Print version ISSN 0041-8781
Rev. Hosp. Clin. vol.55 n.5 São Paulo Sept./Oct. 2000
PATHOPHYSIOLOGY OF CANCER CACHEXIA
Riad N. Younes and Yoshikazu Noguchi
YOUNES RN et al. - Pathophysiology of cancer cachexia. Rev. Hosp. Clín. Fac. Med. S. Paulo 55(5):181-193, 2000.
Cancer cachexia is a frequent complication observed in patients with malignant tumors. Although several decades have passed since the first focus on the metabolic dysfunction's associated with cancer, few effective therapeutic interventions have been successfully introduced into the medical armamentarium.
The present study thoroughly reviews the basic pathophysiology of cancer cachexia and the treatment options already investigated in that field. Experimental and clinical studies were evaluated individually in order to clarify the intricate alterations observed in tumor-bearing patients. The difficulties in introducing sound and effective nutritional support or metabolic manipulation to reverse cancer cachexia are outlined in this review.
DESCRIPTORS: Cancer. Cachexia. Metabolism. Cytokine. Insulin.
The origin of malnutrition in cancer patients is multi-factorial. Anorexia may be attributed to altered taste and smell1, or to changes in the hypothalamic food regulation2. Food intake is diminished by mechanical obstruction of the alimentary tract. Disturbance of digestion and absorption also accompanies some tumors. Nutritional demand in the tumor-bearing state is increased due to alterations either by the neoplasm itself or by the stressed host. Wasting is accelerated by the proteolysis of skeletal muscle and consumption of body fat. Accelerated mobilization and consumption of host protein stores from peripheral tissues occurs to support gluconeogenesis and acute phase protein synthesis3,4. In contrast, simple starvation is associated with a relative sparing of lean tissue with the preferential consumption of fat5,6. Substrate consumption by the tumor, whether based on analogy with glucose consumption in the human brain7, on in vivo studies in transplanted tumors8, or on in vivo use of the substrate by sarcoma-bearing human limbs9, can be substantial and may account for small increases in energy expenditure at rest. However, only a very large tumor (above 1.4 kg) would consume 50% of the intake of the patient at rest10.
Understanding the basic mechanisms of metabolic alterations observed in the tumor-bearing state is the basis for developing optimum treatment for those patients with malignancy.
In this chapter, the basic pathophysiology of metabolic alterations observed in the tumor-bearing state both in animal and humans is presented, followed by a re-focusing on clinical significance and current problems in applying nutritional support to those patients.
I. Metabolic Alterations in Cancer Patients
- Alterations specific to cancer patients-
1. Glucose Metabolism
Altered glucose metabolism in cancer patients is characterized by increased whole-body glucose turnover rate, decreased glucose uptake and utilization due to insulin resistance, and increased hepatic glucose synthesis, or gluconeogenesis, from substrates derived from proteolysis and lipolysis.
Whole-body carbohydrate metabolism
Increased whole-body glucose turnover has been documented in gastrointestinal cancer patients, and this increase was proportional to the extent of the disease11. Whole-body glucose production rates were also significantly increased in patients with lung cancer (n=29, 3.4+0.2 mg/kg/min) compared to levels in controls (n=18, 2.3+0.1 mg/kg/min)12. In those patients, the fasting serum alanine level was significantly lower than for controls, suggesting that alanine was being released at a normal or enhanced rate and was utilized more rapidly for the production of glucose in patients than in controls. Increased Cori cycle activity or glucose carbon recycling in patients with malignant disease is well documented by several studies13,14,15.
Peripheral carbohydrate metabolism
Glucose intolerance is one of the earliest recognized metabolic alterations in patients with cancer. In experimental animal models, hypoglycemia is a characteristic finding. In cancer patients, fasting hypoglycemia is not commonly seen; however, Glicksman and Rawson16 reported that approximately 37% of all patients with cancer had abnormal glucose tolerance. Details of glucose intolerance or insulin resistance are discussed in the following section. The decreased glucose metabolized or glucose clearance from the circulation resulted in both significantly decreased glucose storage and glucose oxidation in gastrointestinal (GI) and lung cancer patients.
Increased circulating lactate was found in animal models as well as in some cancer patients. Studies in vivo of human tumors demonstrated significant glucose use and lactate production17. Lactate thus produced may be used by the liver as a gluconeogenic precursor to synthesize glucose, which may be used by both the host and the tumor. In this process, energy is wasted, because only 2 molecules of ATP are produced by glycolysis while 6 molecules of ATP are utilized to synthesize glucose from lactate.
Hepatic glucose metabolism
Increased gluconeogenesis in the tumor-bearing state has been claimed to be one of the major causes of cancer cachexia, mobilizing peripheral lean tissue mass as a substrate for gluconeogenesis. Roh et al18 reported increased gluconeogenesis from alanine and lactate in tumor-influenced hepatocytes in the presence of decreased serum glucose level. It was associated with increased gluconeogenic capacity and accelerated alanine transport.
The increased energy cost of enhanced gluconeogenesis would only be significant if this process persisted throughout a 24-hour period and may not be detected if feeding is a compensating factor19. Waterhouse et al.20 demonstrated normal suppression of increased gluconeogenesis from alanine with a small amount of carbohydrate in overnight-fasted patients with progressive malignant disease. This finding brings into question the significance of the observed increase in gluconeogenesis in the tumor-bearing state and emphasizes the possible regulation of this catabolic pathway by nutritional manipulation21.
We previously studied the alterations of this pathway by examining a key regulatory enzyme, phosphoenolpyruvate carboxykinase (PEPCK) at both the activity and mRNA levels. PEPCK is a well-studied pacemaker enzyme of gluconeogenesis22. A number of hormones are known to regulate the synthesis of this enzyme23, including glucagon, epinephrine24, and thyroid hormone25, which increases, and insulin, which decreases the synthesis. PEPCK activity in liver cytosol, after a 24-hour fast, was significantly higher in tumor-bearing rats than in their pair-fed controls. The increase in enzyme activity was clearly evident at 8% tumor burden and correlated positively with the degree of tumor burden (r=0.85, p<0.01). Removal of the tumor produced a complete reversal of PEPCK activity 10 days after excision. Regular feeding also abolished this increased enzyme activity. PEPCK mRNA levels were equally elevated in tumor bearers and controls in the 24-hour-fasted state. These results suggest that tumor-bearing stimulates the fasted state associated with hypoglycemia, which in turn triggers induction of the gluconeogenic enzyme, PEPCK. Substrate availability may be a key in induction of gluconeogenesis in this tumor animal model.
