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Biology of Cachexia
Michael J. Tisdale*

The word cachexia is derived from the Greek kakos

meaning bad and hexis meaning condition. It occurs in
a number of disease states, including cancer, acquired immunodeficiency syndrome (AIDS), major trauma, surgery, malabsorption, and severe sepsis. Cachexia is characterized by weight loss
involving depletion of host adipose tissue and skeletal muscle
mass. Weight loss in cancer patients differs from that found in
simple starvation. During the first few days of starvation, glucose utilization by the brain and erythrocytes necessitates depletion of liver and muscle glycogen and an increased glucose
production by the liver, using gluconeogenic amino acids derived from catabolism of muscle. This early phase is replaced in
long-term starvation by the use of fat as a fuel, in which free

fatty acids released from adipose tissue are converted into ketone
bodies, which are utilized for energy by peripheral tissues and
eventually to a great extent by the brain. This leads to conservation of muscle mass. In anorexia nervosa, more than three
quarters of the weight loss arises from fat and only a small
amount from muscle. In contrast, in cancer cachexia, there is
equal loss of both fat and muscle, so that for a given degree of
weight loss there is more loss of muscle in a patient with cachexia than in a patient with anorexia nervosa (1). Thus, although anorexia is common in cancer patients, with reports of
occurrence in 15%40% of subjects at presentation (2), the body
composition changes suggest that anorexia alone is not responsible for cachexia. Also, in malnourished cancer patients, the
measured food intake fails to correspond with the degree of
malnutrition (3), and loss of both muscle and adipose tissue has
been reported to precede the fall in food intake (4). In contrast to
simple starvation, it is not possible to reverse the body composition changes seen in patients with cancer cachexia by the provision of extra calories. Attempts to increase energy intake in
cancer patients through dietary counseling failed to reverse the
cachexia (5). Trials of total parenteral nutrition in cachectic cancer patients also failed to show benefit in terms of increased
median survival time or long-term weight gain (6). Although a
short-term weight gain was observed, this weight was subsequently lost, suggesting the retention of water (7). Analysis of
body composition indicated that patients receiving total parenteral nutrition temporarily maintained body fat stores, but there
was no evidence for preservation of lean body mass. Thus, the
cause of wasting in cancer cachexia is more complex than that in
simple starvation.

Anorexia and Cachexia

Although anorexia alone is unlikely to be responsible for the
wasting seen in cancer patients, it may be a contributing factor.
In addition, its presence is an extremely distressing syndrome
because appetite and the ability to eat have been reported to be
the most important factors in the physical and psychological
aspects of a patients quality of life (8). Anorexic cancer patients
often report early satiety, which together with a reduced appetite
has been postulated to be caused by the production of factors by
the tumor that exert their effects by acting on the hypothalamic

*Correspondence to: Michael J. Tisdale, Ph.D., D.Sc., Pharmaceutical Sciences Institute, Aston University, Birmingham B4 7ET, U.K.
See Note following References.
Oxford University Press

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About half of all cancer patients show a syndrome of cachexia, characterized by loss of adipose tissue and skeletal muscle
mass. Such patients have a decreased survival time, compared with the survival time among patients without weight
loss, and loss of total body protein leads to substantial impairment of respiratory muscle function. These changes cannot be fully explained by the accompanying anorexia, and
nutritional supplementation alone is unable to reverse the
wasting process. Despite a falling caloric intake, patients
with cachexia frequently show an elevated resting energy
expenditure as a result of increases in Cori cycle (i.e., catalytic conversion of lactic acid to glucose) activity, glucose and
triglyceride-fatty acid cycling, and gluconeogenesis. A number of cytokines, including tumor necrosis factor-a, interleukins 1 and 6, interferon g, and leukemia-inhibitory factor,
have been proposed as mediators of the cachectic process.
However, the results of a number of clinical and laboratory
studies suggest that the action of the cytokines alone is unable to explain the complex mechanism of wasting in cancer
cachexia. In addition, cachexia has been observed in some
xenograft models even without a cytokine involvement, suggesting that other factors may be involved. These probably
include catabolic factors, which act directly on skeletal
muscle and adipose tissue and the presence of which has
been associated with the clinical development of cachexia. A
polyunsaturated fatty acid, eicosapentaenoic acid, attenuates
the action of such catabolic factors and has been shown to
stabilize the process of wasting and resting energy expenditure in patients with pancreatic cancer. Such a pharmacologic approach may provide new insights into the treatment
of cachexia. [J Natl Cancer Inst 1997;89:176373]

