorexia was significantly decreased after oral admin- loss occurs in cancer patients, suggesting that it is an early event
istration of branched-chain amino acids to 28 anorectic, non– in the development of cachexia.30 Studies in humans31 and animal
weight-losing cancer patients.16 models of cachexia32 provide evidence for a lipid-mobilizing fac-
Release of chemicals by the tumor or host immune system tor (LMF). This factor acts directly on adipocytes to stimulate
might cause anorexia. Cytokines such as tumor necrosis factor-␣ lipolysis in a cyclic AMP– dependent manner by a mechanism
(TNF-␣)17 and interleukin-1 (IL-1)18 act directly in the brain to similar to that of the lipolytic hormones.33 This effect is different
produce anorexia. Receptors for TNF-␣ and IL-1 are detectable in from that produced by the cytokines, which are thought to enhance
the hypothalamic food-intake regulatory areas of the brain, and lipolysis by inhibition of the clearing enzyme lipoprotein lipase,34
infusion of IL-1 in normal rats causes changes in food intake, meal which would prevent adipocytes from extracting fatty acids from
number, and meal size similar to those characterizing cancer plasma lipoproteins for storage, resulting in a net flux of lipid into
anorexia.19 IL-1 and the ventromedial hypothalamic serotonergic the circulation. However, the total lipoprotein-lipase enzyme ac-
system appear to be closely linked because peripherally infused tivity in the adipose tissue of cancer patients and the relative levels
IL-1 increases brain tryptophan and serotonin concentrations, of the mRNA for lipoprotein-lipase and fatty-acid synthase did not
whereas intracerebrally infused IL-1 increases neuronal firing rate differ from controls.35 There was, however, a twofold increase in
and serotonin release. In rats pharmacologic inhibition of prosta- the relative level of mRNA for hormone-sensitive lipase, suggest-
glandin E2 synthesis with ibuprofen completely blocked the ano- ing that lipolysis was the major mechanism for lipid mobilization
rectic effect of IL-1.20 Anorexia induced by TNF-␣ also can be in cancer cachexia.
blocked by cyclooxygenase inhibitors. It is likely that the two A LMF was recently isolated from a cachexia-inducing murine
cytokines act synergistically because TNF-␣ induces IL-1 secre- tumor (MAC16) and from the urine of patients with unresectable
tion and both stimulate other cytokines such as IL-6 in a cascade pancreatic carcinoma and established weight loss.36 The LMF
manner. Inui21 suggested that cytokines play an important role in showed an apparent Mr of 43 kDa and was homologous with the
long-term inhibition of feeding by mimicking the hypothalamic plasma protein Zn-␣2-glycoprotein in amino-acid sequence, elec-
effect of excessive negative feedback signaling from leptin by trophoretic mobility, and immunoreactivity. Both caused stimula-
persistent stimulation of anorexigenic neuropeptides such as tion of adenylate cyclase in murine adipocyte plasma membranes
corticotropin-releasing factor or by inhibition of the neuropeptide in a GTP-dependent process and release of glycerol from isolated
Y orexigenic network. adipocytes.37 Treatment of mice with LMF caused a decrease in
body weight that consisted entirely of loss of carcass lipid. This
occurred without changes in food or water intake and probably was
related to increased energy expenditure because there was an
PHARMACOLOGIC MANIPULATION OF FOOD INTAKE increase in oxygen uptake by interscapular brown adipose tissue
IN THE TREATMENT OF CANCER CACHEXIA (BAT). This increase might be related to changes in expression of
uncoupling proteins because mice bearing MAC16 tumors showed
Attempts to reverse cachexia in cancer patients by pharmacologic significantly higher uncoupling protein-1 mRNA levels in BAT
manipulation of food intake have encountered the same problems than did controls.38 Increased thermogenesis in BAT can increase
as with nutritional supplementation. Although the serotonin antag- total energy expenditure and thus contribute to tissue wasting.
