The role of triglyceride lipases in cancer associated cachexia
Authors: Suman K. Das, Gerald Hoefler
Journal: Trends in Molecular Medicine (2013)

Cancer associated cachexia (CAC) is a complex multiorgan syndrome frequently associated with various forms of cancer. Affected patients suffer from a dramatic loss of skeletal muscle and adipose tissue. Most cases are accompanied by anorexia, and nutritional supplements are not sufficient to stop or reverse its course. CAC impairs many forms of therapeutic interventions and accounts for 15–20% of all deaths of cancer patients. Recently, several studies have recognized the importance of lipid metabolism and triglyceride hydrolysis as a major metabolic pathway involved in the initiation and/or progression of CAC. In this review, we explore the contributions of the triglyceride lipases to CAC and discuss various factors modulating lipase activity. Cancer associated cachexia (CAC) is a complex multiorgan syndrome frequently associated with various forms of cancer. Affected patients suffer from a dramatic loss of skeletal muscle and adipose tissue. Most cases are accompanied by anorexia, and nutritional supplements are not sufficient to stop or reverse its course. CAC impairs many forms of therapeutic interventions and accounts for 15–20% of all deaths of cancer patients. Recently, several studies have recognized the importance of lipid metabolism and triglyceride hydrolysis as a major metabolic pathway involved in the initiation and/or progression of CAC. In this review, we explore the contributions of the triglyceride lipases to CAC and discuss various factors modulating lipase activity. Triglyceride lipases play an important role in the development of cancer associated cachexia. Blocking triglyceride lipases might prevent the development of cancer associated cachexia. Cachexia is a multifactorial syndrome that occurs in many chronic and end stage diseases. Patients suffering from cancer frequently show signs of mild to severe forms of cachexia, which is referred to as cancer associated cachexia (CAC). The severity of cachexia varies depending on the tumor type, site, and stage [1Dewys W.D. et al.Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group.Am. J. Med. 1980; 69: 491-497Abstract Full Text PDF PubMed Scopus (2004) Google Scholar]. CAC is prevalent in patients suffering from gastrointestinal and pancreatic adenocarcinoma, occurring in 80–90% of patients. It also arises in patients suffering from other carcinomas, as well as sarcomas, malignant lymphoma, and acute leukemia, although to a lesser extent [2Dewys W.D. Weight-loss and nutritional abnormalities in cancer-patients – incidence, severity and significance.Clin. Oncol. 1986; 5: 251-261Google Scholar, 3Blum D. Strasser F. Cachexia assessment tools.Curr. Opin. Support. Palliat. Care. 2011; 5: 350-355Crossref PubMed Scopus (31) Google Scholar]. The occurrence of cachexia relies heavily on the host response to tumor progression, including the activation of an immune response and associated signaling pathways [4Fearon K.C.H. et al.Cancer cachexia: mediators, signaling, and metabolic pathways.Cell Metab. 2012; 16: 153-166Abstract Full Text Full Text PDF PubMed Scopus (757) Google Scholar]. Patients suffering from CAC show anorexia and a loss of body weight, white adipose tissue (WAT), and skeletal muscle mass, which lead to physical impairment [5Tisdale M.J. Mechanisms of cancer cachexia.Physiol. Rev. 2009; 89: 381-410Crossref PubMed Scopus (876) Google Scholar]. Patients suffering from CAC often suffer from profound inflammation which escalates with loss of WAT weight and progression of CAC [6Richards C.H. et al.The relationships between body composition and the systemic inflammatory response in patients with primary operable colorectal cancer.PLoS ONE. 2012; 7: e41883Crossref PubMed Scopus (118) Google Scholar]. A negative energy balance complicates therapeutic interventions and nutritional supplements can only partially ameliorate the symptoms of cachexia [7Evans W.K. et al.Limited impact of total parenteral nutrition on nutritional status during treatment for small cell lung cancer.Cancer Res. 1985; 45: 3347-3353PubMed Google Scholar, 8Kardinal C.G. et al.A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia.Cancer. 