Metabolism in Cancer Cachexia

Metabolic Rate in Cancer Cachexia
In chronic starvation, the basal metabolic rate is reduced as
the body adapts to conserve tissues and energy in a low-protein
low-calorie environment (14). However, when compared with
control groups, cancer patients have been reported to have reduced (15), normal (16), or increased (17) energy expenditures.
Because cancer patients typically have a reduced caloric intake,
even a normal energy expenditure could be classified as being in
excess. In one study of cancer patients with solid tumors, the
basal metabolic rates of the patients were found to be elevated
even before the onset of weight loss (18), thus suggesting that an
elevated basal metabolic rate may be a contributing factor rather
than a consequence of the condition. The elevated basal metabolic rate has been shown to be associated with an increase in
heart rate, and it has been suggested that it may be due to an
elevated adrenergic state (18). Certainly, many cancer patients
show elevated plasma concentrations and increased urinary excretion of adrenergic substances (19), in contrast to malnourished patients without cancer who generally show a decrease in
catecholamine turnover.
The tumor type appears to play an important role in determining whether or not an elevation of resting energy expenditure
is observed. Thus, patients with lung cancer show an increase in
resting energy expenditure compared with that in healthy control
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subjects, whereas patients with gastric or colorectal cancer show

no elevation in resting energy expenditure (20). Patients with
pancreatic cancer have also been reported to have an increased
resting energy expenditure compared with that in control subjects, and this effect was found to be more pronounced in those
patients with an acute-phase response (21). This may explain
why, in a mixed group of cancer patients with gastrointestinal,
gynecologic, or genitourinary cancer, 33% were found to be
hypometabolic, 41% had average metabolic rates, and 26% were
hypermetabolic (15). It has been calculated that an elevation of
12% in the metabolic rate could account for the loss of 12 kg
of body weight per month (17). Brown adipose tissue plays a
thermoregulatory role and has been implicated as an important
effector of both body temperature and energy balance in many
mammals as well as in humans. Weight loss in a rat model of
cancer cachexia has been attributed to a high metabolic rate
produced by the activity of brown adipose tissue (22), although
results from sarcoma-bearing mice with weight loss suggested
that brown adipose tissue could not account quantitatively for
the host wasting (23). Results in humans are sparse, although an
examination of autopsy samples of periadrenal tissue by light
microscopy revealed brown adipose tissue in 80% of cachectic
cancer patients compared with 13% of age-matched control subjects (24). The reasons for these changes in basal metabolic rate
and brown adipose tissue in patients with cancer cachexia are
unknown, although both tumor and host factors, together with
the various aberrations in metabolic processes observed in this
group of cancer patients, probably contribute to this condition.
Carbohydrate Metabolism
Most solid tumors, either because of isoenzyme alterations or
because of their poor vascularization and hence hypoxic nature,
rely almost exclusively on the anaerobic metabolism of glucose
as their main energy source, with most being converted to lactate
(25). Glucose uptake and lactate release by human colon carcinomas have been found to exceed the peripheral tissue exchange
rate by 30-fold and 43-fold, respectively (26). Selective transcriptional regulation of hexokinase isoforms by a tumor may
enable it to have a growth advantage over normal cells. Thus, the
type II isoform has been shown to be the dominant form expressed in AS-30D hepatoma cells in contrast to the type IV
isoform in normal hepatocytes (27). The promoter activity of the
type II hexokinase was found to be resistant to normal hormonal
control, thus enabling tumor cells to maintain glycolysis at an
optimal rate regardless of the metabolic state of neighboring
healthy cells.
Since glycolysis is an inefficient method of energy production from glucose compared with oxidative phosphorylation,
high levels of glucose will be consumed by the tumor. In mice
bearing transplantable colon tumors, glucose utilization by the
tumor was second only to that by the brain (28). This extra
demand for glucose by the tumor was accompanied by a marked
decrease in glucose utilization by host tissues, in particular the
brain, which resembles the situation found in starvation. Despite
this weight loss, cancer patients show a 40% increase in hepatic
glucose production compared with control subjects, in contrast
to the reduced level seen in patients with anorexia nervosa (29).
The increase in glucose production in some cancer patients can
be accounted for by an increase in Cori cycle activity (30).

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sensory cells. Possible candidates for such a factor are the satietins (9). Satietins have been purified from human plasma and
found to consist of two proteins that copurify until they are
purified from one another by affinity chromatography. The
larger protein has been characterized as an extensively glycosylated a1-acid-glycoprotein of a molecular mass of 64 kd,
which is probably a vehicle for satietin D, a 41-kd glycoprotein.
When injected into rats, satietin D has been shown to produce a
long-lasting anorectic effect, although its role in the development of anorexia is not known. There may also be some dysfunction of the hypothalamic neuropeptide Y feeding system in
the tumor-bearing state, since rats bearing a methylcholanthreneinduced sarcoma were found to be refractory to the intrahypothalamic injection of neuropeptide Y; normal rats, by contrast,
increased their food intake by more than 50% in response to such
an injection (10).
Increased serotonergic activity within the central nervous system has been proposed as a possible cause of anorexia. Such
activity is secondary to the enhanced availability of tryptophan
to the brain. Thus, a close relationship between elevated plasmafree tryptophan and anorexia was observed in patients with cancer and reduced food intake (11). The uptake into the brain of
tryptophan is competitive with that of branched chain amino
acids. An attempt to reduce tryptophan uptake by increasing
plasma levels of competitor branched chain amino acids produced a decrease in the incidence of anorexia (12), but it was not
reported whether such patients also regained body weight. However, although the serotonin antagonist cyproheptadine has been
reported to have a weight-enhancing effect in normal subjects, a
randomized, placebo-controlled, double-blinded trial found it to
have no effect on progressive weight loss in cachectic cancer
patients (13).

