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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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, MD, PhD.

The causes of cancer-related cachexia are multifold and can be grouped into three interrelated categories: anorexia and early satiety, mechanical obstruction of the alimentary tract, and metabolic derangement.18

Anorexia and Early Satiety

Anorexia may be defined as the loss of desire to eat or the lack of hunger. Anorexia may result from early satiety, nausea, or a change in taste. Early satiety is the desire to eat associated with an inability to eat adequately.5

Anorexia in cancer patients can be divided into disease related, treatment related, and that caused by emotional distress.19

Abnormalities of taste sensation and olfaction for food aromas have been demonstrated in cancer patients.20,21 These patients displayed an elevated threshold for sweet compared to healthy subjects, which correlated with a loss of taste sensation. Patients experiencing early satiety found the odors of pork, ham, and coffee less pleasant than those without early satiety.

Many factors are causes of anorexia, including increases in serum lactate, known to be produced abundantly by tumor; appearance of ketosis during fasting; hypercalcemia, a common paraneoplastic syndrome; lipolytic substances isolated from the urine of cancer patients; toxohormone-L, a lipolytic factor purified from ascitic fluid of patients with hepatoma; bombesin, a neuropeptide produced by small-cell lung cancer; satietins, proteins isolated from human plasma; glucagon or glucagon-like peptides; increases in serum and central nervous system (CNS) serotonin levels in cancer patients; certain cytokines; and possibly dysfunction of neuropeptidergic circuits in the brain.22–32 These findings suggest that the causes of tumor-induced anorexia are multifactorial. Among these factors, serotonin, cytokines, and neuropepidergic circuit dysfunction are worthy of additional comments.


Abnormal use by tumor cells of tryptophan, the precursor of serotonin, with resultant excess levels of free tryptophan in plasma has been reported in cancer patients.33 Increases in blood tryptophan levels produce excess tryptophan levels in the cerebrospinal fluid, which appears to lead to increased serotonin synthesis/secretion in the ventromedial hypothalamic (VMH) serotonergic system. A close relationship between elevated plasma-free tryptophan and anorexia with reduced food intake was observed in patients with cancer.30 As described below, new findings concerning the role of cytokines and neuropeptide circuits seem to have focused on CNS serotonin as a major component of an explanation for anorexia.34


Cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), released by the tumor or host immune system, were shown to be mediators of anorexia. While TNF-α induces IL-1, both TNF-α and IL-1 appear to be operative in mediating their anorectic effect through the brain as well as directly on the gastrointestinal tract, eg, decrease in gastric emptying.35 Peripherally infused IL-1 increased tryptophan and serotonin concentrations and release in the VMH, suggesting that IL-1 production during tumor growth facilitated tryptophan supply to the brain.36 While interferon-γ (IFN-γ) infusion produced anorexia in clinical trials in patients with renal cell cancer, the appearance of anorexia in mice associated with tumor growth were similar whether mice were wild type or IFN-γ knockout, suggesting that endogenous IFN-γ plays little role in producing anorexia in the tumor-bearing host.37,38 Interleukin-6 (IL-6) appears to have no direct anorectic effect.39,40

Animal studies showed development of tolerance to injections of TNF-α and IL-1.41–43 IL-1 infusion was not anorexigenic in food-deprived rats.44 Serum levels of circulating TNF-α, IL-1, IL-6, and IFN-γ did not correlate with anorexia and weight loss in cancer patients.45 These studies imply that anorexigenic actions of these cytokines are processed by intermediary molecules. Cytokines not only produce anorectic effects but also exert direct catabolic activity on muscle and adipose tissues. This is discussed in separate sections later.