1990; 65: 2657-2662Crossref PubMed Scopus (187) Google Scholar, 9Ovesen L. et al.Effect of dietary counseling on food intake, body weight, response rate, survival, and quality of life in cancer patients undergoing chemotherapy: a prospective, randomized study.J. Clin. Oncol. 1993; 11: 2043-2049PubMed Google Scholar]. Thus, it should not be confused with anorexia. This devastating condition is estimated to be the cause of death in up to 15% of cancer patients [1Dewys W.D. et al.Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group.Am. J. Med. 1980; 69: 491-497Abstract Full Text PDF PubMed Scopus (2004) Google Scholar, 10Deans C. Wigmore S.J. Systemic inflammation, cachexia and prognosis in patients with cancer.Curr. Opin. Clin. Nutr. Metab. Care. 2005; 8: 265-269Crossref PubMed Scopus (255) Google Scholar, 11Fearon K.C. Moses A.G. Cancer cachexia.Int. J. Cardiol. 2002; 85: 73-81Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar]. Despite considerable advancements in understanding the syndrome, effective approaches for managing CAC have been hindered by the lack of an exact definition and reproducible diagnostic criteria. After a comprehensive and thorough review of the literature, a panel of experts recently published a consensus definition of CAC that states 'cancer cachexia is a multi-factorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to functional impairment' [12Fearon K. et al.Definition and classification of cancer cachexia: an international consensus.Lancet Oncol. 2011; 12: 489-495Abstract Full Text Full Text PDF PubMed Scopus (3298) Google Scholar]. The panel recognized cachexia as a progressive disorder rather than a single event and classified the manifestation of cachexia into three stages: pre-cachexia, cachexia, and refractory cachexia. A recently developed scoring system will also be a valuable tool to stage cachectic cancer patients [13Argiles J.M. et al.The cachexia score (CASCO): a new tool for staging cachectic cancer patients.J. Cachexia Sarcopenia Muscle. 2011; 2: 87-93Crossref PubMed Scopus (122) Google Scholar], and the diagnostic criteria proposed in these two studies are a big step forward for diagnosing and managing CAC. However, a thorough understanding of metabolic mechanisms that lead to the occurrence and progression of cachexia is imperative for designing more effective therapies to prevent, or at least ameliorate, the syndrome. Cancer-induced weight loss is attributed mostly to loss of WAT and skeletal muscle mass. Patients suffering from cachexia lose on average 32% of their body weight, 75% of their skeletal muscle, as well as 85% of total body fat [14Fearon K.C. The Sir David Cuthbertson Medal Lecture 1991. The mechanisms and treatment of weight loss in cancer.Proc. Nutr. Soc. 1992; 51: 251-265Crossref PubMed Google Scholar]. The loss of muscle mass might be a result of decreased protein synthesis, increased protein catabolism, or both depending on the tumor or stage of CAC. Recently, Augustsson et al. reported that both visceral and subcutaneous WAT is already significantly reduced in newly diagnosed CAC patients although they did not observe changes in lean body mass at that time [15Agustsson T. et al.Adipose tissue volume is decreased in recently diagnosed cancer patients with cachexia.Nutrition. 2012; 28: 851-855Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. This is consistent with previous observations indicating that at the onset of cachexia WAT volume is reduced before a loss of lean mass occurs [16Fouladiun M. et al.Body composition and time course changes in regional distribution of fat and lean tissue in unselected cancer patients on palliative care – correlations with food intake, metabolism, exercise capacity, and hormones.Cancer. 2005; 103: 2189-2198Crossref PubMed Scopus (230) Google Scholar] and may help in diagnosing early stages of cachexia. Importantly, recent reports recognize a prominent role for lipid metabolism and triglyceride lipases in the initiation and/or progression of CAC [17Chung T.H. et al.YC-1 rescues cancer cachexia by affecting lipolysis and adipogenesis.Int. J. Cancer. 