Lipid Metabolism
Fat constitutes 90% of the adult fuel reserves, and loss of
whole-body fat is a feature of cancer cachexia. Cancer patients
with weight loss have an increased turnover of both glycerol and
fatty acids when compared with patients without weight loss
(38). Fasting plasma glycerol concentrations have been shown to
be higher in weight-losing cancer patients than in weight-stable
cancer patients, thus providing evidence for an increase in lipolysis (39). Increased utilization of fatty acids as a preferred
energy source has been observed even in the presence of high
plasma glucose concentrations, suggesting that, in the presence
of certain tumors, host tissues may increase their utilization of
fatty acids as an energy source (40).
Several clinical studies [reviewed in (41)] have observed an
increased mobilization of fatty acids before weight loss occurs,
suggesting the production of lipid-mobilizing factors either by
the tumor or by host tissues. Although normal individuals suppress lipid mobilization with administration of glucose, there is
an impaired suppression in patients with malignant diseases as
well as continued oxidation of fatty acids (42). Increased fatty
acid oxidation in the absence of increased dietary fat intake
would result in a depletion of fat stores, while increased triglyceride fatty acid cycling and gluconeogenesis from glycerol could
result in an increase in metabolic rate. All of these processes,
therefore, have the potential to contribute to a net loss of body
weight.
Mobilization of fatty acids from host adipose tissue may be

an important factor contributing to tumor growth. Patients with

ovarian or endometrial tumors were found to have lower concentrations of linoleic acid in subcutaneous adipose tissue than
cancer-free subjects, suggesting mobilization to supply lipids to
the tumor (43). Linoleic acid has been found to act as a stimulator of tumor growth both in vitro (44) and in vivo (45). The
effect is probably due to formation of prostaglandins or products
of the lipoxygenase pathways. Rat Walker 256 carcinosarcoma
cells transfected with 12-lipoxygenase-specific antisense oligonucleotide or antisense oligonucleotides directed to conserved
regions of lipoxygenases underwent time- and dose-dependent
apoptosis (46). Also, treatment with lipoxygenase but not with
cyclooxygenase inhibitors induced apoptotic cell death, which
could be partially inhibited by exogenous 12(S)- or 15(S)hydroxyeicosatetraenoic acids (46). This observation suggests
that essential fatty acids from adipose tissue may be required for
tumor expansion by preventing cell death by apoptosis.
Protein Metabolism
Lean body mass and visceral protein depletion are characteristics of patients with cancer cachexia, and the degree of depletion may be associated with reduced survival (47). The major
site of this protein loss has been observed to be the skeletal
musculature (48). An increased rate of whole-body protein turnover has been reported in cachectic cancer patients. A reduced
rate of protein synthesis and an increased rate of degradation
were observed in muscle biopsy specimens from 43 newly diagnosed cancer patients with weight loss (49). An increase in
cathepsin D activity was observed in biopsy specimens from the
rectus abdominal muscle, an increase that was associated with
the rate of protein degradation. In another study (50), a decrease
in muscle protein synthesis was also observed in weight-losing
cancer patients, with no change in total body synthesis or degradation. Muscle protein synthesis accounted for only approximately 8% of the total body synthesis in these patients compared
with 53% for healthy control subjects. The observed maintenance of the total protein synthetic rate in these patients may
therefore be due to a twofold increase in nonskeletal muscle
protein synthesis. This twofold increase in protein synthesis may
be due to increased hepatic synthesis of secretory proteins such
as acute-phase reactants. An elevated whole-body protein turnover may also be apparent in patients with small tumor burdens
(51).
There are also changes in the plasma amino acid profile in
patients with cancer cachexia, and most studies have reported
that such patients exhibit decreases in the concentrations of gluconeogenic amino acids. This result contrasts with the situation
in subjects with severe malnutrition, in whom the concentrations
of branched chain amino acids in plasma are normal or increased. Compared with normal colon tissue, human colon tumors were observed to have a specific requirement for serine and
for the branched chain amino acids valine, leucine, and isoleucine (52). However, the two tissues had similar retention of total
amino acids. Correlations between histidine-induced, enhanced
formiminoglutamic acid excretion, elevated basal metabolic
rate, and reduced serum albumin levels were observed in a study
of eight weight-losing patients with small-cell carcinoma of the
lung (53). Formiminoglutamic acid excretion was reduced in
patients who showed a positive response to chemotherapy,

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Patients with progressive cancer have been shown to have an

increased glucose synthesis not only from lactate (31), but also
from alanine (32) and glycerol (33). The Cori cycle normally
accounts for 20% of glucose turnover, but it was shown to be
increased to 50% in cachectic cancer patients, accounting for the
disposal of 60% of the lactate produced (34). Both glucose production rates and recycling rates were found to be higher in
malnourished cancer patients than in patients without cancer and
with comparable weight loss (35). The increased glucose recycling equivalent to 40% of the daily glucose intake of the cancer
patient has been estimated to lead to a potential loss of 0.9 kg of
body fat per month.
Hypoglycemia has been reported in a number of animal models of cancer, and in humans it is associated with carcinoma of
the stomach, cecum, or bile ducts, pseudomyxoma, and paraganglioma, sometimes occurring before the presence of a tumor
is suspected (36). It was originally thought that hypoglycemia
was due to the high glucose consumption by the tumor, but a
recent study (37) suggests that it arises through the ability of
some tumors, other than insulinoma, to produce insulin or insulin-like substances. Since insulin levels have been shown to be
low in cases of tumor-associated hypoglycemia, the production
by the tumor of an insulin-like growth factor has been suggested
as the cause of enhanced peripheral glucose uptake. The most
likely candidate for the pathogenesis of extrapancreatic tumor
hypoglycemia is the production of a high-molecular-mass (15
25 kd) insulin-like growth factor II (IGF II) by the tumor (37).
Thus, patients with cancer have an increased glucose production and turnover, which may be enhanced by the production of
IGF II. Such changes contribute to an increased energy expenditure by the host.

