The Journal of Nutrition Vol. 129 No. 1 January 1999, pp. 243S-246S

Wasting in Cancer¹

Michael J. Tisdale

Pharmaceutical Sciences Institute, Aston University, Birmingham B4 7ET, United Kingdom

	ABSTRACT

Abstract Introduction References

Progressive weight loss is a common feature of many types of cancer and is responsible not only for a poor quality of life and poor response to chemotherapy, but also a shorter survival time than is found in patients with comparable tumors without weight loss. Although anorexia is common, a decreased food intake alone is unable to account for the changes in body composition seen in cancer patients, and increasing nutrient intake is unable to reverse the wasting syndrome. Although energy expenditure is increased in some patients, cachexia can occur even with a normal energy expenditure. Various factors have been investigated as mediators of tissue wasting in cachexia. These include cytokines such as tumor necrosis factor- (TNF-), interleukin-6 (IL-6), interferon- (IFN-) and leukemia inhibitory factor (LIF), as well as tumor-derived factors such as lipid mobilizing factor (LMF) and protein mobilizing factor (PMF), which can directly mobilize fatty acids and amino acids from adipose tissue and skeletal muscle respectively. Induction of lipolysis by the cytokines is thought to result from an inhibition of lipoprotein lipase (LPL), although clinical studies provide no evidence for an inhibition of LPL in the adipose tissue of cancer patients. Instead there is an increased expression of hormone sensitive lipase, the enzyme activated by LMF. Protein degradation in cachexia is associated with an increased activity of the ATP-ubiquitin-proteasome pathway. The biological activity of both the LMF and PMF was shown to be attenuated by eicosapentaenoic acid (EPA). Clinical studies show that this polyunsaturated fatty acid is able to stabilize the rate of weight loss and adipose tissue and muscle mass in cachectic patients with unresectable pancreatic cancer. Knowledge of the mechanism of cancer cachexia should lead to the development of new therapeutic agents.

	INTRODUCTION

Abstract Introduction References

About half of all cancer patients experience a wasting syndrome called cachexia in which the tumor induces metabolic changes in the host leading to loss of adipose tissue and skeletal muscle mass. Patients with pancreatic and gastric cancer have the highest frequency of weight loss (83-87%) (De Wys et al. 1980), and in patients with pancreatic cancer weight loss (14%) is evident at the time of diagnosis, and is progressive, increasing to a median of 24.5% just before death (Wigmore et al. 1997). Patients with more than 15% weight loss are likely to have significant impairment of respiratory muscle function, which is probably the major contributor to the shortened survival time of cancer patients with weight loss (De Wys et al. 1980). Gender related differences in the rate of weight loss in nonsmall cell lung cancer is responsible for the significantly shorter survival time in men than women (40 versus 78 weeks after diagnosis) (Palomeres et al. 1996). Thus a knowledge of the mechanism(s) of cancer cachexia could lead to the development of agents which would increase the survival time of cancer patients, without necessarily having an antitumor effect.

	ANOREXIA AND ENERGY EXPENDITURE

Cachexia is not a local effect of a tumor, but is thought to arise from distant metabolic effects, i.e. it is a type of paraneoplastic syndrome. Although some theories have suggested a tumor/host competition for nutrients this seems unlikely, since some cancer patients with very large tumors show no signs of cachexia, while in others cachexia can occur when the tumor mass represents less than 0.01% of the host weight (Morrison 1976).

Weight loss can arise from a decreased energy intake, an increased energy expenditure or a combination of both. Anorexia is common in cancer patients with reports of incidences between 15 and 40% at presentation (De Wys 1972). However, cancer patients with weight loss appear to have a decreased food intake when expressed per kg of their usual weight, but not their current weight (Grosvenor et al. 1989). In addition although food intake is reduced in advanced cancer it is often normal in early disease, even though weight loss may be apparent (Costa et al. 1981). These results suggest that anorexia is not responsible for the weight loss in cancer cachexia. Clinical studies directed towards increasing energy intake in cancer patients have failed to reverse the cachexia. Such studies include dietary counseling (Oversen et al. 1993), total parenteral nutrition (TPN) (Evans et al. 1985) and the appetite stimulant cyproheptadine (Kardinal et al. 1990). The appetite stimulant megestrol acetate (Megace) has been reported (Loprinzi et al. 1993a) to induce a weight gain of greater than 5% in 15% of the patients treated, although significant changes in lean body mass were not generally observed (Loprinzi et al. 1993b). A general conclusion from these studies has been that cachectic patients who do gain weight by provision of excess calories show an increase only in body fat, without a significant change in total body nitrogen.