We also measured PEPCK activity in the livers of GI cancer patients. Although there were cases in which PEPCK activity was elevated, the mean value in patients with advanced GI cancer without significant weight loss was not different from that of controls (submitted for publication). Increased gluconeogenesis in cancer patients has been documented by isotope infusion techniques, but no data on PEPCK activity in the liver is available except our current study. If this enzyme is a key, therapy targeting this enzyme may modulate cancer cachexia. Hydrazine sulfate inhibits the conversion of oxaloacetate to phosphoenolpyruvate by inhibiting PEPCK irreversibly, and 3-mercaptopicolinic acid is a specific blocker of PEPCK. Although clinical trials had been attempted on both drugs, no significant benefits were demonstrated26,27,28.
2. Fat Metabolism
Fat loss is frequently observed in advanced malignant disease, but may also occur in patients with early stage cancer when tumor volume is still relatively small29. Studies in experimental animals have shown a progressive depletion of carcass fat stores during tumor growth30,31,32. Profound alterations in host lipid metabolism occur in both tumor-bearing animals33,34,35,36 and humans37,38,35,15,39,40, manifested by hypertriglyceridemia and increased circulating non-esterified fatty acid (NEFA).
Hyperlipidemia and whole-body lipid kinetic study
In our model of Fisher 344 rats with methylcholanthrene-induced (MCA) sarcoma, hyperlipidemia is one of the early changes, progressively aggravated by tumor growth and completely abolished by curative tumor removal. In human cancers, some patients with leukemia and lung cancers have been documented to have elevated levels; however, hyperlipidemia is not universally observed41. Patients with solid tumors such as esophageal, gastric, colorectal, and breast cancer very rarely manifest these alterations42. Shaw and Wolfe43 demonstrated increased rates of glycerol and fatty acid turnover in weight-losing gastrointestinal cancer patients, compared with either weight-stable cancer patients or controls.
De novo fatty acid synthesis
We have previously shown that de novo fatty acid biosynthesis in the livers of tumor-bearing rats is significantly decreased as a function of degree of tumor burden33. Lipogenesis by adipose tissue was also shown to be decreased in the tumor-bearing mouse44. Thompson et al.44 demonstrated a gradual decline of lipogenesis per gram wet weight of liver with tumor growth by measuring the incorporation of 3H from 3H2O into lipids. Their conclusion was that the total amount of lipid synthesis was not significantly altered in tumor-bearing mice, since liver weight increased as the tumor grew. However, the tissue composition analysis of our model45 has previously shown that liver protein content in tumor-bearing animals is no greater than that of pair-fed controls, although liver wet weight of the former is greater than that of the latter.
Arbeit46 and Hansell47 in separate studies documented that patients with diffuse disease or weight loss had significantly higher fat oxidation rates, while Waterhouse et al48 could not see a significant difference in the rate of NEFA oxidation under basal conditions in cancer patients and control. We examined the role of fatty acid oxidation by carnitine palmitoyltransferase activity in the Fisher344 rat with MCA sarcoma49. This enzyme is bound to both the inner and outer surface of the inner mitochondrial membrane and regulates the membrane transport of cytosolic fatty acylCoA into mitochondrial matrix where oxidation takes place50. In this model, there was no difference in enzyme activity between tumor-bearing rats and controls, which suggested that the tumor bearers did not utilize an augmented supply of NEFA for oxidation in the fed state. Since fatty acylCoA formed in the cytosol is either oxidized in the mitochondria or converted to TG and phospholipids in the cytosol, enhancement of the latter may contribute to the significant increase in circulating TG levels.
The rate of free fatty acid (FFA) production in epididymal adipose tissue removed from tumor-bearing rats was shown to be increased, compared to that of controls51. We previously documented on increased rate of lipolysis (elevated FFA-Ra), associated with the maintained FFA clearance rate by the hepatocytes, which are major sites of uptake of FFA in Fisher344 rats with MCA sarcoma52. A significant increase in the FFA-Ra has been also shown in patients with significant weight loss53.
Why is liberation of FFA needed in the tumor-bearing state? Some investigators have suggested that tumor growth is associated with an enhanced mobilization of stored triglycerols so that the resulting liberation of FFA can be utilized for tumor growth54. However, the delivery rate of FFA to rapidly growing tumors is slow39. An augmented supply of NEFA by lipolysis to the liver44,55 may not be utilized for oxidation56 preferentially esterified to form TG, which is secreted as very low density lipoprotein.
The concept of a lipolytic factor secreted by the tumor has been proposed57,58. Costa and Holland32 were able to induce a substantial fat loss in non-tumor-bearing mice following the injection of nonviable tumor preparation. Although data from several studies indirectly support the existence of a tumor-related "lipolytic factor", attempts to discover such a factor have been unsatisfactory in animal models41 and patients40,51.
Lipoprotein lipase (LPL), synthesized by parenchymal cells of adipose and muscle tissues and transported to the vascular endothelium, regulates the rate at which hydrolysis of circulating TG occurs, delivering NEFA for metabolic needs of the tissue59. This enzyme is unique in that the tissue-specific changes in the catalytic activity closely reflect alterations in the physiological state. Reciprocal changes during starvation in LPL activity in muscle, where LPL provides fatty acids for fuel, and adipose tissue, where the acyl groups are used for TG storage, are well documented60,61.
We documented decreased enzyme activity with increasing tumor burden, and the reversal of these changes, by tumor removal in Fisher344 rats with MCA sarcoma62. One possible mechanism to explain the decreased LPL in the fasted tumor-bearing rats is hypoglycemia, induced by the presence of tumor. The LPL response to dietary carbohydrate appears to depend largely on the insulin secretory response to the ingested carbohydrate63. The finding that withdrawal of glucose from the media decreased LPL activity in 3T3-L1 adipocytes56 suggests that the substrate itself may play an important role in the regulation of this enzyme. Ong and Kern64 demonstrated that insulin stimulated LPL by increasing the level of LPL mRNA, whereas glucose stimulates LPL translation and post-translational processing in cultured rat adipocytes.
Our results in adipose tissue agree with those of Thompson et al44 and Lanza-Jacoby 65. Vlassam et al66 documented a reduction in post-heparin plasma LPL activity in overnight fasted patients with malignant-associated weight loss. The level of total peripheral LPL correlated well with the presence of body weight loss in their patients (r=0.6, p<0.01). Our recent data on post-heparin serum LPL in GI and breast cancer patients revealed that decreased LPL activity in those patients was significantly correlated with degree of weight loss and with advanced stages of disease. However, complete tumor removal did not result in reversal of deceased LPL activity, unlike insulin resistance in glucose metabolism67. Decreased LPL activity in the absence of hyperlipidemia, especially in patients with GI or breast cancer, may be induced by malnutrition, not by tumor effects. Therefore, in studying lipid metabolism in cancer patients, classification of subsets of patients into those with and without hyperlipidemia may be the key in further dissecting the mechanisms of these alterations.