Factors Implicated in Production of

Cancer Cachexia
Numerous cytokines, including tumor necrosis factor-a
(TNF-a), interleukin 1 (IL-1), interleukin 6 (IL-6), interferon
gamma (IFN g), and leukemia-inhibitory factor (LIF), have been
postulated to play a role in the etiology of cancer cachexia. Such
cytokines may be produced by tumor or host tissue and are
characterized by the induction of anorexia and a decrease in the
clearing enzyme lipoprotein lipase. The ability to inhibit lipoprotein lipase varies among the cytokines. Thus, while LIF is
twofold to 10-fold less potent than TNF-a, it is 100 times more
potent than IL-6 (59). However, it is unlikely that a decrease in
lipoprotein lipase alone could account for the fat cell depletion
and wasting seen in cachexia, since in type 1 hyperlipidemia
caused by an inherited deficiency in lipoprotein lipase, patients
have normal fat stores and are not cachectic. This fact, together
with the inability of the cytokines to explain all of the metabolic
changes associated with cancer cachexia, has inspired investigators to search for tumor-produced catabolic factors that act
directly on adipose tissue and skeletal muscle initiating the process of cachexia.
Tumor Necrosis Factor-a (TNF-a)
TNF-a was suggested as a possible cachectic factor as a
result of studies on the mechanism of the weight loss observed
in rabbits chronically infected with Trypanosoma brucei brucei.
Administration of TNF-a to laboratory animals induces a state
of cachexia, with anorexia and depletion of adipose tissue and
lean body mass. However, tachyphylaxis rapidly develops following administration of additional TNF-a (60). Tachyphylaxis
was not found to develop in immunodeficient nude mice that
were given an injection of Chinese hamster ovary (CHO) cells
transfected with the human TNF-a gene (61). These cells induced high serum levels of TNF-a (1.022.8 ng/mL) in the mice
and a syndrome resembling cancer cachexia with progressive
wasting, anorexia, and early death. It is interesting that, when
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such cells were transplanted intracerebrally, hypophagia and

weight loss were observed, and the body composition was comparable to that seen in starvation, i.e., a decrease in whole-body
lipid but conservation of protein (62). When the tumor cells were
transplanted intramuscularly, profound anorexia did not develop; after a long period of tumor burden (50 days), however,
cachexia developed and both protein and lipid were depleted.
In addition to inhibition of lipoprotein lipase (59), incubation
of cultured human fat cells with TNF-a has been shown to
induce a marked dose-dependent stimulation of lipolysis by up
to 400% of control values; this stimulation became apparent
after a 6-hour exposure at the earliest (63). TNF-a has been
shown in several studies (6468) to activate muscle protein degradation, although not all of the reports agree that TNF-a does
activate protein degradation directly. In one of the studies (65),
TNF-a administration to healthy (i.e., cancer-free) rats brought
about an enhanced rate of degradation of skeletal muscle protein,
even though body weight loss was not apparent in the animals.
In another of the studies (68), administration of anti-murine
TNF-a immunoglobulin to rats bearing the Yoshida AH-130
ascites hepatoma led to decreases in the rates of protein degradation in the skeletal muscle, heart, and liver tissues, but it had
no effect on weight loss in the animals. However, a direct action
of TNF-a has not been demonstrated by most authors, when
either tyrosine or 3-methylhistidine was used as a measure of the
proteolytic rate (69). Despite this result, a recent report (67) has
shown an increase in ubiquitin gene expression, with no change
in the expression of the C8 proteasome subunit after incubation
with TNF-a for 180 minutes in vitro. These results show that
TNF-a has the potential to act as a modulator of the cachectic
process.
Some animal tumors are thought to produce the cachectic
syndrome through the mediation of TNF-a. The Yoshida AH130 ascites hepatoma induces weight loss in the host, and elevated endogenous circulating TNF-a and prostaglandin E2 levels are observed (68). Administration of anti-TNF-a antibody
before transplantation of the tumor abolished detectable TNF-a
levels, while fractional rates of protein degradation in gastrocnemius muscle, heart, and liver were reduced, although treatment failed to prevent a reduction in body weight. A similar
result was obtained in mice with methylcholanthrene-induced
sarcomas, where anti-TNF-a monoclonal antibody delayed but
did not prevent the development of anorexia and had no effect on
overall body weight (70). In another model, the Lewis lung
adenocarcinoma anti-TNF-a antibody partially reversed the loss
of body fat, without affecting food intake or causing a change in
body weight (70). This finding suggests that TNF-a may not be
responsible for the changes seen in animals or humans with
cancer cachexia.
Similar problems have been encountered in clinical studies on
the role of TNF-a in cancer cachexia. While a short intravenous
infusion of recombinant human TNF-a increased plasma triglyceride levels, glycerol turnover by more than 80% and free fatty
acid turnover by more than 60% (71,72), in the case of long-term
administration, the changes resolved despite the continuous administration of TNF-a (71). Similar effects were seen on protein
metabolism, where whole-body protein turnover was increased
as measured by 15N enrichment of urinary urea and ammonia
(71). Thus, TNF-a has the potential to induce catabolism of

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whereas there was no change in a patient with progressive disease.