2011; 129: 2274-2283Crossref PubMed Scopus (10) Google Scholar, 18Das S.K. et al.Adipose triglyceride lipase contributes to cancer-associated cachexia.Science. 2011; 333: 233-238Crossref PubMed Scopus (388) Google Scholar, 19Fearon K.C. Cancer cachexia and fat-muscle physiology.N. Engl. J. Med. 2011; 365: 565-567Crossref PubMed Scopus (106) Google Scholar, 20Argiles J.M. et al.Mechanisms to explain wasting of muscle and fat in cancer cachexia.Curr. Opin. Support. Palliat. Care. 2007; 1: 293-298Crossref PubMed Google Scholar]. Therefore, in this review we focus on alterations of lipid catabolism in CAC and explore specifically the role of triglyceride lipases and their modulators in CAC. WAT is regarded as the main reservoir of lipids that are stored mostly in the form of triacylglycerol (TAG) and serve as a major source of energy. TAG levels in WAT are maintained by the dynamic equilibrium of two opposing key processes, lipogenesis and lipolysis. In the anabolic process of lipogenesis, glucose, which is transported into adipocytes mainly via GLUT4, is catabolized to acetyl-CoA, which is then acted upon by a series of enzymes and cofactors to generate fatty acids (FAs). Three FAs are then esterified to a single glycerol molecule to create a molecule of TAG and stored as an energy reserve in WAT. In addition to de novo lipogenesis, WAT imports FAs by catabolizing circulating lipoproteins into FA via membrane-bound lipoprotein lipase (LPL). These FAs are imported in the cytoplasm via the action of FA transporters and FA-binding proteins and are subsequently re-esterified into TAG. Conversely, TAG molecules stored in WAT are broken down into FAs and glycerol by a highly regulated process known as lipolysis, a process of three subsequent steps catalyzed by three essential lipases. Adipose triglyceride lipase (ATGL) catalyzes the rate-limiting first step, converting TAG into diacylglycerol (DAG) and a free FA. DAG is then acted upon by hormone sensitive lipase (HSL) to remove the second FA to form monoacylglycerol (MAG). The third and final enzyme, monoglyceride lipase (MGL) converts MAG into glycerol and a third free FA. Thus, three molecules of FA are released in this process that are then either re-esterified to form new TAG or shuttled to metabolically active tissues where they undergo fatty acid oxidation to generate energy or might be used for anabolic processes. Lipolysis is influenced by several additional factors that regulate the activities of these essential lipases, and both lipoloysis and lipogenesis not only regulate the homeostasis of WAT but also direct systemic energy production. Recent studies in animal models of CAC and observation of human WAT have confirmed that fat loss in cachexia is a consequence of TAG depletion and not due to cell death [21Ryden M. et al.Lipolysis – not inflammation, cell death, or lipogenesis – is involved in adipose tissue loss in cancer cachexia.Cancer. 2008; 113: 1695-1704Crossref PubMed Scopus (126) Google Scholar]. The processes leading to the depletion of TAG reserves involve decreased lipogenesis, decreased FA transport, and, most prominently, increased lipolysis [5Tisdale M.J. Mechanisms of cancer cachexia.Physiol. Rev. 2009; 89: 381-410Crossref PubMed Scopus (876) Google Scholar]. Trew and Begg were the first to identify a severe deregulation of lipogenesis in WAT using an animal tumor model [22Trew J.A. Begg R.W. In vitro incorporation of acetate-1-C14 into adipose tissue from normal and tumor-bearing rats.Cancer Res. 1959; 19: 1014-1019PubMed Google Scholar]. This observation was confirmed in many subsequent studies, which also identified declines in the activities of key lipogenic enzymes in WAT, such as fatty acid synthase, citrate cleavage enzyme, and malic enzyme, associated with tumor progression in murine cachexia models [23Lanza-Jacoby S. et al.Sequential changes in the activities of lipoprotein lipase and lipogenic enzymes during tumor growth in rats.Cancer Res. 1984; 44: 5062-5067PubMed Google Scholar]. In stark contrast to these results, lipogenesis was reported to be either upregulated in WAT of mice bearing colonic adenocarcinoma [24Mulligan H.D. Tisdale M.J. Lipogenesis in tumour and host tissues in mice bearing colonic adenocarcinomas.Br. J. Cancer. 