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Metabolic abnormalities in cachexia and anorexia
CACHEXIA-ANOREXIA WORKSHOP
Metabolic Abnormalities in Cachexia and Anorexia Michael J. Tisdale, PhD, DSc From the Pharmaceutical Sciences Research Institute, Aston University, Birmingham, UK An increased glucose requirement by many solid tumors produces an increased metabolic demand on the liver, resulting in an increased energy expenditure. In addition, several cytokines and tumor catabolic products have been suggested as being responsible for the depletion of adipose tissue and skeletal-muscle mass in cachexia. A sulphated glycoprotein of molecular mass 24 kDa, produced by cachexia-inducing tumors and present in the urine of cancer patients actively losing weight, has been shown to be capable of inducing direct muscle catabolism in vitro and a state of cachexia in vivo, with specific loss of the non-fat carcass mass. In vitro studies have shown the bioactivity of this proteolysis-inducing factor to be attenuated by the polyunsaturated fatty acid, eicosapentaenoic acid. Preliminary clinical studies have shown that eicosapentaenoic acid stabilizes body weight and protein and fat reserves in patients with pancreatic carcinoma. Further trials are required to confirm the efficacy of eicosapentaenoic acid and to determine the anticachectic activity in other types of cancer. Nutrition 2000;16:1013–1014. ©Elsevier Science Inc. 2000 Key words: cori-cycle, lipid-mobilizing factor, proteolysis-inducing factor, eicosapentaenoic acid
INTRODUCTION Wasting of body tissues and in particular loss of muscle mass is common in a number of clinical conditions including cancer, autoimmune-deficiency syndrome, chronic renal failure, and chronic gastrointestinal disease and is an important component of the aging process. Cancer patients with cachexia have a decreased performance status, a decreased response to chemotherapy and a shorter survival time1 because a 30% loss of body weight is invariably fatal.2
ALTERATIONS IN CARBOHYDRATE METABOLISM There are marked alterations in carbohydrate metabolism in the tumor-free tissues of patients with cancer, in particular the liver, which probably arise from the utilization of glucose by the tumor as the primary energy source.3 Metabolism of glucose under the hypoxic conditions pertaining to certain regions within most solid tumors produces large amounts of lactate, which is converted back into glucose in the liver—the Cori cycle. Cori-cycle activity has been found to increase from 20% in normal subjects to 50% of glucose turnover in cachectic cancer patients and accounts for the disposal of 60% of the lactate produced by the tumor.4 There is also an increased glucose synthesis from alanine5 and glycerol.6 Gluconeogenesis from lactate uses six ATP molecules for every lactate– glucose cycle and is very energy inefficient for the host. This futile cycle may be responsible at least in part for the increased energy expenditure reported in patients with lung7 and pancreatic8 cancer. A 40% increase in hepatic glucose production has been reported in weight-losing cancer patients9 in contrast to the reduced production seen in patients with anorexia nevosa. Thus, changes in carbohydrate metabolism in cancer patients probably arise as a consequence of meeting the metabolic
Correspondence to: Michael J. Tisdale, PhD, DSc, Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, UK. E-mail: [email protected] Date accepted: May 24, 2000. Nutrition 16:1013–1014, 2000 ©Elsevier Science Inc., 2000. Printed in the United States. All rights reserved.
demands of the tumor and may contribute to the development of the cachectic state.