The pathway responsible for breakdown of myofibrillar proteins is the adenosine triphosphate (ATP)ubiquitin-dependent
proteolytic system, which has been shown to be elevated in
starvation (54), sepsis (55), and metabolic acidosis (56) and after
transplantation of certain tumors such as the Yoshida ascites
hepatoma in rats (57). In this process, proteins for degradation
are first conjugated with ubiquitin, which serves as a signal for
degradation by a large proteolytic complex, the 26S proteasome,
which requires ATP to function. In skeletal muscle of rats bearing the Yoshida ascites hepatoma, a 500% increase in expression
of polyubiquitin genes was observed in relation to both pair-fed
(i.e., non-tumor-bearing rats fed the same amount of food as
tumor-bearing rats) and ad libitum-fed animals (57). Treatment
with clenbuterol suppressed the elevation of protein breakdown
rates toward control values, and this suppression was associated
with a decreased expression of polyubiquitin genes (58). Thus,
understanding more about this proteolytic system and factors
involved in its regulation may provide important clues for the
treatment of muscle wasting in cachexia.

Interleukin 6 (IL-6)
A potential role for IL-6 in the development of cancer cachexia has mainly been provided from animal studies involving
the use of the murine colon-26 adenocarcinoma model (8385),
in which increasing levels of IL-6 appear to lead to the development of cachexia (83). In addition, the administration of antimouse IL-6 monoclonal antibody, but not of anti-mouse TNF-a
monoclonal antibody, attenuated the development of weight loss
and other parameters of cachexia in the mice (83). In another
study (84) in which clonal variants of the colon-26 tumor model
were used, the serum concentrations of IL-6 in mice bearing a
tumor clone that does not induce weight loss were lower than in
mice bearing a tumor clone that does induce weight loss; however, infusion of IL-6 into mice in the former group did not lead
to body weight loss. These results indicate that IL-6 was not
solely responsible for the induction of cachexia. Suramin, a
polysulfonated napthylurea, has been shown to inhibit the binding of IL-6 to cell surface receptor subunits, and it has been
shown to partially block cachexia in the colon-26 model, without
a decrease in tumor burden (85). Since anti-IL-6 antibody treatment did not enhance the effect, this result suggests that suramin

inhibits cachexia, at least in part, by interfering with the binding

of IL-6 to its receptor. IL-6 has also been identified as a mediator
of cachexia by the growth of a uterine cervical carcinoma called
Yomoto in nude mice (86). Administration of a neutralizing
antibody against human IL-6 to mice, after the development of
cachexia, was shown to reduce the loss of body weight and the
wasting of adipose tissue (86).
Agents that regulate cytokines, such as interleukin 12 (IL-12),
reduced the serum levels of IL-6 in mice bearing the murine
colon-26 carcinoma and alleviated the loss of body weight, adipose tissue wasting, and hypoglycemia associated with cachexia
(87). IL-12 also substantially increased IFN g levels in the tumor, and IFN g administered intraperitoneally also prevented the
cachexia, although it did not reduce IL-6 levels. It is interesting
that IFN g has been reported to be a possible mediator of cachexia in other animal model systems (88). Interleukin 10 (IL10) was originally identified as a cytokine synthesis inhibitory
factor. A reduction in serum IL-6 levels was observed in mice
bearing the colon-26 tumor transfected with the IL-10 gene,
although these levels did not reach baseline values and such
mice did not develop cachexia (89). Since cachexia was completely prevented with an incomplete reduction of serum IL-6
levels, the authors suggested that an additional unknown factor
was responsible for the development of cachexia in this model.
This suggestion was also made in another study (90) on mice
bearing the colon-26 tumor. An antibody to the IL-6 receptor
reduced the loss of weight of the gastrocnemius muscle and
suppressed the enzymatic activity of cathepsins B and L and
mRNA levels of cathepsin L and poly-ubiquitin, but it had no
effect on the overall loss of body weight or wasting of adipose
tissue, suggesting that the latter two may not be influenced by
IL-6.
Certainly, IL-6 has the potential to act as a cachectic factor.
Atrophy of muscles is observed in IL-6 transgenic mice; this
atrophy is completely blocked by anti-mouse IL-6 receptor antibody (91). The muscle atrophy is associated with increased
mRNA levels for cathepsins (B and L) and mRNA levels of
ubiquitins (poly- and mono-). Administration of IL-6 to rats has
also been shown to acutely activate both total and myofibrillar
protein degradation in skeletal muscle (92). In an in vitro study
(93) using murine C2C12 myotubes grown in cell culture, exposure of the cells to 100 U/mL recombinant human IL-6 was
found to shorten the half-life of long-lived proteins and to increase the activity of the 26S proteasome and lysosomal (cathepsins B and L) proteolytic pathways. This result suggests that
IL-6 is capable of directly up-regulating pathways of protein
degradation.
Unlike the results obtained with TNF-a, statistically significant increases in IL-6 and C-reactive protein, as a measure of the
acute-phase response, have been found in weight-losing patients
with non-small-cell lung cancer, when compared with patients
with the same tumor, but without weight loss (94). An elevated
level of serum IL-6 has also been reported in patients with colon
cancer and an acute-phase response (95); however, since all
patients had lost weight, it is difficult to associate this elevation
with the induction of cachexia.
The results of these animal and human studies strongly implicate IL-6 in the cachectic process. However, IL-6 probably