Dysregulation of Neuropeptidergic Circuits

Recent studies with hormonal regulation of the neuronal circuits that control food intake have extended our understanding of energy homeostasis and its malfunctions, obesity and cachexia. Both insulin, secreted from the exocrine pancreas, and leptin, produced primarily by adipocytes, circulate at levels proportional to body fat content and enter the CNS in proportion to their plasma levels. As weight increases, insulin secretion is increased both at the basal state and in response to meals to compensate for insulin resistance. Increased insulin secretion as obesity progresses promotes insulin delivery to the brain, where it helps to limit further weight gain. Insulin also promotes both fat storage and leptin synthesis by fat cells. Leptin has a more important role than insulin in the CNS control of energy homeostasis. Thus, leptin deficiency causes severe obesity with hyperphagia that persists despite high insulin levels. In contrast, obesity is not induced by insulin deficiency.46

Both insulin and leptin interact with several distinct hypothalamic neuropeptide-containing pathways. Neuropeptides implicated in the control of energy homeostasis are divided into orexigenic (anabolic) and anorexigenic (catabolic) signaling molecules (Table 144-1). Among orexigenic peptides, neuropetide Y (NPY) has been the most widely studied. Leptin inhibited gene npy expression and gene knockout of npy reduced hyperphagia and obesity in ob/ob mice. Intraventricular or hypothalamic injections of NPY in rats stimulated food intake and decreased energy expenditure, primarily from a reduction in thermogenesis in brown adipose tissue and by facilitating fat deposition in white adipose tissue, partly through increased insulin activity. During active depletion of body fat stores and/or reduced leptin/insulin signaling to the brain, npy gene expression and secretion of the NPY peptide in the hypothalamus are increased. Anorexigenic molecules have an opposite set of characteristics. Neuronal synthesis of these peptides increases in response to increased adiposity signaling in the brain. Corticotropin-releasing hormone (CRH) decreases food intake and increases sympathetic nervous activity leading to increased thermogenesis, lipolysis, and blood glucose levels. Chronic administration of CRH caused sustained anorexia and progressive weight loss. Melanocortins such as α-melanocyte-stimulating hormone (α-MSH) bind to melanocortin receptors, MC3 and MC4, expressed in the brain. Tonic signaling of MC4 receptors limits food intake and body fat mass.46

Table 144-1. Orexigenic (Anabolic) and Anorexigenic (Catabolic) Neuropeptides.

Table 144-1

Orexigenic (Anabolic) and Anorexigenic (Catabolic) Neuropeptides.

Dysregulation of this neuropeptidergic circuit controlling food intake and energy expenditure and thus energy homeostasis may play a role in the development of the cancer anorexia-cachexia syndrome.32 Thus, rats bearing methylcholanthrene-induced sarcomas exhibited refractory feeding response to intrahypothalamic injection of NPY, as compared to controls.47 Reduced affinity of hypothalamic NPY receptors as well as refractory adenylate cyclase in response to NPY suggested that the postsynaptic NPY-signaling systems were altered in the hypothalamus of tumor-bearing rats.48,49

Several cytokines including TNF-α, IL-1, and leukemia inhibitory factor (LIF) increase the expression of leptin messenger ribonucleic acid (mRNA) in adipose tissue and increase plasma leptin levels50; IL-1β blocked hypothalamic NPY mRNA levels and decreased NPY-induced feeding, whereas it stimulated CRH in parallel with suppression of food intake.51,52 Conversely, at different doses NPY blocked and reversed IL-1β-induced anorexia.53 In addition, TNF-α and IFN-γ were also shown to stimulate CRH expression and/or release.54 Cytokines may play an important role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin by persistent stimulation of anorexigenic neuropeptides such as CRH or by inhibition of the NPY orexigenic network (Figure 144-1).32

Figure 144-1. A simplified provisional model for the central nervous system circuitry of food intake and energy balance in cancer anorexia and cachexia.

Figure 144-1

A simplified provisional model for the central nervous system circuitry of food intake and energy balance in cancer anorexia and cachexia. AGRP = agouti-related protein; CART = cocaine- and amphetamine-regulated transcript; CRH = corticotropin-releasing (more...)