ALTERATIONS IN LIPID METABOLISM Fat is a high-energy fuel reserve, and loss of adipose tissue arising from an increase in lipolysis is common in cancer patients.10 Such fat is used to meet the increased metabolic demands on the host caused by the presence of the tumor. In addition, metabolism of the polyunsaturated fatty acid, linoleic acid, through the 12lipoxygenase pathway may be essential in preventing apoptotic death in tumor cells.11 Mobilization of fatty acids from adipose tissue may occur before weight loss, suggesting the presence of a lipid-mobilizing factor (LMF) produced either by tumor or host tissues.12 A number of studies13–19 have provided evidence for the production of LMF by tumors that induce cachexia. These separate reports may describe the same or similar tumor factors, but to date no definitive identification of an LMF has been published. However, LMF acts directly on adipose tissue with the release of free fatty acids and glycerol through an elevation of the intracellular mediator cyclic AMP20 in a manner similar to that produced by the natural lipolytic hormones. In contrast, cytokines inhibit the clearing enzyme lipoprotein lipase, which would prevent adipocytes from extracting fatty acids from plasma lipoproteins for storage, resulting in a net flux of lipid into the circulation. It is unlikely that a single mediator will be found to explain catabolism of muscle and fat in all cachexias. Although evidence to date provides some support for a role of cytokines in wasting disorders from autoimmune-deficiency syndrome,21 there is less evidence for a role in cancer cachexia. Indeed, neither total lipoprotein-lipase enzyme activity, a marker for cytokine action, nor the relative level of mRNA for lipoprotein lipase and fatty-acid synthase were found to be significantly different in the adipose tissue of cancer patients when compared with control subjects.22 Rather, there was a two-fold increase in the relative level of mRNA for hormone-sensitive lipase, which is thought to mediate the action of LMF. This result and those of others on LMF bioactivity in the serum and urine of cancer patients17 suggest that 0899-9007/00/$20.00 PII S0899-9007(00)00409-3
1014
Tisdale
tumor catabolic products may be more important than cytokines in mediating loss of adipose tissue in cancer cachexia.
ALTERATIONS IN PROTEIN METABOLISM Depletion of lean body mass in cancer cachexia is a major factor responsible for the reduced survival time of cancer patients.23 Both reduced rates of protein synthesis and increased rates of protein degradation have been observed in biopsies of skeletal muscle from cachectic-cancer patients.24 Whereas muscle-protein synthesis is depressed, synthesis of secretory proteins, such as acutephase reactants, by the liver is actually increased, so that there may be no change in total body-protein synthesis.25 However, in these patients muscle-protein synthesis only accounted for 8% of total body synthesis versus 53% for healthy control subjects. Although to date no studies have been reported in cancer patients, degradation of myofibrillar proteins probably occurs by the adenosine triphosphate– ubiquitin– dependent proteolytic system because studies in animals have implicated this pathway not only in cachexia26 but also in starvation, sepsis, denervation atrophy, and metabolic acidosis. Loss of skeletal-muscle mass in both cancer patients27 and an experimental model of cachexia in the mouse28 has been shown to correlate with the presence in the serum of bioactivity capable of inducing protein degradation in isolated skeletal muscle. Such bioactivity has been termed the proteolysis-inducing factor (PIF). This material has recently been purified and characterized and shown to be a sulfated glycoprotein of molecular weight 24 kDa.29,30 Interestingly, bioactivity appears to reside in the carbohydrate rather than in the protein component of the molecule.31 Using antibodies obtained from mice transplanted with a cachexiainducing tumor, the 24-kDa glycoprotein was shown to be excreted in the urine of patients with cancer cachexia but not in those with similar tumor types without cachexia.29 Material was undetectable in the urine of patients with other weight-losing conditions such as major burns, multiple injuries, or surgery-associated catabolism and sepsis, suggesting that it may be confined to cancer cachexia, although more data are required to confirm this idea. Administration of PIF to non–tumor-bearing mice produced a state of cachexia, with rapid weight loss, due to selective depletion of the non-fat mass.29 Weight loss occurred despite normal food and water intake, suggesting that cachexia and anorexia are not inextricably linked. PIF has been shown to induce protein degradation in isolated gastrocnemius31 and soleus32 muscles. In vivo studies have shown an increase (by 50%) in protein degradation and a decrease (by 50%) in protein synthesis in gastrocnemius muscle, suggesting a bimodal attack on protein balance. Protein degradation in vitro has associated with a significant elevation of prostaglandin E2, which may act as an intracellular messenger because attenuation of protein breakdown with a monoclonal antibody to PIF also inhibited the prostaglandin E2 response.32 Protein degradation in vitro induced by PIF was also attenuated in muscles of mice previously administered the polyunsaturated fatty acid eicosapentaenoic acid, possibly by inhibiting prostaglandin E2 production.33 Eicosapentaenoic acid has been shown to counteract weight loss in both mice with a cachexia-inducing tumor33 and in patients with pancreatic cancer, with stabilization of protein and fat reserves accompanied by a temporary reduction in acute-phase protein production and stabilization of resting-energy expenditure.34 This suggests that in the future it may be possible to attenuate the cachectic syndrome by appropriate pharmacologic intervention.