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adipose tissue and skeletal muscle in humans, although anorexia

has not been reported to be a major dose-limiting toxicity. Several studies have failed to detect elevated circulating levels of
TNF-a in cachectic cancer patients (73,74) or have failed to
associate the elevation with the development of cachexia (75).
Elevation of serum TNF-a levels seems to be associated more
with the clinical status of the patient. Thus, in a study of 91
patients with B-cell chronic lymphocytic leukemia, serum levels
of TNF-a were elevated in all stages of the disease with a
progressive increase in relation to the stage (76). TNF-a levels
were found to be substantially higher in patients with endometrial carcinoma than in healthy postmenopausal women or in
women with endometrial hyperplasia, and serum TNF-a levels
were associated with advancing stage of disease (77). Increased
serum levels of TNF-a receptors were found in a range of solid
tumor types, and the incidence and extent of the increase also
were associated with the staging of the disease (78).
The inability to associate serum levels of TNF-a with the
development of cachexia may be due to the very rapid blood
transit of cytokines, so that they can be transported from the sites
of production to the target tissues without causing an elevated
serum concentration. However, elevated concentrations of
TNF-a have been reported in patients with both malaria (79) and
visceral leishmaniasis (80), which has been associated with
death and cachexia. In addition, although animal experiments
have shown TNF-a to be a potent inhibitor of lipoprotein lipase
(59), there appears to be no difference between cancer patients
and control subjects in either the total lipoprotein lipase activity
or the relative levels of the messenger RNA (mRNA) for lipoprotein lipase and fatty acid synthesis (74), thus raising a question of a local effect for this cytokine. In rats infected with
Escherichia coli, pentoxifylline (a potent inhibitor of TNF-a
secretion) decreased the anorexia, loss of body weight, and
muscle protein observed and partially prevented the decrease in
muscle protein synthesis induced by infection (81). However, in
a clinical study (82), pentoxifylline failed to reduce anorexia or
cachexia in 35 patients with cancer.

does not act alone but may either induce or act in synergy with
other cachectic factors.
Interleukin 1 (IL-1)

Interferon Gamma (IFN g)

Interest in the role of IFN g in the pathogenesis of cancer
cachexia developed as a result of observations confirming that it
had properties similar to those of TNF-a with respect to fat
metabolism in vitro (101). Weight loss in mice bearing the
Lewis lung tumor is associated with IFN g production, and
administration of an anti-IFN g antibody reduced the depletion
of body fat but had no effect on total body protein (102). In rats
that had received transplants of the MCG 101 sarcoma, anti-IFN
g antibody reduced weight loss and anorexia and increased survival, but the treatment was partial and short-lived, suggesting
that IFN g may not be the sole mediator (103). Inoculation of
CHO cells transfected with the IFN g gene into mice resulted in
a dose-related development of anorexia and marked weight loss
due to fat and muscle depletion, not wholly attributable to the
reduction in food intake (104). Such a result should not be interpreted to mean that IFN g by itself can induce cachexia, since
both IFN g release and the presence of the tumor cells were
found to be required. While serum TNF-a levels of patients with
multiple myeloma did not differ from those found in healthy
control subjects, IFN g was found to be raised in 53% of the
patients (105). However, no association was observed between
the level of IFN g and clinical parameters of the disease. These
results suggest that IFN g alone may not be responsible for the
induction of cachexia.
Leukemia-Inhibitory Factor (LIF)
LIF has also been suggested to play a role in the cancer
cachexia syndrome through its ability to decrease lipoprotein
lipase activity. Nude mice implanted with the human cell line
1768 REVIEW

Lipid-Mobilizing Factors (LMFs)

LMFs act directly on adipose tissue with the release of free
fatty acid and glycerol in a manner similar to that of the lipolytic
hormones. Like the induction by hormones, the induction of
lipolysis is associated with an elevation of intracellular cyclic
adenosine monophosphate (108), possibly as a result of stimulation of adenylate cyclase. Evidence for the production by tumors of an LMF was provided by Costa and Holland (109), who
showed that nonviable preparations of the Krebs-2 carcinoma,
when injected into mice, were able to induce the early, rapid
stage of fat depletion, which represented true cachexia in this
model. Ascites serum from rats transplanted with the Walker
256 carcinoma increased stimulation of lipolysis in an in vitro
assay (110), whereas serum from mice bearing a thymic lymphoma when injected into non-tumor-bearing controls produced
massive fat loss (111), providing further evidence for an LMF.
This latter factor was also detected in extracts of the tumor, in
tissue culture medium, and in the sera of patients with adenocarcinomas of the cervix and stomach, thus suggesting that the
LMF was tumor derived and circulatory. Other studies have
shown that the level of LMF in the sera of cancer patients was
proportional to the extent of weight loss (112) and was reduced
in patients responding to chemotherapy (113).
Most studies provide evidence that the LMF is an acidic
protein, although there appears to be variations in the molecular
weight. A heat-stable protein of molecular mass around 5 kd was
isolated from a thymic lymphoma (114), and another heat-stable
protein of molecular mass 6 kd was isolated from the conditioned medium of the A375 human melanoma cell line (115). A
heat-labile material of molecular mass between 65 kd and 75 kd
was isolated from the ascites fluid of patients with hepatoma and
mice with sarcoma 180 (116). Tryptic digestion of the active
material produced a low-molecular-weight material that was still
active.
These studies provide strong evidence for the production of
LMF by tumors. The production of this material appears to be
related to the process of cachexia, since LMF is absent or present
in reduced amounts in tumors that do not induce cachexia (117)
and is absent from normal serum, even under conditions of star-