3. Protein Metabolism
Tumors have been known not only as "glucose eaters" but also as "nitrogen sinks", depleting the host of protein mass and resulting in characteristic alterations in protein metabolism. Several investigators have suggested that redistribution or translocation of peripheral proteins to support visceral or tumor protein synthesis is an essential feature of amino acid metabolism in cancer cachexia68. Because the rate of protein synthesis in human tumors is approximately the same as that of the tissue of origin69, and human tumors rarely exceed 1% of body mass70, the observed alterations in whole-body protein metabolism are unlikely to be secondary to the tumor itself, but rather to tumor-influenced alterations in host protein metabolism71.
Basal postabsorptive aminograms in several homogeneous groups of patients with different malignancies have been reported with variable results. Only one paper by Clarke et al.72 showed elevations of alanine, isoleucine, and lysine, but all the others showed either decrease or no alterations. Heber et al.12 demonstrated decreased alanine levels in patients with advanced lung cancer. Those may support the hypothesis that gluconeogenesis from alanine and other gluconeogenic precursor proteins is increased. In 55 patients with a variety of tumors, proline levels were significantly reduced in lymphoma and sarcoma patients. Patients with esophageal cancer and weight loss demonstrated a marked reduction in all circulating amino acids except BCAA. No cancer-specific amino acid profile has emerged from the studies so far published73,74. However, it appears that patients with extraintestinal nonobstructive malignancies have minimal aberrations in their amino acid profiles, and it is possible that with more advanced malignancy with weight loss, more profound changes in amino acid concentrations occur.
Whole-body protein metabolism
With few exceptions, whole-body protein turnover, synthesis, and catabolism have been reported to be elevated in both tumor-bearing animals75 and cancer patients. Those changes are not tumor-site specific but may be related to the advancement of the tumor. Shaw et al43 examined rates of whole-body protein synthesis and catabolism by isotopic infusion of alpha-[15N]-lysine and [15N]2-urea in 20 patients with advanced-weight-loss (AWL) upper gastrointestinal cancer, 7 patients with early non-weight-loss (ENWL) lower gastrointestinal cancer, and a group of volunteers. ENWL cancer patients and normal volunteers had similar protein dynamics, and in both groups, glucose infusion resulted in a significant decrease in protein loss. In AWL cancer patients, the rate of net protein catabolism was significantly higher than in either the volunteer or ENWL group (p<0.05). Glucose infusion did not result in a decrease in net protein catabolism. TPN significantly decreased net protein catabolism from 2.24+0.30 to 0.17+0.09 gm/kg/day (p<0.01). This decrease was due to the combined effect of a significant decrease in whole-body protein catabolism coupled with an increase in whole-body protein synthesis. Increase in whole-body protein catabolismand whole-body protein synthesis to a lesser extentin patients with cancer cachexia from a variety of tumors (n=47) was also confirmed in the subsequent study by the same group by intraoperative isotopic infusion of 14C-leucine83. They concluded that patients with cancer cachexia were actively losing protein as a result of an increase in whole-body protein catabolism that was only partially compensated for by an increase in whole-body protein synthesis. In a patient group studied by Borzotta et al.79, patients with advanced malignancy or stage 4 cancer had significantly greater protein turnover, synthesis, and catabolism than patients with localized disease. Similarly, significant correlation between alterations in protein metabolism and stages of disease was documented by Carmichael et al.68.
Skeletal muscle protein metabolism and regional amino acid kinetic study
A common effect of tumor-bearing on protein metabolism in skeletal muscle has been shown to be depressed protein synthesis and increased protein breakdown. Clark et al.90, demonstrated those changes in the skeletal muscle in rats bearing the Wealker 256 carcinoma. Gastrocnemius muscle weight, RNA/DNA ratio, and incorporation of 14C-valine were significantly decreased. Incorporation of 3H-lysine into protein in the gastrocnemius polysome preparation was decreased, and net tyrosine release and 14CO2 production from 14C- leucine, representing protein degradation, were increased.
Lundholm et al.85,77 examined the regional amino acid kinetics in rectus abdominus muscle obtained at surgery from 43 cancer patients with a variety of tumors and 55 controls. They demonstrated a significant decrease in the in vitro incorporation of 14C-leucine into skeletal muscle protein and an increase in the fractional degradation rate of proteins in cancer group compared with control. Emery et al.77 confirmed the significantly decreased protein synthesis in 5 cancer patients with weight loss by 13C-leucine enrichment in quadriceps protein obtained by percutaneous biopsy. Protein synthesis in muscle was 0.030%/hour in cancer patients and 0.198 in controls (p<0.01). Although most claimed decreased protein synthesis rates in the muscle, only one group found the fractional synthetic rate of protein in rectus abdominus muscle to be increased in cancer patients with cancer cachexia83.
Contrary results were also reported. Newman et al.91, evaluated forearm phenylalanine exchange kinetics by infusion of L-phenylalanine under baseline and postabsorptive conditions in 16 cancer patients and 12 healthy controls and found no significant difference in phenylalanine kinetics in the basal state. Indirect evaluation of skeletal muscle protein catabolism by 3-methylhistidine documented no increase in cancer patients92. Whether those differences derive from differences in methodology or different types of tumor or stages is not clear.
Hepatic protein metabolism
Generally, protein synthesis in the liver has been reported to be increased in the tumor-bearing state. In the MCA 101 tumor-bearing mouse, increased incorporation of leucine in liver tissue was documented by Lundholm et al.93. They suggested that the tumor-bearing state was associated with an increased translational capacity.. Several systems have been defined as mechanisms of amino acid transport in liver. In the Fisher344 rat with MCA sarcoma, both System N (glutamine) and System y+ (arginine) were increased in the presence of the tumor, while System A (MeAIB) was unaltered. The observation that hepatic glutamine transport activity remained augmented after tumor resection longer than any other transport systems studied suggested a key role for this amino acid in overall hepatic nitrogen metabolism and might partially explain the persistent glutamine depletion that was characteristic of the tumor-bearing host94. The arginine pathway, which plays a pivotal role in regulating ureagenesis, polyamine biosynthesis, and nitric oxide production, was significantly stimulated in liver of the tumor-bearing Fisher 344 rats. This response was mediated by an increase in activity of System y+95.