REFERENCES 1. De Wys WD. Weight loss and nutritional abnormalities in cancer patients: incidence, severity and significance. In: Calman K, Fearon KCH, eds. Clinics in oncology, Vol. 5. London: W.B. Saunders, 1986:251
Nutrition Volume 16, Number 10, 2000 2. Brennan MF. Uncomplicated starvation versus cancer cachexia. Cancer Res 1986;37:2359 3. Holm E, Hagmuller E, Staedt U, et al. Substrate balances across colonic carcinomas in humans. Cancer Res 1995;5:1373 4. Holroyde CP, Gabuzda TG, Putnam RC, Paul P, Reichard GA. Altered glucose metabolism in metastatic carcinoma. Cancer Res 1975;35:3710 5. Lundholm K, Holm G, Schersten T. Gluconeogenesis from alanine in patients with progressive malignant disease. Cancer Res 1979;39:1968 6. Lundholm K, Edstom S, Karlberg I. Glucose turnover, gluconeogenesis from glycerol and estimation of net glucose cycling in cancer patients. Cancer 1982; 50:1142 7. Fredrix EW, Soeters PB, Wouters EF, et al. Effect of different tumor types on resting energy expenditure. Cancer Res 1991;51:6138 8. Falconer JS, Fearon KC, Plester CE, Ross JA, Carter DC. Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg 1994;219:325 9. Tayek JA. A review of cancer cachexin and abnormal glucose metabolism in humans with cancer. J Am Coll Nutr 1992;11:445 10. Drott C, Persson H, Lundholm K. Cardiovascular and metabolic response to adrenaline-infusion in weight-losing patients with and without cancer. Clin Physiol 1989;9:427 11. Tang DG, Chen YO, Honn KV. Arachidonate lipoxygenases as essential regulators of cell survival and apoptosis. Proc Natl Acad Sci USA 1996;93:5241 12. Costa G, Bewley P, Aragon M, Siebold J. Anorexia and weight loss in cancer patients. Cancer Treat Rep 1981;65:3 13. Tisdale MJ, Beck SA. Production of lipolytic and proteolytic factors by a murine tumor-producing cachexia in the host. Cancer Res 1987;47:5919 14. Costa G, Holland JF. Effect of Krebs-2 carcinoma on the lipide metabolism of male Swiss mice. Cancer Res 1962;22:1081 15. Kralovic RC, Zepp FA, Cenedella RJ. Studies on the mechanism of carcass fat depletion in experimental cancer. Eur J Cancer 1977;13:1071 16. Kitada S, Hays EF, Mead JF. A lipid mobilizing factor in serum of tumor-bearing mice. Lipids 1980;15:168 17. Groundwater P, Beck SA, Barton C, et al. Alteration of serum and urinary lipolytic activity with weight loss in cachectic cancer patients. Br J Cancer 1990;62:816 18. Beck SA, Groundwater P, Barton C, Tisdale MJ. Alterations in serum lipolytic activity of cancer patients with response to therapy. Br J Cancer 1990;62:822 19. Taylor DD, Gercel-Taylor C, Jenis LJ, Devereux DF. Identification of a human tumor-derived lipolysis-promoting factor. Cancer Res 1992;52:829 20. Tisdale MJ, Beck SA. Inhibition of tumour-induced lipolysis in vitro and cachexia and tumor growth in vivo by eicosapentaenoic acid. Biochem Pharmacol 1991;41:103 21. Lahdevirta J, Maury CPJ, Teppo AM, Repo H. Elevated levels of circulatory cachectin/tumor necrosis factor in patients with the acquired immunodeficiency syndrome. Am J Med 1988;85:289 22. Thompson MP, Cooper ST, Parry BR, Tuckey JA. Increased expression of the mRNA for the hormone-sensitive lipase in adipose tissue of cancer patients. Biochim Biophys Acta 1993;1180:236 23. Nixon DW, Heymsfield SB, Cohen AE, et al. Protein-calorie undernutrition in hospitalized cancer patients. Am J Med 1980;68:683 24. Lundholm K, Bylund AC, Holm J, Schersten T. Skeletal muscle metabolism in patients with malignant tumor. Eur J Cancer 1976;12:465 25. Emery PW, Edwards RH, Rennie MJ, Souhami RL, Halliday D. Protein synthesis in muscle measured in vivo in cachectic patients with cancer. Br Med J 1984;289:584 26. Temparis S, Asensi M, Taillandier D, et al. Increased ATP-ubiquitin– dependent proteolysis in skeletal muscles of tumor-bearing rats. Cancer Res 1994;54:5568 27. Belizario JE, Katz M, Chenker E, Raw I. Bioactivity of skeletal muscle proteolysis-inducing factors in the plasma proteins from cancer patients with weight loss. Br J Cancer 1991;63:705 28. Smith KL, Tisdale MJ. Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia. Br J Cancer 1993;67:680 29. Todorov P, Cariuk P, McDevitt T, et al. Characterization of a cancer cachectic factor. Nature 1996;379:739 30. Todorov PT, Deacon M, Tisdale MJ. Structural analysis of a tumor-produced sulfated glycoprotein capable of initiating muscle protein degradation. J Biol Chem 1997;272:12279 31. Todorov PT, McDevitt TM, Cariuk P, et al. Induction of muscle protein degradation and weight loss by a tumor product. Cancer Res 1996;56:1256 32. Lorite MJ, Cariuk P, Tisdale MJ. Induction of muscle protein degradation by a tumour factor. Br J Cancer 1997;76:1035 33. Beck SA, Smith KL, Tisdale MJ. Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover. Cancer Res 1991;51:6089 34. Wigmore SJ, Ross JA, Falconer JS, et al. The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer. Nutrition 1996; 12:S27
Metabolic Abnormalities in Cachexia and Anorexia Michael J. Tisdale, PhD, DSc From the Pharmaceutical Sciences Research Institute, Aston University, Birmingham, UK An increased glucose requirement by many solid tumors produces an increased metabolic demand on the liver, resulting in an increased energy expenditure. In addition, several cytokines and tumor catabolic products have been suggested as being responsible for the depletion of adipose tissue and skeletal-muscle mass in cachexia. A sulphated glycoprotein of molecular mass 24 kDa, produced by cachexia-inducing tumors and present in the urine of cancer patients actively losing weight, has been shown to be capable of inducing direct muscle catabolism in vitro and a state of cachexia in vivo, with specific loss of the non-fat carcass mass. In vitro studies have shown the bioactivity of this proteolysis-inducing factor to be attenuated by the polyunsaturated fatty acid, eicosapentaenoic acid. Preliminary clinical studies have shown that eicosapentaenoic acid stabilizes body weight and protein and fat reserves in patients with pancreatic carcinoma. Further trials are required to confirm the efficacy of eicosapentaenoic acid and to determine the anticachectic activity in other types of cancer. Nutrition 2000;16:1013–1014. ©Elsevier Science Inc. 2000 Key words: cori-cycle, lipid-mobilizing factor, proteolysis-inducing factor, eicosapentaenoic acid
INTRODUCTION Wasting of body tissues and in particular loss of muscle mass is common in a number of clinical conditions including cancer, autoimmune-deficiency syndrome, chronic renal failure, and chronic gastrointestinal disease and is an important component of the aging process. Cancer patients with cachexia have a decreased performance status, a decreased response to chemotherapy and a shorter survival time1 because a 30% loss of body weight is invariably fatal.2
ALTERATIONS IN CARBOHYDRATE METABOLISM There are marked alterations in carbohydrate metabolism in the tumor-free tissues of patients with cancer, in particular the liver, which probably arise from the utilization of glucose by the tumor as the primary energy source.3 Metabolism of glucose under the hypoxic conditions pertaining to certain regions within most solid tumors produces large amounts of lactate, which is converted back into glucose in the liver—the Cori cycle. Cori-cycle activity has been found to increase from 20% in normal subjects to 50% of glucose turnover in cachectic cancer patients and accounts for the disposal of 60% of the lactate produced by the tumor.4 There is also an increased glucose synthesis from alanine5 and glycerol.6 Gluconeogenesis from lactate uses six ATP molecules for every lactate– glucose cycle and is very energy inefficient for the host. This futile cycle may be responsible at least in part for the increased energy expenditure reported in patients with lung7 and pancreatic8 cancer. A 40% increase in hepatic glucose production has been reported in weight-losing cancer patients9 in contrast to the reduced production seen in patients with anorexia nevosa. Thus, changes in carbohydrate metabolism in cancer patients probably arise as a consequence of meeting the metabolic
Correspondence to: Michael J. Tisdale, PhD, DSc, Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, UK. E-mail: [email protected] Date accepted: May 24, 2000. Nutrition 16:1013–1014, 2000 ©Elsevier Science Inc., 2000. Printed in the United States. All rights reserved.