onist, cyproheptadine, has a small effect on appetite, it did not Patients with lung39 and pancreatic40 carcinomas had increased
significantly prevent progressive weight loss in cachectic cancer resting energy expenditures compared with those in control sub-
patients.22 Medroxyprogesterone acetate (100 mg orally three jects. There is evidence suggesting that BAT levels are higher in
times per day) produced a significant improvement in the appetite cachectic cancer patients than in age-matched control subjects.41 In
of but not weight gain in patients with advanced malignant dis- vitro studies with LMF showed that lipolysis is attenuated by the
ease.23 Megestrol acetate, a progestational agent used in the treat- ␤-adrenergic receptor blocker propanolol,33 and propranolol was
ment of metastatic breast cancer, improved appetite and food shown to reduce the basal metabolic rate of cancer patients.42
intake in cachectic cancer patients with evidence of weight gain These findings and the stimulation of oxygen consumption in BAT
(6.8 kg) in a proportion of the patients treated.24 However, this by LMF suggest that this action is mediated through a ␤3-
weight gain was due mostly to increases in fat mass and partly to adrenergic receptor. ␤3-Adrenergic agonists upregulate uncoupling
440 Tisdale Nutrition Volume 17, Number 5, 2001

protein-1, leading to a net increase in energy utilization.43 Resting rat soleus muscle55 and total cellular ubiquitin-conjugated muscle
energy expenditure, whole-body oxygen uptake, and carbon- proteins in C2C12 myotubes,56 suggesting an activation of the
dioxide production were found to be increased in cancer patients ubiquitin-pathway, although no evidence was presented for in-
with progressive weight loss after ␤-adrenoceptor blockage.44 creased proteasome expression. Another study using C2C12 myo-
Those investigators concluded that wasting of body tissues can be tubes showed that TNF-␣ prolongs the half-lives of long-lived
explained in part by an increased ␤-adrenoceptor activity leading proteins and reduces the protease activities of the 20S proteasome
to elevated cardiovascular activity. Those results suggested that and the lysosomal-proteolytic enzymes cathepsins B and B⫹L.57
production of LMF by cachectic tumors accounts for the loss of In the same system, IL-6 shortened the half-lives of long-lived
body fat and the increase in energy expenditure. proteins and increased the activities of the 20S proteasome and the
cathepsins with an increase in transcription. However, in vivo,
IL-6 produced no change in ubiquitin gene expression58 and no
PROTEIN METABOLISM IN CACHEXIA effect on body weight or food intake, despite being associated with
increased acute-phase–protein production.59 Statistically signifi-
Loss of skeletal muscle in cancer patients can arise from a decrease cant increases in serum IL-6 were found in weight-losing patients
in protein synthesis, an increase in catabolism, or some combina- with non–small cell lung cancer when compared with patients with
tion. Many studies reported increases in whole-body protein turn- the same tumor type but without weight loss.60 These results
overs in cancer patients,45 but such studies are complicated be- suggest that IL-6 is a marker rather than a mediator of the cachec-
cause non–skeletal muscle protein synthesis might actually tic process. Although interferon-␥ increased ubiquitin gene expres-
increase, possibly because of hepatic production of acute-phase sion in rat skeletal muscle after intravenous administration58 as
protein.46 In a group of weight-losing cancer patients, in whom no with TNF-␣, the serum level of interferon-␥ did not correlate with
changes in total-body–protein synthesis or degradation was de- weight loss and anorexia in cancer patients.61 These results suggest
tected, muscle protein synthesis accounted for only 8% of total- that other factors are involved in muscle-protein catabolism in
body synthesis compared with 53% for healthy controls.47 How- cachexia.
ever, there was a twofold increase in non–skeletal muscle protein Belizario et al.62 provided evidence for a circulatory skeletal-
synthesis contributing to the observed maintenance of the total- muscle proteolysis-inducing factor (PIF) in patients with weight
protein–synthetic rate. Although the protein-synthetic rate is sub- losses greater than 10%, which appeared to be unrelated to the
stantially reduced in cachexia,48 net loss of protein appears to be recognized cytokines. Previous studies33 with the murine MAC16
related to increased breakdown rather than decreased synthesis of colon carcinoma provided evidence for tumor production of PIF,
muscle protein. which was specific to cachexia-inducing murine tumors. With
There are three major proteolytic pathways responsible for the tyrosine release from isolated gastrocnemius muscle as a measure
catabolism of proteins in skeletal muscle: 1) the lysosomal system of bioactivity, PIF was found to be maximally present in the serum
is concerned mainly with the proteolysis of extracellular proteins of mice bearing the MAC16 tumor, with a weight loss between
and cell surface receptors,49 2) the cytosolic calcium-activated 11% and 20%.63 PIF was subsequently isolated from the MAC16