In human studies, an increased in vitro incorporation of 14C-leucine into homogenized hepatic proteins of cancer patients compared with normal controls was demonstrated85. Increased fractional synthesis rates (FSR) of protein in liver (p<0.05) and of albumin (p<0.01) have been confirmed in vivo in cancer cachexia patients compared with either non-weight losing cancer patient or normal control83. Patients with NWLC had a mean FSR of protein in liver of 18.3%+2.2% per day. In contrast, the corresponding value in the patients with cancer cachexia was 29.7%+5.0% per day.
4. Energy Metabolism
Studies on energy metabolism during prolonged fasting are a sharp contrast to the condition of cancerdecreased energy expenditure with increasing starvation. In the cancer, the propensity for elevated energy expenditure in the face of reduced intake has been attributed to a maladaptation of the host to the starvation state4. Although there is general agreement that cancer patients experience elevated energy expenditures, several studies have been reported with varied results.
Some investigators have attempted to overcome the problems of the Harris-Benedict formula by normalizing the REE to the metabolically active tissue (body cell mass)46. In noncachectic sarcoma patients (n=7), there was a significantly lower percentage of BCM than in controls. Reflecting this, the REE corrected for BSA was 25% greater in male sarcoma patients than in male controls (p<0.05), and this difference was doubled when REE was corrected for BCM (p<0.01). They concluded that both REE and vital, functional BCM could be significantly altered in sarcoma patients before any overt signs of cachexia develop99.
Hansell et al.47 assessed the hypothesis that different tumor types exert different effects on REE. REE in 84 cancer patients correlated significantly with body weight and lean tissue mass. The slope of the regression line for the bronchial cancer patients was significantly different from the colorectal and gastric cancer patients when REE was related to LBM. When REE in the same organ was compared, and results differed. In gastric cancer patients, Frederic et al96 could not demonstrate any elevation, while Dempsey et al.98 found significant elevation.
There is no widespread agreement concerning alterations in energy metabolism in cancer patients. The use of a heterogeneous cancer group may be inappropriate in studies of REE as in other parameters in cancer. When REE is significantly elevated there is more likelihood for the disease to be widely spread.
Recently, there has been much interest in a variety of monokines, because they can elicit a metabolic response very similar to that seen in the cachectic syndrome induced by tumors: loss of appetite, loss of body weight (body fat and protein), and induction of acute phase protein synthesis100. These similarities alone do not prove a cause-and-effect relationship. Possible transfer of endogenous mediators via the circulation was demonstrated by the development of cachexia in non-tumor-bearing rats after parabiotic anastomosis to sarcoma-bearing cachectic rats 101). However, the results reported by different investigators are not always the same.
TNF-alpha/cachectin, a 17kDa protein consisting of 157 amino acids, is produced by stimulated reticuloendothelial cells, principally macrophages and monocytes102. The receptors for TNF have been identified in nearly all tissues103. The half-life is 14-18 min in humans and 10 min in mice104. TNF is a well-documented growth factor for many normal cells, stimulating cellular growth and differentiation105, and inducing production of a variety of compounds, including PGE2, collagenase, platelet activating factor, IL-1 and IL-6106. TNF also enhances angiogenesis107.
A single injection of TNF alpha can cause a characteristic weight loss due to a reduction in food and water intake and a decreased carcass water content108. However, when rats received chronic (5-day) infusions of rH-TNF, profound anorexia and fluid retention, but not accelerated nitrogen losses, were observed109. Darling and Norton110 reported that a continuous i.v. infusion of TNF, rather than an intermittent bolus i.v. resulted in a decreased food intake and a decreased nitrogen balance. After 4 days of treatment, rats treated with intermittent bolus doses of TNF developed tolerance. The TNF decreases LPL activity and increases hepatic lipogenesis111,112. Cells transfected with the TNF gene inserted near an active promotor were injected into nude mice, which produced a sustained release of TNF and resulted in a severe wasting of host body fat and lean tissue mass, progressive cachexia and eventual death113,114,115. Active TNF genes were demonstrated in the tumor and lymphoid tissue of MCA sarcoma-bearing mice116 and in human colorectal tumors117. However, only a few papers have documented increased serum TNF in tumor-bearing patients118,119. No correlation between severity of cachexia and TNF concentrations was found120,121.
IL-6, a 26kDa protein, is perhaps the most extreme example of a pleiotropic cytokine. It has a broad range of activities on different cells and was originally found as a growth factor for transformed B-cells122. Some of its functions include stimulation and differentiation of B-cells (BSF-2)123, supporting hybridoma and plasmacytoma cell growth (HGF/PGF), and stimulating synthesis of host response proteins by liver following exposure to toxic materials or injury (HSF) 124. IL-6 is secreted by monocytes, fibroblasts, keratinocytes, endothelial cells,and B-cells. A specific, high affinity receptor for IL-6 is distributed on many different cells throughout the organism.
Is IL-6 the circulating message that induces anorexia125 and the hepatic acute phase reactants? Elevated serum levels of IL-6 were demonstrated in Balb/c x DBA/2(CD) mice with colon 26 carcinoma126. The effects of IL-6 in vivo were assessed by inoculating nude mice with Chinese hamster ovarian cells that had been transfected with the murine IL-6. Only those inoculated with the transfected IL-6 gene demonstrated a number of paraneoplastic syndromes including hypercalcemia, cachexia, leukocytosis, and thrombocytosis127. Both the injection of IL-6 in mice and the culture of 3T3-L1 adipocytes in the presence of IL-6 reduced tissue and heparin-releasable LPL activity in a dose-dependent manner128. IL-6 was also demonstrated immunohistochemically in human tumor specimens129. Furthermore, some of the alterations were reversed by neutralizing antibodies to IL-6 (eg. the hypercalcemia associated with a human squamous cell carcinoma130, the depletion of carcass weight and epididymal fat, hypoglycemia, and the increase in serum amyloid P126).
Why are cytokines not found in the circulation ?
To determine a cause and effect relationship between a molecule and any putative effects it may have in vivo, the molecule must first be demonstrated to be in the circulation at the time when host response is initiated125.
Although Stovroff et al. demonstrated that TNF in the circulation of cachectic sarcoma-bearing rats was correlated with tumor burden and disappeared following tumor resection114, and Balkwill et al detected labile TNF activity by means of an enzyme-linked immunosorbent assay in 50% of 226 freshly obtained serum samples from cancer patients with active disease 118, increased circulating TNF concentrations are not a regular finding in human or experimental cancer disease116,132,121. The magnitude of weight loss and the appearance of TNF in the circulation seem to be poorly correlated133. Analytical results at a molecular level are also controversial. Northern blot analysis of human colorectal cancer specimens showed the presence of mRNA for TNF in 15 of 28 tumor samples and 6 of 26 matched normal tissue samples. TNF localized by in situ hybridization was demonstrated to correlate to activated macrophages that infiltrated the tissue. No one had detectable IL-1 or IL-6 mRNA in tumor or normal tissues, although all tissues tested expressed TGF-1134. Up-regulation of TNF gene transcription was also found in the liver and spleen despite an inability to detect circulating cachectin116.