Patients with cancer have a highly variable change in energy expenditure. Thus in comparison with control groups patients with malignant disease have been reported to have a reduced (Knox et al. 1983), normal (Nixon et al. 1988) or an elevated (Fredrix et al. 1991) energy expenditure. Tumor type appears to play an important role in determining energy expenditure. Thus patients with lung (Fredrix et al. 1990) and pancreatic (Falconer et al. 1994) cancer have an increased resting energy expenditure (REE) compared with healthy control subjects. However, patients with gastric and colorectal cancer (Fredrix et al. 1990) were reported to have no elevation of REE. Thus weight loss can occur in some patients with what appears to be a normal energy intake and a normal energy expenditure. This suggests that tumor and/or host factors play an important role in the depletion of body lipid and protein during the process of cachexia.

	FACTORS INFLUENCING FAT METABOLISM IN CACHEXIA

Fat constitutes 90% of the adult fuel reserves and depletion of fat is commonly seen in cancer cachexia. Fasting plasma glycerol concentrations have been shown to be higher in weight-losing cancer patients compared with weight-stable individuals, providing evidence for an increased lipolyis (Drott et al. 1989). Cancer patients with weight loss also have an increased glycerol and fatty acid turnover when compared with normal subjects or cancer patients without weight loss (Shaw and Wolfe 1987).

Two mechanisms have been proposed to account for the decrease in body lipids in cancer cachexia: (i) Inhibition of the clearing enzyme lipoprotein lipase (LPL), which would prevent adipocytes from extracting fatty acids from plasma lipoproteins for storage, and would result in a net flux of lipid into the circulation. (ii) Direct stimulation of triglyceride hydrolysis in adipocytes by activation of triglyceride lipase, in a manner similar to that observed with lipolytic hormones. The cytokines tumor necrosis factor-alpha (TNF-), interleukin 6 (IL-6), interferon- (IFN-) and leukemia inhibitory factor (LIF) are all thought to decrease carcass lipids through inhibition of LPL (Strassman and Kambayashi 1995). The potency of the various cytokines in inhibiting LPL is not the same. Thus LIF is two- to ten-fold less potent than TNF- and IL-6 is 100-fold less potent than LIF. Also in 3T3-LI adipocytes LIF caused a small increase in lipolysis, whereas TNF- increased lipolysis greater than two-fold, demonstrating that the catabolic effects of LIF are less than that of TNF- (Marshall et al. 1994). Stimulation of lipolysis by TNF- is not direct, since it became apparent only after a 6 h exposure at the earliest (Hauner et al. 1995). In contrast a number of reports (Beck and Tisdale 1987, Kitada et al. 1980, Masuno et al. 1981) have documented the production by cachexia-inducing tumors of a lipid mobilizing factor (LMF) that causes immediate release of glycerol when incubated with murine epididymal adipocytes. Induction of lipolysis by LMF was associated with an increase in the intracellular level of cyclic AMP, possibly formed in response to activation of adenylate cyclase (Tisdale and Beck 1991).

Elevation of plasma levels of fatty acids and triglycerides in cachectic cancer patients (Rofe et al. 1994) has often been used as an argument for cytokine involvement in cancer cachexia. However, patients with AIDS experience hypertriglyceridemia, but still maintain their body weight for prolonged periods of time (Grunfeld et al. 1989). In addition TNF- induced hypertriglyceridemia persists in animals despite the development of tachyphylaxis to its anorectic/cachectic effect. Further studies showed the hypertriglyceridemia to be the result of stimulation of hepatic lipogenesis rather than inhibition of LPL (Grunfeld and Feingold 1991). Thompson et al. (1993) were not only unable to detect elevated TNF- levels in cachectic cancer patients, but in addition the total LPL enzyme activity and the relative levels of the mRNA's for LPL and fatty acid synthase were not significantly different between cancer patients and controls. There was, however, a two-fold elevation in the relative level of the mRNA for hormone-sensitive lipase in the adipose tissue of the cachectic cancer patients, providing evidence for lipid breakdown through the cyclic AMP pathway. Disruption of lipid metabolism through inhibition of LPL alone is unlikely to induce the large depletion of body fat seen in cancer cachexia. Patients with type 1 hyperlipidemia have an inherited deficiency of LPL, but are not cachectic and have normal fat stores.

The serum and urine of cachectic cancer patients contains a LMF the activity of which has been shown to correlate with the extent of weight loss (Groundwater et al. 1990). Such activity is not detectable in normal subjects or in patients with weight loss due to Alzheimer's disease. The LMF appears to correlate with tumor burden, since activity was found to be reduced in patients responding to chemotherapy (Beck et al. 1990). Further evidence for the importance of LMF in cancer cachexia has been provided by clinical studies on the polyunsaturated fatty acid (PUFA), eicosapentaenoic acid (EPA) (Wigmore et al. 1996). In vitro studies using a LMF isolated from a cachexia-inducing murine tumor (MAC16) showed that out of a range of PUFA only EPA was an effective inhibitor of biological activity and only EPA was effective in vivo against the cachexia induced by the MAC16 tumor. Patients with unresectable pancreatic cancer receiving EPA showed a stabilization in the rate of weight loss, adipose tissue and muscle mass as well as the REE (Wigmore et al. 1996). This study is the first to show that pharmacological interference with a tumor factor is capable of counteracting the wasting of cachexia.