It is noteworthy that there are reports that describe an opposite view. Thus, NPY mRNA levels are not always increased in anorectic tumor-bearing rats when compared with pair-fed or control animals.55 While synthesis and secretion of leptin appear to be stimulated by cytokines such as IL-1, circulating leptin levels are not elevated in cachectic cancer patients.56,57

Thus, a number of factors have been proposed as putative mediators of cancer anorexia, including hormones (eg, leptin), neuropeptides (eg, NPY), cytokines (eg, IL-1, TNF), and neurotransmitters (eg, serotonin and dopamine). Rather than these factors representing separate and distinct pathogenic entities, it appears that close interrelationships exist among them. Indeed, many studies suggest that different anorexia-related factors converge on a common final pathway, that is, hypothalamic monoaminergic neurotransmission and serotonergic activity in particular as a major target.58,59

Emotional Distress

Anorexia may occur with emotional distress, for example, at the time cancer is diagnosed, prior to major treatment decisions, and upon discovering that cancer is advancing. Anorexia from emotional distress is usually transient, however, and the impact of this type of anorexia on cancer cachexia is insufficient to explain it. One cause of weight loss can be a psychotic depression, which may be unrecognized because many of the symptoms and effects are attributed directly to the cancer. The use of antidepressants for a true psychotic depression established by psychiatric consultation can have a profound positive effect on appetite.

Anorexia versus Cachexia

Anorexia should not be equated with cachexia. In cachectic cancer patients the measured food intake fails to correspond with the degree of malnutrition.60 Loss of both muscle and adipose tissue precede the decrease in food intake.61 Some patients present initially with significant weight loss as their first and only symptom in the face of dietary intake that ordinarily would be normal. Thus, children with diencephalic syndrome exemplify the discordance of weight loss and apparently normal or supranormal food intake.62 This syndrome is detailed in a later section (Specific Organ Dysfunction).

Alimentary Tract Dysfunction

Abnormalities in perception of taste and smell have been described in cancer patients. Tumors of the mouth, oropharynx, esophagus, stomach, pancreas, liver, and peritoneum may compromise oral intake from mechanical interference with anatomic structures. Intestinal obstruction is a common complication of cancer. Malabsorption secondary to pancreatic insufficiency because of pancreas carcinoma or secondary to the infiltration of the intestine or mesentery by lymphoma has been described.63,64

Direct encroachment of a tumor on the gastrointestinal tract, atrophic changes in the mucosa and muscles of the stomach, a reduction in the duration or activity of digestive enzymes, which may lead to delayed gastric emptying, and slowing of peristalsis are all pathogenic mechanisms that may contribute to early satiety.5,6 Early satiety is common in patients with decreased upper gastrointestinal motility.65 Increases in blood glucose levels sometimes seen in cancer patients may cause delay in gastric emptying resulting in a prolonged sense of fullness and suppression of appetite.

Major surgery for cancer, particularly on the gastrointestinal tract, may produce abnormalities in taste, and difficulties in swallowing, digestion, or absorption that may contribute indirectly to anorexia. Chemotherapy commonly induces abnormal perception of taste, mucositis, and nausea and vomiting. Radiotherapy to the head and neck can induce stomatitis, xerostomia, and alterations in taste and smell. Radiotherapy to the abdomen can induce anorexia, nausea, vomiting, diarrhea, and malabsorption.

Biochemical and Metabolic Derangement

The situation of cancer cachexia is similar to that seen with human immunodeficiency virus (HIV) or sepsis: weight loss can result from complex metabolic events. Several biochemical and metabolic derangements are considered to be causally related to the pathogenesis of cancer cachexia.

Increased Glucose Use and Futile Substrate Cycles

High rates of glucose use with production of lactic acid are characteristic features of the neoplastic cell. In mice bearing transplantable colon tumors, glucose use by the tumors was second only to that by the brain.66 Hexokinase, which catalyzes the first step of the glycolytic pathway and which is often highly overexpressed in tumor cells, is a major player in this process.67 Binding of tumor hexokinase to the outer mitochondrial membrane provides the enzyme with preferential access to mitochondrially generated adenosine triphosphate (ATP) and increases the activity and stability of the enzyme.68 The end product of the hexokinase reaction, glucose-6-phosphate, serves not only as a source of ATP via glycolysis, but is also a key intermediate in the metabolic processes essential for cell growth and proliferation. Alteration of an isozyme appears closely linked to this process. Thus, the promoter activity of the type II isoform of hexokinase, the dominant form expressed in AS-30 hepatoma cells, was found to be resistant to normal hormonal control.69 Recently, the distal region of the promoter was found to display consensus motifs for hypoxia-inducible factor (HIF-1) and subjecting transfected hepatoma cells to hypoxic conditions activated the type II hexokinase promoter almost sevenfold in the presence of glucose.70 The tumor cell was able to maintain glycolysis regardless of the metabolic state of surrounding normal cells.