Many factors have been used to explain the low circulating levels of some of the cytokines. However, the difficulty in detecting TNF in the plasma of cancer patients and the ease of detecting it in cases of sepsis and severe infection does not lead us to conclude that the same molecule works differently in different disease state (i.e. as an autocrine or paracrine factor in cancer and as an endocrine factor in infection). No other hormones function through different mechanisms, depending on the pathologic conditions, unless other factors can recognize the different pathologies. There are increasing data that suggest a role for cytokines in mediating cancer cachexia. However, other reports argue against it. Whether cytokines and a cytokine network are responsible for inducing cancer-specific metabolic alterations or not has to be clarified in further study.
6. Insulin Resistance in Cancer
Insulin resistance in the tumor-bearing state was found as early as 1919 by Rohdenberg et al.135. Lundholm et al.136 showed that a decrease in glucose after insulin infusion is quantitatively smaller in cancer patients compared with controls. Insulin resistance is generally defined as quantitative decrease in response to insulin infusion137. It is not rare to find an abnormal glucose tolerance in cancer patients. Glicksman et al.138, examining 600 cancer patients by glucose tolerance tests, found that 37% of those examined demonstrated a diabetic pattern. In contrast with other alterations, more data on insulin resistance has come from human studies. Initially, it was considered that insulin resistance was the result of malnutrition; however, insulin resistance was found even in those with early sarcoma, esophageal cancer139, and non-oat cell carcinoma.
Insulin resistance in glucose metabolism
Lundholm et al.144 documented that in malnourished cancer patients, both insulin sensitivity and responsiveness were decreased in 50%, 70-80% of infused glucose during glucose clamp was taken up by the peripheral tissue, and insulin sensitivity in the peripheral tissue was lower than that in the whole body sensitivity. The decreased insulin sensitivity in the peripheral tissue was difficult to reverse with a large amount of insulin.
Copeland et al.143, examining 12 patients with colorectal cancer, documented that responsiveness (maximal glucose disposal) was decreased compared to controls, but sensitivity (insulin concentration of half maximal glucose disposal) was not different. These findings suggest that insulin resistance occurs as a post-receptor defect. Most data so far reported agree that glucose disposal is decreased in many cancer patients. The only contradictory paper came from Byerley on patients with head and neck tumors140. In their study, glucose disposal rate was increased in cancer patients, suggesting an increased drainage of glucose into the tumor. However, insulin clearance rate was increased in their patients, which might result in increased glucose disposal.
We examined insulin sensitivity in both weight-losing and weight-stable patients with cancer and compared their results with those of a normal volunteer. There was significant decrease in glucose metabolized and metabolic clearance of glucose in both the weight-stable and weight-losing patients compared with controls. This decrease was reversed by complete tumor removal, suggesting that insulin resistance in patients with cancer is not a result of cancer-associated malnutrition but is related to the tumor itself67.
Insulin resistance in lipid metabolism
There have not been many papers on this issue. The presence of insulin resistance in LPL activity was documented in studies in vivo and in vitro with MCA sarcoma-bearing rats146. McRussel et al.145 found that hyperlipidemia (FFA, 80+62uM) observed in patients with small cell lung cancer under chemotherapy with hyperalimentation did not respond to the high insulin level of 5.07+1.66 ng/ml and suggested the presence of insulin resistance in those patients. In our study during glucose clamp, changes in TG, FFA, very low density lipoprotein (VLDL), and LDL levels were not related with M values calculated from the insulin clamp technique. In septic cancer patients, insulin resistance in FFA turnover was more apparent than resistance in suppressing endogenous insulin production. The antilipolytic effect of insulin is induced by 1/4 of the amount necessary for glucose utilization and ½ of that required for suppressing endogenous glucose production. Therefore, insulin resistance in lipid metabolism may be more difficult to be demonstrated147.
Insulin resistance in protein metabolism
The influence of insulin on protein synthesis from phenylalanine in the C57BL/6J mouse skeletal muscle and from leucine in the rectal muscle of cancer patients revealed no difference between cancer patients and controls148. Amino acid alterations during hyperinsulinemic glucose clamp were not related with glucose metabolized or M values (unpublished data). Insulin action on arterial BCAA concentrations and forearm BCAA flux was investigated in 6 weight-losing patients with localized gastrointestinal cancer by euglycemic hyperinsulinemic clamp. Progressive euglycemic insulin infusion induced a marked, comparable insulin-dependent decrease in arterial plasma BCAA concentrations in both patients and controls. There was no difference in post-absorptive forearm BCAA flux with progressive hyperinsulinemia. Insulin-induced branched-chain hypoamino acidemia was unimpaired in this group of patients. Those provide evidences of differential resistance to insulin action in glucose and protein metabolism 74.
Mechanisms of insulin resistance in cancer
Mechanisms of insulin resistance in cancer patients have not yet been clarified. Therefore, mechanisms in diabetes mellitus referred to here and theoretical mechanisms are summarized in table 1. The increase in catabolic hormones in cancer patients such as glucagon, cortisol, and catecholamine is one possibility147. Ojamaa et al.149 suggested a decrease in insulin receptor mRNA and synthesis rate of insulin receptors, a defect at the post-translational levels, or decreased translocation of the transport proteins to the plasma membrane in diabetic patients. Haring et al.150, studying the Claudman S91 melanoma cell, documented decreased affinity of receptors to insulin and decreased autophosphorylation of beta-subunit tyrosine kinase. Significant correlation between decreased activation of tyrosine specific protein kinase (beta-subunit) and insulin resistance has been suggested. From the fact that the number of insulin receptors necessary for insulin to induce its effect is less than 5% of total insulin receptors, Krett et al.151 suggested the greater importance of post-receptor events as compared to number of insulin-binding sites.
The mechanisms of defects in kinase is complex, including 1) defects in autophosphorylation of receptor kinase, 2) an alteration in ATP-binding sites for insulin receptor tyrosine kinase, resulting in decreased activity of insulin receptor tyrosine kinase, 3) presence of insulin insensitivity. Other possible mechanisms may include a defect in internalization of insulin receptors, decreased intracellular uptake of insulin-receptor complex, and a defect in signal transduction between receptor kinase and glucose transporter. Dissection of the mechanisms of insulin resistance may give us another key to solve the complex mechanisms of cancer cachexia.