1991; 63: 719-722Crossref PubMed Scopus (24) Google Scholar] or no significant change was detected in WAT of tumor bearing patients [21Ryden M. et al.Lipolysis – not inflammation, cell death, or lipogenesis – is involved in adipose tissue loss in cancer cachexia.Cancer. 2008; 113: 1695-1704Crossref PubMed Scopus (126) Google Scholar, 25Thompson M.P. et al.Increased expression of the mRNA for hormone-sensitive lipase in adipose tissue of cancer patients.Biochim. Biophys. Acta. 1993; 1180: 236-242Crossref PubMed Scopus (89) Google Scholar]. However, Notarnicola et al. recently showed that both mRNA levels and the activity of FA synthase are reduced in WAT adjacent to the tumor, compared with distant WAT, in samples from 32 colorectal cancer patients [26Notarnicola M. et al.Low levels of lipogenic enzymes in peritumoral adipose tissue of colorectal cancer patients.Lipids. 2012; 47: 59-63Crossref PubMed Scopus (32) Google Scholar]. Differences in the anatomical origin of WAT and/or differences in cancer types might explain these discrepancies. Elevated levels of serum TAG and cholesterol are often detected in patients suffering from CAC [5Tisdale M.J. Mechanisms of cancer cachexia.Physiol. Rev. 2009; 89: 381-410Crossref PubMed Scopus (876) Google Scholar], and a marked increase in FA and glycerol concentrations are observed in cancer patients suffering from cachexia as compared to weight-stable cancer patients [27Shaw J.H. Wolfe R.R. Fatty acid and glycerol kinetics in septic patients and in patients with gastrointestinal cancer. The response to glucose infusion and parenteral feeding.Ann. Surg. 1987; 205: 368-376Crossref PubMed Scopus (164) Google Scholar, 28Drott C. et al.Cardiovascular and metabolic response to adrenaline infusion in weight-losing patients with and without cancer.Clin. Physiol. 1989; 9: 427-439Crossref PubMed Scopus (60) Google Scholar, 29Legaspi A. et al.Whole body lipid and energy metabolism in the cancer patient.Metabolism. 1987; 36: 958-963Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 30Gercel-Taylor C. et al.Aberrations in normal systemic lipid metabolism in ovarian cancer patients.Gynecol. Oncol. 1996; 60: 35-41Crossref PubMed Scopus (42) Google Scholar]. Murine models of CAC also show increased serum levels of FA and glycerol, suggesting increased TAG catabolism and delipidation of fat reserves [18Das S.K. et al.Adipose triglyceride lipase contributes to cancer-associated cachexia.Science. 2011; 333: 233-238Crossref PubMed Scopus (388) Google Scholar]. Ryden et al. have confirmed these findings and state that increased lipolysis and not cell death or impaired lipogenesis is involved in WAT loss in cachectic patients [21Ryden M. et al.Lipolysis – not inflammation, cell death, or lipogenesis – is involved in adipose tissue loss in cancer cachexia.Cancer. 2008; 113: 1695-1704Crossref PubMed Scopus (126) Google Scholar]. Similarly, TAG hydrolase activity in visceral WAT of cancer patients shows a strong negative correlation with body mass index (BMI), whereas such a correlation is absent in patients without tumor [18Das S.K. et al.Adipose triglyceride lipase contributes to cancer-associated cachexia.Science. 2011; 333: 233-238Crossref PubMed Scopus (388) Google Scholar]. Observations made by several other groups, including us, in patient samples and animal models of cachexia reinforced the hypothesis that increased lipolysis is a major determinant of adipose tissue loss in CAC [18Das S.K. et al.Adipose triglyceride lipase contributes to cancer-associated cachexia.Science. 2011; 333: 233-238Crossref PubMed Scopus (388) Google Scholar, 21Ryden M. et al.Lipolysis – not inflammation, cell death, or lipogenesis – is involved in adipose tissue loss in cancer cachexia.Cancer. 2008; 113: 1695-1704Crossref PubMed Scopus (126) Google Scholar, 28Drott C. et al.Cardiovascular and metabolic response to adrenaline infusion in weight-losing patients with and without cancer.Clin. Physiol. 1989; 9: 427-439Crossref PubMed Scopus (60) Google Scholar, 29Legaspi A. et al.Whole body lipid and energy metabolism in the cancer patient.Metabolism. 