demands of the tumor and may contribute to the development of the cachectic state.
ALTERATIONS IN LIPID METABOLISM Fat is a high-energy fuel reserve, and loss of adipose tissue arising from an increase in lipolysis is common in cancer patients.10 Such fat is used to meet the increased metabolic demands on the host caused by the presence of the tumor. In addition, metabolism of the polyunsaturated fatty acid, linoleic acid, through the 12lipoxygenase pathway may be essential in preventing apoptotic death in tumor cells.11 Mobilization of fatty acids from adipose tissue may occur before weight loss, suggesting the presence of a lipid-mobilizing factor (LMF) produced either by tumor or host tissues.12 A number of studies13–19 have provided evidence for the production of LMF by tumors that induce cachexia. These separate reports may describe the same or similar tumor factors, but to date no definitive identification of an LMF has been published. However, LMF acts directly on adipose tissue with the release of free fatty acids and glycerol through an elevation of the intracellular mediator cyclic AMP20 in a manner similar to that produced by the natural lipolytic hormones. In contrast, cytokines inhibit the clearing enzyme lipoprotein lipase, which would prevent adipocytes from extracting fatty acids from plasma lipoproteins for storage, resulting in a net flux of lipid into the circulation. It is unlikely that a single mediator will be found to explain catabolism of muscle and fat in all cachexias. Although evidence to date provides some support for a role of cytokines in wasting disorders from autoimmune-deficiency syndrome,21 there is less evidence for a role in cancer cachexia. Indeed, neither total lipoprotein-lipase enzyme activity, a marker for cytokine action, nor the relative level of mRNA for lipoprotein lipase and fatty-acid synthase were found to be significantly different in the adipose tissue of cancer patients when compared with control subjects.22 Rather, there was a two-fold increase in the relative level of mRNA for hormone-sensitive lipase, which is thought to mediate the action of LMF. This result and those of others on LMF bioactivity in the serum and urine of cancer patients17 suggest that 0899-9007/00/$20.00 PII S0899-9007(00)00409-3
1014
Tisdale
tumor catabolic products may be more important than cytokines in mediating loss of adipose tissue in cancer cachexia.