Tumor-bearing hosts suffer from tumor-induced metabolic alterations, some of which are secondary to malnutrition and others that are tumor-specific changes. In evaluating those alterations, the type of the tumor and the stages of the cancer may have to be taken into account.
As in other data, animal results may not necessarily be applicable to tumor-bearing humans. Nutritional support can reverse most but not all alterations. Indications of nutritional support have to be determined from patient-benefit considerations as well as tumor growth. The selection of patients for intensive nutritional support should be recognized as a science not an art. To this end, further dissection of basic mechanisms of tumor-induced metabolic alterations is necessary.
YOUNES RN e col. - Fisiopatolgia da caquexia em câncer. Rev. Hosp. Clín. Fac. Med. S. Paulo 55(5): 181-193, 2000.
A caquexia é uma complicação freqüentemente observada em pacientes portadores de tumores malignos. Apesar de várias décadas transcorrerem desde a descrição inicial das disfunções metabólicas associadas ao câncer, poucas medidas terapêuticas foram induzidas com sucesso na prática médica.
O presente estudo apresenta uma revisão detalhada da fisiopatologia básica da caquexia em câncer, e as opções terapêuticas desenvolvidas nesta área. Estudos experimentais, assim como clínicos, são avaliados individualmente para esclarecer as alterações complexas observadas em pacientes portadores de tumores. As dificuldades encontradas para introduzir manipulações metabólicas e terapias de suporte nutricional eficientes são discutidas nesta revisão.
DESCRITORES: Câncer. Caquexia. Metabolismo. Citoquina. Insulina.
1. DEWYS WD & WALTERS K. - Abnormalities of taste sensation in cancer patients. Cancer 1975;36:1888-1896. [ Links ]
2. MORRISON SD - Control of food intake in cancer cachexia. Cancer Res 1977; 37:2359-2364. [ Links ]
3. MOLDAWER LL, GEOGIEFF M & LUNDHOLM KG - Interleukin 1, tumor necrosis factor/cachectin and the pathogenesis of cancer cachexia. Clin Physiol 1987 ; 7:263-274. [ Links ]
4. MOLDAWER LL, ANDERSEN C, GELIN J et al. - Regulation of food intake and hepatic protein metabolism by recombinant derived monokines. Am J Physiol 1988; 253:G450-456. [ Links ]
5. BRENNAN MF - Uncomplicated starvation versus cancer cachexia. Cancer Res 1977; 37: 2359-2364 [ Links ]
6. ESPAT NJ, COPELAND EM & MOLDAWER LL - Tumor necrosis factor and cachexia: a current perspective. Surg Oncol 1994; 3: 255-262. [ Links ]
7. SCHEINBERG P & STEAD Jr. EA - The cerebral blood flow in male subjects as measured by the nitrous oxide technique: normal values for blood flow, oxygen utilization, glucose utilization, and peripheral resistance, with observations on the effect of tilting and anxiety. J Clin Invest 1949; 28:1163-1171. [ Links ]
8. GULLINO PM, GRANTHAM FH, COUTNEY AH et al. - Relationship between oxygen and glucose consumption by transplanted tumors in vivo. Cancer Res 1967; 27:1041-1052. [ Links ]
9. NORTON JA, BURT ME & BRENNAN MF In vivo utilization of substrate by human sarcoma-bearing limbs. Cancer 1980; 45:2934-2939. [ Links ]
10. BRENNAN MF - Total parenteral nutrition in the cancer patient. NEJM 1981; 305:375-382. [ Links ]
11. KOKAL WA, MCCULLOCH A, WRIGHT PD et al. - Glucose turnover and recycling in colorectal cancer. Ann Surg 1983; 198:601-604. [ Links ]
12. HEBER D, BYERLY LO, CHLEBOWSKI RT - Metabolic abnormalities in the cancer patient. Cancer 1985; 55:225-229. [ Links ]
13. EDEN E, EDSTROM S, BENNEGARD K et al. - Glucose flux in relation to energy expenditure in malnourished patients with and without cancer during periods of fasting and feeding. Cancer Res 1984; 44:1718-1724. [ Links ]
14. LUNDHOLM K, EDSTORM S, KARLBERG I et al. - Glucose turnover, gluconeogenesis from glycerol, and estimation of net glucose cycling in cancer patients. Cancer 1982; 50:1142-1150. [ Links ]
15. BURT ME, GORSCHBOTH CM & BRENNAN MF - A controlled, prospective, randomized trial evaluating the metabolic effects of enteral and parenteral nutrition in cancer patients. Cancer 1982; 49:1092-1105. [ Links ]
16. GLICKSMAN AS & RAWSON RW - Diabetes and altered carbohydrate metabolism in patients with cancer. Cancer 1956; 9:1127-1134. [ Links ]
17. KALLINOWSKI F, SCHLENGER KH, RUNKEL S et al. - Blood flow, metabolism, cellular microenviroment and growth rate of human xenografts. Cancer Res 1989; 49:3759-3764. [ Links ]
18. ROH MS, EKMAN L, JEEVANANDAM M et al. - Gluconeogenesis in tumor influenced hepatocyte. Surgery 1984; 96:427-434. [ Links ]
19. YOUNG VR - Energy metabolism and requirements in the cancer patients. Cancer Res 1977; 37:2336-2347. [ Links ]
20. WATERHOUSE C, JEANPRETRE N & KEILSON J - Gluconeogenesis from alanine in patients with progressive malignant disease. Cancer Res 1979; 39:1968-1972. [ Links ]
21. BRENNAN MF - Malnutrition in patients with gastrointestinal malignancy: significance and management. Dig Dis Sci 1986; 31:77s-90s. [ Links ]
22. SHRAGO E, LARDY HA, NORDLIE RC et al. - Metabolic and hormonal control of phosphoenolpyruvate carboxykinase and malic enzyme in rat liver. J Biol Chem 1963; 238:3188-3192. [ Links ]
23. NELSON K, CIMBALA MA & HANSON RW - Regulation of the turnover of the mRNA for hepatic phosphoenolpyruvate carboxykinase(GTP). In: VENEZIALA CM, (Ed.) - The regulation of carbohydrate formation and utilization in mammals. Baltimore, University Park Press, 1981. p.349-392. [ Links ]