1987; 36: 958-963Abstract Full Text PDF PubMed Scopus (124) Google Scholar]. This observation is also supported by a comprehensive transcriptomics analysis of adipose tissue describing a significant upregulation of genes involved in the FA degradation pathway, as well as genes involved in the tricarboxylic acid cycle (TCA) cycle and the oxidative phosphorylation (OXPHOS) pathway in CAC patients [31Dahlman I. et al.Adipose tissue pathways involved in weight loss of cancer cachexia.Br. J. Cancer. 2010; 102: 1541-1548Crossref PubMed Scopus (96) Google Scholar]. In conclusion, cancer shifts lipid metabolism to a catabolic state, thus decreasing the fat mass in cachectic patients. As a result, systemic lipid metabolism is severely disturbed which, in turn, might cause lipotoxic effects in other tissues including skeletal muscle (Box 1). Indeed Stephens et al. observed that intramyocellular lipid droplets increased in size and number in the course of cachexia progression in cancer patients [32Stephens N.A. et al.Intramyocellular lipid droplets increase with progression of cachexia in cancer patients.J. Cachexia Sarcopenia Muscle. 2011; 2: 111-117Crossref PubMed Scopus (109) Google Scholar]. This is supported by our observations of increased TAG concentrations in Musculus gastrocnemius of Lewis lung carcinoma (LLC) bearing cachectic mice [18Das S.K. et al.Adipose triglyceride lipase contributes to cancer-associated cachexia.Science. 2011; 333: 233-238Crossref PubMed Scopus (388) Google Scholar]. Moreover, cancer impedes adipogenesis, which is evident by downregulation of key adipogenic factors: CCAAT/enhancer binding protein β (C/EBPβ), C/EBPα, peroxisome proliferator-activated receptor γ (PPARγ), and sterol regulatory element-binding protein-1c (SREBP-1c) [33Bing C. et al.Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumour-bearing mice.Br. J. Cancer. 2006; 95: 1028-1037Crossref PubMed Scopus (122) Google Scholar]. Figure 1 illustrates various tumor associated mechanisms that may influence lipid homeostasis in WAT and lead to CAC.Box 1Does a tumor 'benefit' from the induction of cachexia?Although several factors and mechanisms associated with CAC have been identified in the past decades, answers to the basic questions of how and why tumors cause cachexia remain elusive. It could be argued that the induction of cachexia is a stochastic process attributable to random mutations occurring in the tumor. It would be difficult to explain, however, why it occurs at such a high frequency. Certainly, a very plausible explanation is found in the association with the antitumor reaction of the host that is observed in the majority of cases, which leads to inflammatory reactions and the release of various cytokines. Although this is very likely to be the cause in many cases of CAC, there is also a great number and variety of tumors with intense host reaction that do not lead to CAC. A third, so far not widely investigated hypothesis is that the tumor somehow benefits from the release of substances, such as FA from WAT, during CAC development. A rapidly developing cancer requires glucose, lactate, FA, and amino acids, among other things, to maintain its high energy demands and requires building blocks for 'biomass' to achieve high proliferation rates. It is thus conceivable that the tumor benefits from CAC by acquiring these factors. Murine models of cancer have demonstrated that dietary supplements significantly affect tumor growth [94Sauer L.A. et al.Dietary factors and growth and metabolism in experimental tumors.J. Nutr. Biochem. 2007; 18: 637-649Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], and the importance of circulating FA in tumor growth has been already reported in murine models of acute fasting or streptozotocin-induced diabetes where increased circulating FA concentration lead to increased tumor proliferation [95Sauer L.A. Dauchy R.T. Blood nutrient concentrations and tumor growth in vivo in rats: relationships during the onset of an acute fast.Cancer Res. 1987; 47: 1065-1068PubMed Google Scholar, 96Sauer L.A. et al.Stimulation of tumor growth in adult rats in vivo during an acute fast.Cancer Res. 1986; 46: 3469-3475PubMed Google Scholar, 97Sauer L.A. Dauchy R.T. Stimulation of tumor growth in adult rats in vivo during acute streptozotocin-induced diabetes.Cancer Res. 1987; 47: 1756-1761PubMed Google Scholar]. In addition, lipid-lowering drugs such as benzafibrate induce tumor growth, probably by inducing β-oxidation of FAs in MAC16, a cachexia-inducing adenocarcinoma that is also characterized by increased FA levels in serum [98Mulligan H.D. Tisdale M.J. Effect of the lipid-lowering agent bezafibrate on tumour growth rate in vivo.Br. J. Cancer. 