Lactic acid produced via glucose metabolism may be used by other tissues for energy purposes or may be transported to the liver for resynthesis to glucose. The cyclic metabolic pathway, in which glucose is converted to lactic acid by glycolysis in tumor tissue and then reconverted to glucose in the liver, is referred to as the Cori cycle. Conversion of glucose to lactate in cancer cells yields two ATPs, whereas lactate to glucose conversion in the liver requires six ATPs. Thus a systemic energy-losing or futile substrate cycle, involving this interplay of tumor glycolysis and host gluconeogenesis may be an important cause of cancer cachexia.71 Assuming that all lactate produced is recycled to glucose, the cancer cell acts as an energy parasite. It may be calculated, however, that if 85% of lactate passes through the gluconeogenic pathway and 15% is oxidized, the host's handling of tumor-produced lactate would be energetically neutral. It has been suggested that the increase in the Cori cycle is insignificant in terms of energy expenditure and that increased glucose turnover itself is responsible for weight loss and development of cachexia.72


TNF-α, IL-1, IL-6 (and its subfamily members such as ciliary neurotrophic factor [CNTF] and LIF), and IFN-γ produced by host immune cells and/or tumor cells have all been implicated as mediators of cancer cachexia.73–75 These cytokines are characterized by the induction of anorexia; weight loss; an acute-phase protein response; protein and fat breakdown; rises in levels of cortisol and glucagon and falls in insulin level; insulin resistance; anemia; fever; and elevated energy expenditure in animals. Direct interaction with leptin, neuropeptides, and serotonin as mechanisms of induction of cancer anorexia was described above.


TNF-α was simultaneously discovered as cachectin because it caused systemic suppression of lipoprotein lipase and development of hypertriglyceridemia, a state frequently seen in cachectic animals.76 One mechanism by which TNF-α induces a net catabolic state in the host is by mediating increased catabolism at the level of specific tissues such as muscle and fat.77,78 TNF-α increases activities of both phosphofructokinase and fructose bisphosphate phosphatase in myocytes in culture producing an increased substrate cycling between fructose-6-phosphate and fructose-1,6-bisphosphate.79 Each of the fructose-6-phosphate/fructose-1,6-bisphosphate cycles loses one ATP. TNF increased ubiquitin gene expression in isolated rat muscle, total cellular ubiquitin-conjugated muscle protein in C2C12 myotubules and reduced the protease activities of the 20S proteasome and the lysosomal-proteolytic enzymes cathepsins B and B+L.80–82 In adipocytes, TNF-α induced a state of cellular catabolism and lipolysis by suppressing the biosynthesis of several lipogenic enzymes.83

Elevation of serum TNF-α and/or TNF-α receptor levels has been associated with the clinical status of patients with B-cell chronic lymphocytic leukemia, endometrial carcinoma, and other solid tumors.84,85 Administration of TNF-α in humans induced anorexia, negative nitrogen balance, and increases in serum triglycerides and in very-low-density lipoprotein.86,87 In contrast, TNF-α was rarely detected in patients with clinical cancer cachexia and administration of recombinant TNF-α did not produce demonstrable cachexia.88 Patients with type I hyperlipidemia caused by an inherited deficiency in lipoprotein-lipase have normal fat stores and are not cachectic. These observations suggest that TNF-α administration or suppression of lipoprotein-lipase alone cannot explain loss of adipose tissue and cachexia in cancer patients.