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IL-1 has been shown to have many effects similar to those of

TNF-a; these similar effects include suppression of lipoprotein
lipase and enhancement of intracellular lipolysis. Administration
of recombinant IL-1 was observed to induce anorexia, weight
loss, hypoalbuminemia, and elevated amyloid P levels in the
mouse (96). Indeed, this cytokine was observed to have a greater
anorexigenic effect than TNF-a when administered in isomolar
quantities. However, in the MCG 101 sarcoma tumor model of
cachexia in mice, IL-1 mRNA was present at low levels as
determined by northern blot analysis in the spleen, liver, intestine, and brain and at elevated levels in the spleen (97). IL-1 and
TNF-a protein were both detected in tumor tissue, but at levels
similar to those in normal tissue. Neutralizing antibodies against
the IL-1 receptor were observed to cause statistically significant,
but minor, inhibitory effects on cachexia and anorexia in this
model (98). Administration of the IL-1 receptor antagonist to
rats bearing the Yoshida ascites hepatoma was also found to be
completely ineffective in preventing tissue depletion and protein
hypercatabolism (99). Transfection of a cachectic tumor cell line
(colon-26) with the gene for the IL-1 receptor antagonist also
failed to abolish the capacity of the tumor to produce cachexia
(100). These results cast doubt on a role of this cytokine in the
induction of tissue wasting in cancer cachexia.

SEKI, which expresses large amounts of LIF, develop a severe

cachexia (106). LIF mRNA has also been shown to be present in
two types of melanoma xenograft that induce weight loss in
transplanted animals, whereas none was detected in noncachexia-inducing xenografts (106). Although inhibition of lipoprotein lipase has been suggested to account for the cachectic
effect of LIF, it is unlikely that a decrease in lipoprotein lipase
alone could account for the fat cell depletion, and no mechanism
has been proposed to explain skeletal muscle catabolism. It
seems unlikely that any of the cytokines alone are able to explain
the complex mechanism of wasting seen in cancer cachexia, and
other factors must be involved. This view is substantiated in a
study of the factors responsible for the cachectic syndrome in
nude mice bearing human tumor xenografts (107). In four of the
eight models, a cytokine such as LIF or IL-6 produced by the
cancer cells may be responsible; however, in the remaining four
cancer cell lines, the inducing factor was unknown. In these
cases, the inducing factors may be catabolic factors, which act
directly on host tissues.

vation (118). No report to date has provided sequence information on these LMFs; therefore, further studies are required.
Protein-Mobilizing Factors (PMFs)

Treatment of Cancer Cachexia

Weight loss is associated with psychologic distress and a
lower quality of life. In addition, patients with weight loss have
a shorter survival time and a decrease in response to therapy
(124). About half of all patients with cancer show some weight
loss (124), but those with pancreatic cancer show it at the highest
frequency (125); in the latter study, the investigators found that
all patients at the time of diagnosis had lost weight (median,
14.2% of pre-illness stable weight), and this weight loss was
progressive, increasing to a median of 24.5% just before death.
Patients with more than 15% weight loss are likely to have
substantial loss of total body protein, and at this level of lean
tissue depletion, physiologic function (e.g., respiratory muscle
function) is markedly impaired (126). Thus, such patients need
effective therapy if death from cachexia is not to occur.
As previously discussed, nutritional support in the form of
total parenteral nutrition has failed to replete lean body mass.
Even worse, a meta-analysis of the published trials on patients
receiving total parenteral nutrition while undergoing chemotherapy showed a decreased survival, a poorer tumor response,
and a significantly significant increase in infectious complications (127).
An improvement in appetite alone does not fully reverse the
cachectic syndrome. Thus, patients with advanced malignant
disease receiving medroxyprogesterone acetate (100 mg taken
orally three times a day) showed a great improvement in appe-

Summary
Although cancer cachexia superficially resembles starvation,
nutritional intervention alone is unable to reverse the condition.
Tremendous progress has been made in the last 10 years in
elucidating the role of various factors in host tissue catabolism,
and the results of these studies are now being translated into
treatment regimens for the benefit of patients with cachexia.
Cachexia is an important cause of mortality in cancer patients,
accounting directly for between 10% (137) and 22% (138) of all
cancer deaths, as well as death from other causes such as infection. Thus, an effective therapy for cachexia not only should
improve the quality of life of cancer patients, but also may be