24. TILGHMAN SM, HANSON RW, RESHEF L et al. - Rapid loss of translatable messenger RNA of phosphoenolpyruvate carboxykinase during glucose repression in liver. Proc Natl Acad Sci USA 1974; 1304-1308. [ Links ]
25. SUSSMUTH W, HOPPNER W & SEITZ HJ - Permissive action of thyroid hormones in the cAMP-mediated induction of phosphoenolpyruvate carboxykinase in hepatocytes in culture. Eur J Biochem 1984; 143:607-611. [ Links ]
26. CHLEDOWSKI RT, HEBER D, RICHARDSONO B et al. - Influence of hydrazine sulfate on abnormal carbohydrate metabolism in cancer patients with weight loss. Cancer Res 1984; 44:857-861. [ Links ]
27. GOLD J - Hydracine: a current prospective. Nutr Cancer 1987; 9:59-66. [ Links ]
28. BURT ME, PETERS MI, BRENNAN MF et al. - Hypoglycemia with glycerol infusion as antineoplastic therapy: a hypothesis. Surgery 1985; 97:231-233. [ Links ]
29. COSTA G, SAMAL B, BRENNAN J et al. - Changes in the composition of human muscle during the growth of malignant tumors. Proc Am Assoc Cancer Res 1965; 6:12. [ Links ]
30. HAVEN FL, BLOOR WR & RANDALL C - Lipids of the carcass, blood plasma, and adrenals of the rat in cancer. Cancer Res 1949; 9:511. [ Links ]
31. MIDER GB, SHERMAN CD & MORTON JJ - The effect of Walker Carcinoma 256 on the total lipid content of rats. Cancer Res 1949; 9:222. [ Links ]
32. COSTA G & HOLLAND JF - Effects of Krebs-2 carcinoma on the lipid metabolism of male Swiss mice. Cancer Res 1962; 22:1081. [ Links ]
33. NOGUCHI Y, VYDELINGUM NA, CONLON KC et al. - Hypertriglyceridemia in the tumor-bearing state is associated with decreased hepatic malic enzyme activity. Surg Forum 1988; 39:462-463. [ Links ]
34. DEVEREUX D, ROBY C, DECKERS P et al. - Effects of tumor bearing and removal on lipid metabolism in the rat. Surg Forum 1982; 33:406. [ Links ]
35. SPIEGEL R, SCHAEFER E, MAGRATH I et al. - Plasma lipid alterations in leukemia and lymphoma. Amer J Med 1982; 72:775. [ Links ]
36. BABAYAN RK & DEVEREUX DF - Alteration of lipid metabolism associated with renal adenocarcinoma in the Wistar-Lewis rat. J Urol 1984; 132:410. [ Links ]
37. LEGASPI A, JEEVANANDAM M, STARNES HF Jr. et al. - Whole body lipid metabolism in the cancer patient. Metabolism 1987; 36:958-963. [ Links ]
38. DILMAN VM, BERSTEIN IM, OSTROUMOVA MN et al. - Peculiarities of hyperlipidemia in tumour patients. Br J Cancer 1981; 43:637-643. [ Links ]
39. MUELLER PS & WATKEN DM - Plasma unesterified fatty acid concentration in neoplastic disease. J Lab Clin Med 1961; 57:95. [ Links ]
40. CARTER AC, LEFKON BW, FARLIN M et al. - Metabolic parameters in women with metastatic breast cancer. J Clin Endocrinol 1975; 40:260. [ Links ]
41. MAYS ET - Serum lipids in human cancer. J Surg Res 1969; 9:273. [ Links ]
42. NOMURA K, NOGUCHI Y & MATSUMOTO A - Plasma interleukin-6 is not a mediator of changes in lipoprotein lipase activity in cancer patients. Hepatogastroenterol 1997; 44(17):1517-26. [ Links ]
43. SHAW JHF & WOLFE RR - Glucose and urea kinetics in patients with early and advanced gastrointestinal cancer: the response to glucose infusion, parenteral feeding, and surgical resection. Surgery 1987; 101:181-191. [ Links ]
44. THOMPSON MP, KOONS JE, TAN ETH et al. - Modified lipoprotein activities, rates of lipogenesis, and lipolysis as factors to lipid depletion in C57BL mice bearing the preputial gland tumor, ESR-586. Cancer Res 1981; 41:3228-3232. [ Links ]
45. WARREN RS, JEEVANANDAM M & BRENNAN MF - Protein synthesis in the tumor-influenced hepatocyte. Surgery 1985; 98:275. [ Links ]
46. ARBEIT JM, LEES DE, CORSEY R et al. - Resting energy expenditure in controls and cancer patients with localized and diffuse disease. Ann Surg 1984; 199:292-298. [ Links ]
47. HANSELL DT, DAVIES JWL & BURNS HJG - The effects on resting energy expenditure of different tumor types. Cancer 1986; 58:1739-1744. [ Links ]
48. WATERHOUSE C & KEMPERMAN JH - Carbohydrate metabolism in subjects with cancer. Cancer Res 1971; 31:1273. [ Links ]
49. NOGUCHI Y, VYDELINGUM NA & BRENNAN MF - Tumor-induced alterations in hepatic malic enzyme and carnitine palmitoyltransferase activity. J Surg Res 1993; 55:357-363. [ Links ]
50. BIEBER LL & FARRELL S - Carnitine acyltransferases. In: BOYER PD (Ed.) - The Enzymes. New York, Academic Press 1985. p. 627-644. v. 16 [ Links ]
51. KRALOVIC RC, ZEPP FA & CENEDELLA RJ - Studies of the mechanism of carcass fat depletion in experimental cancer. Eur J Cancer 1977; 13:1071. [ Links ]
52. YOUNES RN, VYDELINGUM NA, NOGUCHI Y et al. - Lipid kinetic alterations in tumor-bearing rats: reversal by tumor excision. J Surg Res 1990; 48:324-328. [ Links ]
53. SHAW JHF & WOLFE RR - 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. [ Links ]
54. HENDERSON JF & LEPAGE GA - The nutrition of tumors: a review. Cancer Res 1959; 19:887. [ Links ]
55. DEVEREUX DF & HOLLANDER DM - Effects of tumor bearing and removal on blood levels of lipids, lipolytic activity, and glycerol and on carcass weight in the rat. Surgery 1987; 101:228-233. [ Links ]
56. CHERNICK SS, SPOONER PM, GARRISON MM et al. - Effect of epinephrine and other lipolytic agents on intracellular lipolysis and lipoprotein activity in 3T3-L1 adipocyte. J Lipid Res 1986; 27:286-294. [ Links ]
57. FREDERICK GL & BEGG RW - A study of hyperlipemia in the tumor-bearing rat. Cancer Res 1956; 16:548. [ Links ]