IL-1 has many effects that mimic TNF-α.89 In mice bearing rapidly growing tumor, administration of neutralizing antibody against either TNF-α or against an IL-1 receptor resulted in significant improvements in food intake and a trend to increased whole-body lipid content.90 In contrast, IL-1 receptor antagonist was ineffective in preventing tissue depletion and protein catabolism when administered to rats bearing Yoshida ascites hepatoma.91 Cachexia-producing colon-26 adenocarcinoma cells expressing the gene for IL-1 receptor antagonist nevertheless produced cachexia when transplanted in mice.92 Recently, the genotype for a diallelic polymorphism of the IL-1β gene was examined in patients with pancreas cancer.93 The possession of a genotype resulting in increased IL-1β production was associated with shortened survival and increased serum C-reactive protein (CRP) level. This may reflect the role of IL-1β in inducing an acute-phase protein response and cachexia in cancer.


Involvement of IL-6 in the development of cancer cachexia has been suggested from a number of animal models.73,94 IL-6 induced proteolysis by activating intracellular proteases (cathepsin B and L, proteosomes) in C2C12 myotubes in culture and degradation of skeletal muscle proteins in rat.95,96 IL-6 also induced gluconeogenesis in hepatocytes in culture.96,97 The administration of antibody to mouse IL-6 or anti-IL-6 receptor antibody attenuated the development of cachexia in mice, and reduced the weight loss and wasting of muscle and adipose tissue after development of cachexia.98–100 Prevention of muscle atrophy in tumor-bearing mice by anti-IL-6 receptor antibody appears to be mediated by modulation of lysosomal and ATP-ubiquitin-dependent proteolytic pathways.98 In vivo, however, IL-6 administration produced no changes in ubiquitin gene expression, and no effect on body weight or food intake, despite being associated with increased acute-phase protein production.40

In order to examine the role of host-derived cytokines on tumor growth and cachexia, cytokine gene knockout mice were examined.39 In IL-6 gene knockout mice that carried MCG 101 tumor, both rapid tumor growth and cachexia were attenuated as compared to wild-type mice bearing the same tumor. The absence of host-derived IL-12, IFN-γ, or TNF receptor type 1 or 2 genes did not attenuate tumor growth or prevent subsequent cachexia. Indomethacin administration in both wild-type and gene knockout mice reduced plasma prostaglandin levels and improved carcass weight. These results indicate that IL-6 derived from both tumor and host tissues is a significant tumor growth factor with similar effect as IL-1 and TNF-α, and that host- and tumor-derived cytokines and prostaglandins interact with tumor growth and promote cachexia in a complex fashion. Overall, host cytokines appeared less important than tumor-derived cytokines to explain net tumor growth that indirectly explains subsequent cachexia and anorexia.39 The influence of IL-1 on cachexia appears to be mediated through IL-6, and IL-6 seems to act in concert with other cytokines in a final common pathway of cachexia.101,102

In patients with lung cancer, increased IL-6 levels were correlated with extensive disease, impaired performance status, enhanced acute-phase response, weight loss, and malnutrition.103,104

The exact role of IL-1 and IL-6 in the development of cancer cachexia in humans remains speculative, however. Serum IL-6 concentrations were significantly elevated in tumor-bearing animals but only minimally in patients with cancer.105 IL-1 and IL-6 serum levels were not always measurable.106 Administration of IL-6 administration failed to produce cachexia, and transgenic mice expressing IL-6 constitutively did not develop cachexia.107,108 It has been suggested that IL-6 is necessary but not sufficient for the induction of cachexia, and that additional factor(s) besides IL-1β control production of IL-6 and other cachexigenic factors.93

The superfamily of IL-6 includes LIF and CNTF. These substances are discussed in later sections.


IFN-γ may have a bearing on the development of cancer cachexia. Interferons and TNFs have similar catabolic effects on 3T3 cells in vitro.109 Monoclonal antibody against IFN-γ given prior to injection of Lewis lung tumor cells prevented cachexia from developing.110 IFN-γ was found to be increased in 51% of patients with multiple myeloma.111 The levels of IFN-γ had no correlation with the clinical parameters, however.

Tumor Byproducts

Various pharmacologically active tumor byproducts have been reported as causal factors of cachexia.