ALTERATIONS IN PROTEIN METABOLISM Depletion of lean body mass in cancer cachexia is a major factor responsible for the reduced survival time of cancer patients.23 Both reduced rates of protein synthesis and increased rates of protein degradation have been observed in biopsies of skeletal muscle from cachectic-cancer patients.24 Whereas muscle-protein synthesis is depressed, synthesis of secretory proteins, such as acutephase reactants, by the liver is actually increased, so that there may be no change in total body-protein synthesis.25 However, in these patients muscle-protein synthesis only accounted for 8% of total body synthesis versus 53% for healthy control subjects. Although to date no studies have been reported in cancer patients, degradation of myofibrillar proteins probably occurs by the adenosine triphosphate– ubiquitin– dependent proteolytic system because studies in animals have implicated this pathway not only in cachexia26 but also in starvation, sepsis, denervation atrophy, and metabolic acidosis. Loss of skeletal-muscle mass in both cancer patients27 and an experimental model of cachexia in the mouse28 has been shown to correlate with the presence in the serum of bioactivity capable of inducing protein degradation in isolated skeletal muscle. Such bioactivity has been termed the proteolysis-inducing factor (PIF). This material has recently been purified and characterized and shown to be a sulfated glycoprotein of molecular weight 24 kDa.29,30 Interestingly, bioactivity appears to reside in the carbohydrate rather than in the protein component of the molecule.31 Using antibodies obtained from mice transplanted with a cachexiainducing tumor, the 24-kDa glycoprotein was shown to be excreted in the urine of patients with cancer cachexia but not in those with similar tumor types without cachexia.29 Material was undetectable in the urine of patients with other weight-losing conditions such as major burns, multiple injuries, or surgery-associated catabolism and sepsis, suggesting that it may be confined to cancer cachexia, although more data are required to confirm this idea. Administration of PIF to non–tumor-bearing mice produced a state of cachexia, with rapid weight loss, due to selective depletion of the non-fat mass.29 Weight loss occurred despite normal food and water intake, suggesting that cachexia and anorexia are not inextricably linked. PIF has been shown to induce protein degradation in isolated gastrocnemius31 and soleus32 muscles. In vivo studies have shown an increase (by 50%) in protein degradation and a decrease (by 50%) in protein synthesis in gastrocnemius muscle, suggesting a bimodal attack on protein balance. Protein degradation in vitro has associated with a significant elevation of prostaglandin E2, which may act as an intracellular messenger because attenuation of protein breakdown with a monoclonal antibody to PIF also inhibited the prostaglandin E2 response.32 Protein degradation in vitro induced by PIF was also attenuated in muscles of mice previously administered the polyunsaturated fatty acid eicosapentaenoic acid, possibly by inhibiting prostaglandin E2 production.33 Eicosapentaenoic acid has been shown to counteract weight loss in both mice with a cachexia-inducing tumor33 and in patients with pancreatic cancer, with stabilization of protein and fat reserves accompanied by a temporary reduction in acute-phase protein production and stabilization of resting-energy expenditure.34 This suggests that in the future it may be possible to attenuate the cachectic syndrome by appropriate pharmacologic intervention.
REFERENCES 1. De Wys WD. Weight loss and nutritional abnormalities in cancer patients: incidence, severity and significance. In: Calman K, Fearon KCH, eds. Clinics in oncology, Vol. 5. London: W.B. Saunders, 1986:251