	FACTORS INFLUENCING MUSCLE METABOLISM IN CACHEXIA

Lean body mass and visceral protein depletion is characteristic of patients with cancer cachexia and the degree of depletion may be associated with reduced survival (Nixon et al. 1980). The major site of this protein loss is the skeletal musculature (McMillan et al. 1994). A reduced rate of protein synthesis and an increased rate of degradation has been observed in muscle biopsies from cancer patients with weight loss (Lundholm et al. 1976). Elevated whole body protein turnover may be apparent in patients with a small tumor burden (Fearon et al. 1988), and in one study increased total body protein turnover was observed in patients with pre-cachectic lung cancer (Heber et al. 1982), which was found to be inversely proportional to the small degree of weight loss that had occurred.

TNF- appears to be involved with an enhanced protein degradation, although this does not appear to be related to weight loss. Thus treatment with TNF- has been shown to enhance protein degradation in rat skeletal muscle in vivo, and although body weight loss was not apparent there was a reduced protein accumulation (Llovera et al. 1993). Treatment of rats bearing the Yoshida AH-130 ascites hepatoma with goat anti m TNF- IgG decreased protein degradation rates in heart, liver and gastrocnemius muscle, but did not affect weight loss (Costelli et al. 1993). In both skeletal muscle from rats treated with TNF- (Llovera et al. 1993) and from rats bearing the Yoshida AH-130 hepatoma (Llovera et al. 1994) an increase in polyubiquitin gene expression was observed. Atrophy of muscles was also observed in IL-6 transgenic mice which was associated with increased mRNA levels of ubiquitins (poly and mono). The pathway responsible for the accelerated proteolysis in starvation, acidosis and after transplantation of certain tumors is thought to be the ubiquitin-proteasome system. Although early studies failed to find a direct action of TNF- on protein degradation, when either tyrosine or 3-methylhistidine were used as a measure of the proteolytic rate (Goldberg et al. 1988), a recent report (Llovera et al. 1997) has shown an increase in ubiquitin gene expression in rat soleus muscle after incubation with TNF- for 180min in vitro, with no change in the expression of the C8 proteasome subunit. Also using C₂C₁₂ myotubes in vitro Ebisui et al. (1995) found that recombinant human IL-6 (rh IL-6) shortened the half-life of long lived proteins and increased the activity of the 26S proteasome and cathepsins B and B+L. Interestingly recombinant human TNF- (rh TNF-) was shown to prolong the half-lives of long-lived proteins while reducing the protease activities of the 26S proteasome and cathepsins B and B+L. The variability of the response of cytokines in different systems and the lack of correlation with the wasting process may be due to the fact that they do not act directly, but instead cause induction of further factor(s), which themselves may be responsible for the wasting.

One such mediator could be a protein mobilizing factor (PMF), which has been recently isolated from a cachexia-inducing murine tumor (MAC16) and from the urine of patients with cancer cachexia (Todorov et al. 1996a). This material was shown to be a sulfated glycoprotein or proteoglycan of molecular weight 24 kDa, the structure of which was distinct from the recognized cytokines. Administration of the PMF to non tumor-bearing mice induced a state of cachexia with loss of 2.7 g body weight over a 24 h period without an effect on food and water intake. Blood glucose levels were significantly decreased, but there was no alteration in plasma triglyceride levels, unlike the effect observed with cytokines. Body composition analysis showed a reduction in lean body mass without a change in water composition. The PMF was capable of inducing tyrosine release from isolated gastrocnemius muscle and the effect could be blocked by a monoclonal antibody specific to the PMF (Todorov et al. 1996b). Western blotting of urine using the monoclonal antibody showed the 24 kDa glycoprotein to be present in all cancer patients with weight loss, but absent from cancer patients with little or no weight loss, confirming the specificity to the cachectic state. In addition it was absent from the urine of normal subjects or those with weight loss due to major burns, multiple injuries or surgery-associated catabolism and sepsis (Todorov et al. 1996a). Thus this material appears to be specific for muscle wasting in cancer. In addition the PMF was shown to be attenuated by EPA (Smith and Tisdale 1993) which has been shown to preserve muscle mass in cachectic cancer patients (Wigmore et al. 1996).

	SUMMARY AND CONCLUSION

Unlike simple starvation, where body fat is lost preferentially, cancer cachexia is associated with depletion of both fat and skeletal muscle mass. Although anorexia is frequently associated with cachexia a reduction of nutrient intake alone could not explain the progressive wasting. Instead the process appears to be mediated by circulatory tumor-produced catabolic factors acting either alone or in concert with certain cytokines. A knowledge of the mechanisms involved should lead to the development of effective pharmacological intervention. Effective therapy should not only improve the quality of life of the cancer patient, but should lead to an increase in survival. Since cachexia is so common in cancer host products may be required for tumor homeostasis. Thus further knowledge in this area may lead to the development of new agents for the treatment of cancer.

	FOOTNOTES

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