Lipolytic Factors

Three different lipolytic factors have been characterized or purified. First, a lipolytic factor termed toxohormone-L was found in pleural effusions of patients with malignant lymphoma, as well as in ascites from patients with ovarian carcinoma and hepatoma.25 It is an acidic protein with a molecular weight of 65 to 75 kilodaltons (kDa). Toxohormone-L elicited fatty acid release in rat adipose tissue in vitro, and injections into rat resulted in suppression of food and water intake. Toxohormone-L and related substances were considered responsible for the cancer cachexia syndrome in nude mice bearing human cancer cell lines.112

Second, LIF was originally isolated from conditioned medium of Krebs II ascites tumor cells. This factor has a differentiation-inducing activity on myeloid leukemia cell lines. In independent work the identical material was purified from conditioned medium of human melanoma cell line SEKI. The substance was found to be an effective lipoprotein-lipase inhibitor.113,114 Comparisons among nude mice bearing various human melanoma cell lines revealed that the degree of LIF mRNA expression correlated with the development of cachexia.115

Third, British workers purified and characterized what they termed lipid-mobilizing factor (LMF), which was derived from MAC16 murine adenocarcinoma and from urine of cancer patients with cachexia.116,117 LMF, an acidic peptide, lacked triglyceride lipase activity and was different from natural lipolytic hormones, which were all basic LMF isolated from the murine tumor and that from the patients' urine both had an apparent molecular weight of 43 kDa and was homologous with the plasma protein Zn-α2-glycoprotein. Both caused stimulation of adenylate cyclase in murine adipocyte plasma membranes in a guanosine triphosphate (GTP)-dependent process and release of glycerol from isolated adipocytes. An increase in oxygen uptake by interscapular brown adipose tissue suggested that LMF exerted its effect by increases in energy expenditure.117 This increase might be related to changes in expression of uncoupling proteins (UCPs), because mice bearing MAC16 tumor showed higher UCP-1 mRNA levels in brown adipose tissue than did controls.118 The stimulation of oxygen consumption in brown adipose tissue by LMF suggested that this action is mediated through a β3-adrenergic receptor. β3-Adrenergic agonists upregulate UCP-1, leading to a net increase in energy use.119 Resting energy expenditure, whole-body oxygen uptake, and carbon dioxide production were found to be decreased in cancer patients with progressive weight loss after β-adrenoceptor blockage.120 Wasting of body tissue can be explained in part by an increased β-adrenoceptor activity leading to elevated cardiovascular activity. Production of LMF by cachexia-producing tumors appears to account for the loss of body fat and the increase in energy expenditure.1

In cancer patients with weight loss, the LMF found in serum and urine were much higher than those in noncancer control patients with comparable weight loss and was proportional to the degree of weight loss.121 Patients who responded to therapy showed a decrease in the plasma levels of the LMF, which correlated with the levels of response.122

Proteolysis-Mobilizing Factor or Proteolysis-Inducing Factor

Serum from cachectic mice bearing MAC16 adenocarcinoma and plasma from cancer patients with weight loss contained factors that induced proteolysis in skeletal muscles.1,123,124 These factors are termed proteolysis-mobilizing factor (PMF). PMF was purified from cachexia-inducing MAC16 murine tumors as well as from the urine of patients with cancer cachexia using a monoclonal antibody raised from mice bearing the MAC16 tumor.124 The PMFs derived from murine and human sources were identical: both were characterized as a sulfated glycoprotein with a molecular weight of 24 kDa, with a unique amino acid sequence.125–127 The murine monoclonal antibody can attenuate weight loss induced by human PMF in mice.128 PMF was readily detected in the urine of cachectic cancer patients, whereas it was absent in the urine of normal subjects and of patients with weight loss caused by trauma or sepsis.

Body composition analysis of mice with weight loss from PMF showed specific depletion of the nonfat carcass mass.128 Weight loss was associated with loss of skeletal muscles, but there was no effect on the heart and an increase in liver weight.128,129 These body-weight changes were similar to those observed in rats transplanted with the cachexia-inducing Yoshida ascites hepatoma.130 Protein degradation induced by PMF appears to be mediated through the ubiquitin-proteasome pathway.129