1991; 64: 1035-1038Crossref PubMed Scopus (12) Google Scholar]. Benzafibrate does not affect tumor growth of non-cachexia-inducing MAC13 adenocarcinoma, presumably because FA serum levels are not increased in this model [98Mulligan H.D. Tisdale M.J. Effect of the lipid-lowering agent bezafibrate on tumour growth rate in vivo.Br. J. Cancer. 1991; 64: 1035-1038Crossref PubMed Scopus (12) Google Scholar]. Eicosapentaenoic acid inhibits tumor-induced lipolysis and also decreases the growth of MAC16 tumors [99Tisdale M.J. Beck S.A. Inhibition of tumour-induced lipolysis in vitro and cachexia and tumour growth in vivo by eicosapentaenoic acid.Biochem. Pharmacol. 1991; 41: 103-107Crossref PubMed Scopus (102) Google Scholar]. The fact that some rapidly proliferating human tumors are associated with CAC further supports this hypothesis. By contrast, the development of severe CAC in patients with a relatively small tumor burden is also well documented. In summary, it is very likely that the diversity in genetic changes in tumors results in diversity of tumor metabolism that leads to many ways of inducing CAC and potential benefits for tumor growth. Although several factors and mechanisms associated with CAC have been identified in the past decades, answers to the basic questions of how and why tumors cause cachexia remain elusive. It could be argued that the induction of cachexia is a stochastic process attributable to random mutations occurring in the tumor. It would be difficult to explain, however, why it occurs at such a high frequency. Certainly, a very plausible explanation is found in the association with the antitumor reaction of the host that is observed in the majority of cases, which leads to inflammatory reactions and the release of various cytokines. Although this is very likely to be the cause in many cases of CAC, there is also a great number and variety of tumors with intense host reaction that do not lead to CAC. A third, so far not widely investigated hypothesis is that the tumor somehow benefits from the release of substances, such as FA from WAT, during CAC development. A rapidly developing cancer requires glucose, lactate, FA, and amino acids, among other things, to maintain its high energy demands and requires building blocks for 'biomass' to achieve high proliferation rates. It is thus conceivable that the tumor benefits from CAC by acquiring these factors. Murine models of cancer have demonstrated that dietary supplements significantly affect tumor growth [94Sauer L.A. et al.Dietary factors and growth and metabolism in experimental tumors.J. Nutr. Biochem. 2007; 18: 637-649Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], and the importance of circulating FA in tumor growth has been already reported in murine models of acute fasting or streptozotocin-induced diabetes where increased circulating FA concentration lead to increased tumor proliferation [95Sauer L.A. Dauchy R.T. Blood nutrient concentrations and tumor growth in vivo in rats: relationships during the onset of an acute fast.Cancer Res. 1987; 47: 1065-1068PubMed Google Scholar, 96Sauer L.A. et al.Stimulation of tumor growth in adult rats in vivo during an acute fast.Cancer Res. 1986; 46: 3469-3475PubMed Google Scholar, 97Sauer L.A. Dauchy R.T. Stimulation of tumor growth in adult rats in vivo during acute streptozotocin-induced diabetes.Cancer Res. 1987; 47: 1756-1761PubMed Google Scholar]. In addition, lipid-lowering drugs such as benzafibrate induce tumor growth, probably by inducing β-oxidation of FAs in MAC16, a cachexia-inducing adenocarcinoma that is also characterized by increased FA levels in serum [98Mulligan H.D. Tisdale M.J. Effect of the lipid-lowering agent bezafibrate on tumour growth rate in vivo.Br. J. Cancer. 