system is involved mainly in tissue injury, necrosis, and autoly- tumor and the urine of patients with cancer cachexia by using
sis,50 and 3) the ATP-ubiquitin– dependent pathway is believed to affinity chromatography with an antibody cloned from splenocytes
be responsible for the accelerated proteolysis in a variety of of mice transplanted with the MAC16 tumor and delayed cachex-
wasting conditions such as fasting, sepsis, metabolic acidosis, ia.64,65 PIF was shown to be a sulfated glycoprotein with an Mr of
acute diabetes, weightlessness, and cancer cachexia.49 In this pro- 24 kDa and consisting of a short central polypeptide chain of
cess, ubiquitin is bound covalently to the protein substrate, which 4-kDa Mr with serine- and asparagine-linked oligosaccharide
acts as a signal for degradation by the multisubunit proteasome. chains.66 When administered to mice by intravenous injection, PIF
This process requires ATP and might contribute to the elevated produced rapid decreases in body weight (about 10% weight loss
daily energy expenditure observed in cancer cachexia. There is no in 24 h), without reductions in food and water intake.64 Body-
information on the role of this process in the skeletal muscle of composition analysis of weight loss showed specific depletion of
cancer patients, but in experimental cachexia models such as the non-fat carcass mass.67 Weight loss was associated with loss of
Yoshida ascites hepatoma51 and Yoshida sarcoma52 in rats and the soleus and gastrocnemius muscles, but there was no effect on the
MAC16 colon carcinoma in mice,53 there was a coordinate in- heart and an increase in liver weight.53 These body-weight changes
crease in the expression of ubiquitin, the 14-kDa ubiquitin carrier were similar to those observed in rats transplanted with the
protein-E2, thought to be the rate-limiting step in ubiquitin con- cachexia-inducing Yoshida ascites hepatoma.51 These results sug-
jugation, and subunits of the 26S proteasome, providing evidence gest that the action of PIF is mediated predominantly on skeletal
that this pathway plays a major role in muscle atrophy. This muscle. Other studies68 showed that the decrease in lean body
process is independent of the amount of protein consumed, so it is mass induced by PIF was caused by an increase (by 50%) in
not surprising that simple nutritional supplementation cannot re- protein degradation and a decrease (by 50%) in protein synthesis in
verse muscle catabolism in cancer cachexia. gastrocnemius muscle. PIF appears to act directly to induce these
changes because it initiated protein degradation directly in isolated
gastrocnemius muscle through a mechanism requiring the N- and
MEDIATORS OF THE PROCESS OF MUSCLE O-linked oligosaccharide chains.66 Induction of protein degrada-
CATABOLISM IN CACHEXIA tion in isolated soleus muscle by PIF required ATP, and in vivo
administration was associated with the accumulation of ubiquitin–
There have been suggestions that cytokines, in particular TNF-␣, protein conjugates in gastrocnemius muscle.53 These results sug-
IL-6, or interferon-␥, are responsible for the loss of tissues in gest that protein degradation induced by PIF is mediated through
cancer cachexia. However, some of the reports are conflicting, the ubiquitin–proteasome pathway.
making interpretation of the data difficult. Treatment of rats with Production of PIF appears to be associated specifically with
TNF-␣ enhances protein degradation in skeletal muscle associated cancer cachexia, and it was not found in the urine of patients
with higher levels of free and conjugated ubiquitin.54 There has undergoing major surgery or in those with burns, multiple injuries,
been some controversy as to whether this is a direct effect of sepsis, or sleeping sickness, even though the rate of weight loss
TNF-␣ because most studies with isolated skeletal muscle did not exceeded that found in cancer patients.67 Patients with carcinoma
show increases in the proteolytic rate when tyrosine or of the pancreas, lung, colon, breast, rectum, liver, and ovary and in
3-methylhistidine was used as the index of proteolysis. However, whom the rate of weight loss was greater than or equal to 1 kg/mo
TNF-␣ caused increases in ubiquitin gene expression in isolated showed evidence of PIF excretion in the urine.67 Eighty percent of
Nutrition Volume 17, Number 5, 2001 Cancer Anorexia and Cachexia 441

patients with pancreatic carcinoma excreted PIF in the urine.69 edge of the mechanism of tissue catabolism in cachexia should
These patients had significantly greater total weight losses and lead to effective therapeutic intervention. Because weight loss
rates of weight loss than did patients whose urine did not contain decreases the survival time of cancer patients and decreases per-
PIF; they also had greater losses of lean body mass. There appears formance status,80 effective therapy would extend patient survival
to be a high degree of structural conservation between murine and and improve quality of life.
human PIF. Both appear to have the same amino-acid sequence of
the polypeptide chain64 and the same size and arrangement of
oligosaccharide chains,70 and the murine monoclonal antibody can
attenuate weight loss induced by human PIF in mice.67 This
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