Production of PMF appears to be associated specifically with cancer cachexia and it was not found in the urine of patients undergoing major surgery or in those with burns, multiple injuries, sepsis, or sleeping sickness, even though the rate of weight loss exceeded that found in cancer patients.131 Patients with cancer of the pancreas, lung, colon, breast, rectum, liver, and ovary, and in whom the rate of weight loss was greater than or equal to 1 kg per month, showed evidence of PMF excretion in the urine.128 Eighty percent of patients with pancreas cancer excreted PMF in the urine.131

Hormonal Aberration

Hormonal aberration may be a contributory factor to cancer cachexia. In a unique endocrine animal tumor model, estrogen was incriminated as the cause of cancer cachexia.132 Abnormally low levels of testosterone or hypogonadism have been described in male patients with advanced cancer; these findings correlated with weight loss and adverse outcome.133,134 Plasma cortisol values and arterial glucagon levels in patients with malignant tumors were significantly increased, however, compared with patients with benign surgical disorders.135,136 This finding is in accord with the hypothesis that glucocorticoids are involved in the increased protein catabolism of skeletal muscles and other organs in cachectic cancer patients.

Prostaglandin Elevation

In animal systems, marked weight loss and wasting of muscle and adipose tissue after tumor transplantation were associated with the presence of circulating TNF-α and high levels of prostaglandin E2.137 Indomethacin reduced weight loss and increased survival of mice with transplantable tumors receiving chemotherapy.138 Ibuprofen, a cyclooxygenase inhibitor, abrogated IL-1-induced anorexia in rats.139 Close interaction of host- and tumor-derived cytokines and prostaglandins were suggested from animal models.38 These observations indicate that prostaglandin E2 contributes to cancer anorexia and cachexia.

Tumor Parasitism

Selective parasitism of the host by the tumor in the form of a successful competition for substrates with limited availability may be a cause of cachexia. Animal studies demonstrated that translocation of nitrogen from host to tumor constitutes nearly the total nitrogen depression of the host.140 Tumors are effective nitrogen traps independent of protein intake, despite the wasting of normal host tissue.141 Because cachexia can appear in patients with very small tumors, however, and the total tumor mass in the majority of cancer patients at death rarely exceeds 0.5 kg, it is unlikely that a simple competition of available nitrogen between tumor and host is responsible for the development of cachexia, especially in early stage cancer.

Dysfunction of Neuropeptidergic Circuit

Dysfunction of neuropeptidergic circuits as the mechanism of the cancer anorexia-cachexia syndrome has been discussed in the section on anorexia above. A brief mention of CNTF is added here. CNTF was first characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord, leading to its evaluation in humans suffering from motor neuron disease. In these trials, CNTF caused unexpected and substantial weight loss, raising concerns that it might produce cachectic-like effects. Countering this possibility was the suggestion that CNTF was working via a leptin-like mechanism to cause weight loss, based on the findings that CNTF acts via receptors that are not only related to leptin receptors, but also similarly distributed within hypothalamic nuclei involved in feeding. Recent observations show that CNTF can activate hypothalamic leptin-like pathways in diet-induced obesity models unresponsive to leptin, that CNTF improves prediabetic parameters in these models, and that CNTF acts very differently from the prototypical cachectic cytokine, IL-1.142 CNTF suppressed food intake without triggering hunger signals or associated stress responses that are otherwise associated with food deprivation. The involvement of CNTF in the development of cancer cachexia has been suggested but direct evidence has not been reported.

Metabolic Derangement Produced by Treatment

Surgery is associated with stress response, which includes hypermetabolism, tissue breakdown, and protein loss. This response leads to weight loss, fatigue, and deterioration in functional status. Postoperative weight loss results from increased energy expenditure caused by the stress response and a decreased dietary intake.143 Pancreatic resection can result in pancreatic exocrine and endocrine insufficiency creating major nutritional problems such as steatorrhea and hyperglycemia. In addition, major hepatic resections cause metabolic abnormalities in the immediate postoperative period. Extensive resection of the small bowel can lead to malabsorption of many nutrients.

A majority of chemotherapeutic agents are toxic, producing a variety of metabolic effects.147l-Asparaginase and IL-12 exemplify this: profound weight loss and/or hypoalbuminemia are among the common manifestations in patients treated with these compounds.144–146

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Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK13243


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