1991; 64: 1035-1038Crossref PubMed Scopus (12) Google Scholar]. Benzafibrate does not affect tumor growth of non-cachexia-inducing MAC13 adenocarcinoma, presumably because FA serum levels are not increased in this model [98Mulligan H.D. Tisdale M.J. Effect of the lipid-lowering agent bezafibrate on tumour growth rate in vivo.Br. J. Cancer. 1991; 64: 1035-1038Crossref PubMed Scopus (12) Google Scholar]. Eicosapentaenoic acid inhibits tumor-induced lipolysis and also decreases the growth of MAC16 tumors [99Tisdale M.J. Beck S.A. Inhibition of tumour-induced lipolysis in vitro and cachexia and tumour growth in vivo by eicosapentaenoic acid.Biochem. Pharmacol. 1991; 41: 103-107Crossref PubMed Scopus (102) Google Scholar]. The fact that some rapidly proliferating human tumors are associated with CAC further supports this hypothesis. By contrast, the development of severe CAC in patients with a relatively small tumor burden is also well documented. In summary, it is very likely that the diversity in genetic changes in tumors results in diversity of tumor metabolism that leads to many ways of inducing CAC and potential benefits for tumor growth. LPL is a member of the triglyceride hydrolase family and is attached to the surface of endothelial cells most abundantly in WAT, skeletal muscle, and heart. LPL hydrolyzes TAG present in circulating very-low-density lipoproteins (VLDLs) and chylomicrons (lipoprotein particles very rich in triglycerides). Free FAs are subsequently transported directly into parenchymal cells. Increased circulating TAG, low-density lipoproteins (LDLs), and VLDL in cancer patients as well as in animal models of CAC suggest the downregulation of LPL activity. Obeid and Emery found decreased LPL activity early during progressive tumor growth in mice [34Obeid O.A. Emery P.W. Lipid metabolism in cachectic tumor-bearing rats at different stages of tumor growth.Nutr. Cancer. 1993; 19: 87-98Crossref PubMed Scopus (23) Google Scholar], and decreased LPL activity is also reported in patients suffering from gastric and colorectal carcinoma, but not in breast carcinoma patients [35Nomura K. et al.Plasma interleukin-6 is not a mediator of changes in lipoprotein lipase activity in cancer patients.Hepatogastroenterology. 1997; 44: 1519-1526PubMed Google Scholar]. Interestingly, circulating levels of interleukin (IL)-6 did not correlate with LPL activity in these patients. Similarly, a decrease in LPL activity was noted in later stages of tumor cachexia in mice bearing MAC16 adenocarcinoma [36Briddon S. et al.Changes in activity of lipoprotein lipase, plasma free fatty acids and triglycerides with weight loss in a cachexia model.Cancer Lett. 1991; 57: 49-53Abstract Full Text PDF PubMed Scopus (19) Google Scholar]. Leukemia inhibitory factor (LIF) and tumor necrosis factor-α (TNF-α) are both reported to decrease the activity as well as mRNA expression of LPL in cultured adipocytes [37Marshall M.K. et al.Leukemia inhibitory factor induces changes in lipid metabolism in cultured adipocytes.Endocrinology. 1994; 135: 141-147Crossref PubMed Scopus (49) Google Scholar, 38Berg M. et al.Characterization of differentiation factor/leukaemia inhibitory factor effect on lipoprotein lipase activity and mRNA in 3T3-L1 adipocytes.Cytokine. 1994; 6: 425-432Crossref PubMed Scopus (66) Google Scholar]. Thus, increased circulating levels of LIF and TNF-α in CAC patients and mice models might explain decreased LPL activities. In addition, Nara-Ashizawa et al. have reported the presence of a factor that seems to be different from the well-known cytokines involved in cachexia, IL-1β, IL-6, IL-1, TNF-α, transforming growth factor-β (TGF-β), and LIF [39Nara-Ashizawa N. et al.Lipolytic and lipoprotein lipase (LPL)-inhibiting activities produced by a human lung cancer cell line responsible for cachexia induction.Anticancer Res. 2001; 21: 3381-3387PubMed Google Scholar]. Treatment with benzafibrate, an antihyperlipidemic drug, has been shown to enhance LPL activity in tumor bearing rats, which resulted in the preservation of epididymal WAT and partial prevention of hyperlipidemia [40Nomura K. et al.Stimulation of decreased lipoprotein lipase activity in the tumor-bearing state by the antihyperlipidemic drug bezafibrate.Surg. Today. 1996; 26: 89-94Crossref PubMed Scopus (15) Google Scholar]. Similar effects have been shown for NO1886 and pronalrestat in B16 melano