Nutrition Volume 16, Number 10, 2000 2. Brennan MF. Uncomplicated starvation versus cancer cachexia. Cancer Res 1986;37:2359 3. Holm E, Hagmuller E, Staedt U, et al. Substrate balances across colonic carcinomas in humans. Cancer Res 1995;5:1373 4. Holroyde CP, Gabuzda TG, Putnam RC, Paul P, Reichard GA. Altered glucose metabolism in metastatic carcinoma. Cancer Res 1975;35:3710 5. Lundholm K, Holm G, Schersten T. Gluconeogenesis from alanine in patients with progressive malignant disease. Cancer Res 1979;39:1968 6. Lundholm K, Edstom S, Karlberg I. Glucose turnover, gluconeogenesis from glycerol and estimation of net glucose cycling in cancer patients. Cancer 1982; 50:1142 7. Fredrix EW, Soeters PB, Wouters EF, et al. Effect of different tumor types on resting energy expenditure. Cancer Res 1991;51:6138 8. Falconer JS, Fearon KC, Plester CE, Ross JA, Carter DC. Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg 1994;219:325 9. Tayek JA. A review of cancer cachexin and abnormal glucose metabolism in humans with cancer. J Am Coll Nutr 1992;11:445 10. Drott C, Persson H, Lundholm K. Cardiovascular and metabolic response to adrenaline-infusion in weight-losing patients with and without cancer. Clin Physiol 1989;9:427 11. Tang DG, Chen YO, Honn KV. Arachidonate lipoxygenases as essential regulators of cell survival and apoptosis. Proc Natl Acad Sci USA 1996;93:5241 12. Costa G, Bewley P, Aragon M, Siebold J. Anorexia and weight loss in cancer patients. Cancer Treat Rep 1981;65:3 13. Tisdale MJ, Beck SA. Production of lipolytic and proteolytic factors by a murine tumor-producing cachexia in the host. Cancer Res 1987;47:5919 14. Costa G, Holland JF. Effect of Krebs-2 carcinoma on the lipide metabolism of male Swiss mice. Cancer Res 1962;22:1081 15. Kralovic RC, Zepp FA, Cenedella RJ. Studies on the mechanism of carcass fat depletion in experimental cancer. Eur J Cancer 1977;13:1071 16. Kitada S, Hays EF, Mead JF. A lipid mobilizing factor in serum of tumor-bearing mice. Lipids 1980;15:168 17. Groundwater P, Beck SA, Barton C, et al. Alteration of serum and urinary lipolytic activity with weight loss in cachectic cancer patients. Br J Cancer 1990;62:816 18. Beck SA, Groundwater P, Barton C, Tisdale MJ. Alterations in serum lipolytic activity of cancer patients with response to therapy. Br J Cancer 1990;62:822 19. Taylor DD, Gercel-Taylor C, Jenis LJ, Devereux DF. Identification of a human tumor-derived lipolysis-promoting factor. Cancer Res 1992;52:829 20. Tisdale MJ, Beck SA. Inhibition of tumour-induced lipolysis in vitro and cachexia and tumor growth in vivo by eicosapentaenoic acid. Biochem Pharmacol 1991;41:103 21. Lahdevirta J, Maury CPJ, Teppo AM, Repo H. Elevated levels of circulatory cachectin/tumor necrosis factor in patients with the acquired immunodeficiency syndrome. Am J Med 1988;85:289 22. Thompson MP, Cooper ST, Parry BR, Tuckey JA. Increased expression of the mRNA for the hormone-sensitive lipase in adipose tissue of cancer patients. Biochim Biophys Acta 1993;1180:236 23. Nixon DW, Heymsfield SB, Cohen AE, et al. Protein-calorie undernutrition in hospitalized cancer patients. Am J Med 1980;68:683 24. Lundholm K, Bylund AC, Holm J, Schersten T. Skeletal muscle metabolism in patients with malignant tumor. Eur J Cancer 1976;12:465 25. Emery PW, Edwards RH, Rennie MJ, Souhami RL, Halliday D. Protein synthesis in muscle measured in vivo in cachectic patients with cancer. Br Med J 1984;289:584 26. Temparis S, Asensi M, Taillandier D, et al. Increased ATP-ubiquitin– dependent proteolysis in skeletal muscles of tumor-bearing rats. Cancer Res 1994;54:5568 27. Belizario JE, Katz M, Chenker E, Raw I. Bioactivity of skeletal muscle proteolysis-inducing factors in the plasma proteins from cancer patients with weight loss. Br J Cancer 1991;63:705 28. Smith KL, Tisdale MJ. Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia. Br J Cancer 1993;67:680 29. Todorov P, Cariuk P, McDevitt T, et al. Characterization of a cancer cachectic factor. Nature 1996;379:739 30. Todorov PT, Deacon M, Tisdale MJ. Structural analysis of a tumor-produced sulfated glycoprotein capable of initiating muscle protein degradation. J Biol Chem 1997;272:12279 31. Todorov PT, McDevitt TM, Cariuk P, et al. Induction of muscle protein degradation and weight loss by a tumor product. Cancer Res 1996;56:1256 32. Lorite MJ, Cariuk P, Tisdale MJ. Induction of muscle protein degradation by a tumour factor. Br J Cancer 1997;76:1035 33. Beck SA, Smith KL, Tisdale MJ. Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover. Cancer Res 1991;51:6089 34. Wigmore SJ, Ross JA, Falconer JS, et al. The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer. Nutrition 1996; 12:S27