Journal of the National Cancer Institute, Vol. 89, No. 23, December 3, 1997

REVIEW 1769

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Using bioassays to detect protein degradation, investigators

have found evidence for the existence of PMF(s) in the sera of
both animals (119) and humans (120) with cancer cachexia. The
bioactivity appears to be associated with the loss of skeletal
muscle mass and is absent from the sera of healthy control
subjects. This material has now been purified from a cachexiainducing murine tumor (MAC16) and from the urine of patients
with cancer cachexia by use of affinity chromatography with a
monoclonal antibody derived from mice bearing the MAC16
tumor (121). The PMF from both murine and human sources
appeared to be identical and was characterized as a sulfated
glycoprotein of a molecular mass of 24 kd and of unique amino
acid sequence (122,123). Although the PMF was readily detected in the urine of cachectic cancer patients, irrespective of
the tumor type, it was absent from the urine of cancer patients
with little or no weight loss, from the urine of normal subjects,
or from the urine of patients with weight loss due to trauma or
sepsis (122). When the PMF was injected into non-tumorbearing mice, rapid weight loss (about 10% in 24 hours) was
observed, without a reduction in food and water intake, and body
composition analysis showed selective depletion of the lean
body mass. Evidence for a direct effect of the PMF was provided
by the induction of protein degradation in isolated gastrocnemius muscles (121). The conservation in structure of this material
between murine and human sources suggests that production of
a PMF may be important in the growth and survival of some
tumors.

tite, but this effect did not result in weight gain or an improvement in performance status, energy levels, mood, or relief from
pain (128). Results with the appetite stimulant megestrol acetate
look more promising in terms of weight gain. A number of
clinical studies (129,130,131) have been performed, all of which
report an increase in appetite and weight gains of up to 6.8 kg
over baseline values in 16% of patients treated. However, body
composition analysis, as determined by use of dual-energy x-ray
absorptiometry and tritiated body water methodologies measured at the time of maximum weight gain, showed that the
majority of patients gained weight from an increase in adipose
tissue, while an increase in body fluid was responsible for a
small portion of the weight gained (131). An increase in lean
body mass was not observed. Such body composition changes
are similar to those observed in patients receiving total parenteral nutrition (7).
Pharmacologic approaches to the treatment of cancer cachexia have been more successful. Hydrazine sulfate, an agent that
inhibits the enzyme phosphoenolpyruvate carboxykinase, has
been demonstrated to favorably influence the abnormal glucose
and protein metabolism in cachectic cancer patients (132) and to
maintain or even increase body weight (133). Ibuprofen, a cyclooxygenase inhibitor, has been shown to reduce the resting
energy expenditure in patients with pancreatic cancer, suggesting that it may have a role in abrogating the catabolic processes
that contribute to weight loss (134). Serum C-reactive protein
levels were also reduced. The polyunsaturated fatty acid eicosapentaenoic acid, another cyclooxygenase inhibitor, has also been
shown to counteract the weight loss in patients with pancreatic
cancer with stabilization of protein and fat reserves (135). This
result was accompanied by a temporary reduction in acute-phase
protein production and stabilization of resting energy expenditure. The effect appears to be specific for eicosapentaenoic acid,
since patients receiving a related polyunsaturated fatty acid,
gammalinolenic acid, continued to lose weight. A similar structureactivity relationship was observed in mice with cachexia
induced by the MAC16 tumor (136). Eicosapentaenoic acid appears to act by attenuating the action of catabolic factors in
cachexia. Induction of lipolysis by an LMF was inhibited by
eicosapentaenoic acid, and the effect appeared to be due to prevention of the rise in adipocyte cyclic adenosine monophosphate
levels (108). Administration of eicosapentaenoic acid also led to
statistically significant reductions in protein degradation in vivo
(136), possibly as a result of the ability to inhibit prostaglandin
E2 production in skeletal muscle by a PMF (119).

expected to extend the survival time. In addition, since some

tumors may depend on the products from host tissue catabolism
for survival, such therapy may also have an antitumor effect.
Considering that cachexia is common in those cancers for which
therapy is currently limited, this could prove to be of great
clinical benefit.

(8)
(9)
(10)

Appendix: Methodology
Purpose

(11)

Our goal was to review the metabolic processes that contribute to cancer cachexia-related tissue wasting and to critically
assess the role of cytokines and catabolic factors as mediators of
these processes; studies of this condition in humans were emphasized as much as possible.

(12)

(13)

Information Source

Criteria for Evaluating Validity

(14)
(15)

(16)

(17)

(18)

Data from studies on humans rather than on experimental

animals have been used whenever possible, particularly if results
from the latter contradict the human evidence. Results from
animal experiments that involved use of models not appropriate
to the human condition have been excluded; these included studies of tumors that are rapidly growing or where the weight of the
tumor was large in relation to the weight of the animal. Since
cachexia is an in vivo phenomenon, priority was given to studies
in which whole animals were used.

(19)

(20)

(21)

(22)

Methods for Summarizing Evidence

There was insufficient data in this area to warrant highly
structured quantitative techniques, and a simple narrative approach has been used to summarize the evidence.

(23)

(24)

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Note
Manuscript received June 30, 1997; revised August 29, 1997; accepted September 29, 1997.

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