58. DEVEREUX DF, REDGRAVE TG, LODA MF et al. - Tumor-associated metabolism in the rat is a unique physiologic entity. J Surg Res 1985; 38: 149. [ Links ]
59. KOMPIANG IP, BENSADOUN A, YANG MWW. - The effect of an antilipoprotein lipase serum on plasma triglyceride removal. J Lipid Res 1976; 17:498-505 [ Links ]
60. ALOUSI AA & MELLOV S - Effect of hyperthyroidism, epinephrine, and diet on heart lipoprotein lipase activity. Am J Physiol, 1964; 206:603-609. [ Links ]
61. HOLLENBERG CH - The effect of fasting on the lipoprotein lipase activity of rat heart and diaphragm. J Clin Invest 1960; 39:1282-1287. [ Links ]
62. NOGUCHI Y, VYDELINGUM NA, YOUNES RN et al. - Tumor-induced alterations in tissue lipoprotein lipase activity and mRNA levels. Cancer Res 1991; 51:863-869. [ Links ]
63. ECKEL RH - Adipose tissue lipoprotein lipase. In: BORENSZTAJN J (Ed.) - Lipoprotein Lipase. Chicago IL, Evener, 1987. p. 79-132. [ Links ]
64. ONG JM & KERN PA - The role of glucose and glycosylation in the regulation of lipoprotein lipase synthesis and secretion in rat adipocytes. J Biol Chem 1989; 264:3177-3182. [ Links ]
65. LANZA-JACOBY S, LANSEY SC, MILLER EE et al. - Sequential changes in the activities of lipoprotein lipase and lipogenic enzymes during tumor growth in rats. Cancer Res 1984; 44:5062-5067. [ Links ]
66. VLASSARA H, SPIEGEL RJ, SANDAVAL D et al. - Reduced plasma lipoprotein lipase activity in patients with malignancy associated with weight loss. Horm Metab Res 1986; 18:698-703. [ Links ]
67. YOSHIKAWA T, NOGUCHI Y & MATSUMOTO A - Effects of tumor removal and body weight loss on insulin resistance in patients with cancer. Surgery 1994; 116:62-66. [ Links ]
68. CARMICHAEL MJ, CLAGUE MB, KEIR MJ et al. - Whole body protein turnover, synthesis and breakdown in patients with colorectal carcinoma. Br J Surg 1980; 67:736-739. [ Links ]
69. STEIN TP, MULLEN JL, ORAM-SMITH et al. - Relative rates of tumor, normal gut, liver and fibrinogen protein synthesis in man. Am J Physiol 1978; 234:E648-652. [ Links ]
70. COSTA G. - Cachexia, the metabolic component of neoplastic disease. Cancer Res 1977; 37:2327-2335. [ Links ]
71. PISTERS PWT & PEARLSTONE D - Protein and amino acid metabolism in cancer cachexia: Investigative techniques and therapeutic interventions. Crit Rev Clin Lab Sci 1993; 30:223-272. [ Links ]
72. CLARKE EF, LEWIS AM & WATERHOUSE C - Peripheral amino acid levels patients with cancer. Cancer 1978; 42:2909-2913. [ Links ]
73. NORTON JA, GORSCHBOTH CM, WESLEY RA et al. - Fasting plasma amino acid levels in cancer patients. Cancer 1985; 56:1181-1186. [ Links ]
74. PISTERS PWT, CERSOSIMO E, ROGATKO A et al. - Insulin action of glucose and branched-chain amino acid metabolism in cancer cachexia: Differential effects of insulin. Surgery 1992; 111:301-310. [ Links ]
75. NORTON JA, SHAMBERGER R, STEIN P et al. - The influence of tumor-bearing on protein metabolism in the rat. J Surg Res 1981; 30:456-462. [ Links ]
76. HEBER D, BYERLAY LO & TCHEKMEDYIAN S - Hormonal and metabolic abnormalities in the malnourished cancer patients: effects on host-tumor interaction. J parenteral Nutr 1992; 16:60S-64S. [ Links ]
77. EMERY PW, EDWARDS RHT, RENNIE MJ et al. - Protein synthesis in muscle measured in vivo in cachectic patients with cancer. Br Med J 1984; 289:584-586. [ Links ]
78. FEARON KCH, HANSELL DT, PRESTON T et al. - Influence of whole body protein turnover on resting energy expenditure in patients with cancer. Cancer Res 1988; 48:2590-2595. [ Links ]
79. BORZOTTA AP, CLAGUE MB & JOHNSTON IDA - The effects of gastrointestinal malignancy on whole body protein metabolism. J Surg Res 1987; 43:505-512. [ Links ]
80. WATERHOUSE C & MASON J - Leucine metabolism in patients with malignant disease. Cancer 1987; 48:939-944. [ Links ]
81. EDEN E, EKMAN L, BENNEGARD K et al. - Whole-body tyrosine flux in relation to energy expenditure in weight-losing cancer patients. Metabolism 1984; 33:1020-7. [ Links ]
82. JEEVANANDAM M, LOWRY SF & BRENNAN MF - Effect of the route of nutrient administration on whole-body protein kinetics in man. Metabolism 1987; 36:968-973. [ Links ]
83. SHAW JHF, HUMBERSTONE DM, DOUGLAS RG et al. - Leucine kinetics in patients with benign disease, non-weight-losing cancer, and cancer cachexia: studies at the whole-body and tissue level and the response to nutritional support. Surgery 1991; 109:37-50. [ Links ]
84. HESLIN MJ, NEWMAN E, WOLF RF et al. - Effect of hyperinsulinemia on whole body and skeletal muscle leucine carbon kinetics in humans. Am J Physiol 1992; 262:E911-E918. [ Links ]
85. LUNDHOLM K, BYLUND AC & HOLM J - Skeletal muscle metabolism in patients with malignant tumor. Eur J Cancer 1976; 12:465-473. [ Links ]
86. SHAW JHF & WOLFE RR - Whole-body protein kinetics in patients with early and advanced gastrointestinal cancer: the response to glucose infusion and total parenteral nutrition. - Surgery 1988; 103:148-155. [ Links ]
87. NEWMAN E, HESLIN MF, WOLF RF et al. - The effect of insulin on glucose and protein metabolism in the forearm of cancer patients. Surg Oncol 1992; 1:257-267. [ Links ]
88. LUNDHOLM K, EDSTORM S, EKMAN L et al. - A comparative study of the influence of malignant tumor on host metabolism in mice and man: evaluation of an experimental model. Cancer 1978; 42:453-461. [ Links ]
89. STARNS HF, WARREN RS Jr. & BRENNAN MF Protein synthesis in hepatocytes isolated from patients with gastrointestinal malignancy. J Clin Invest 1987, 80:1384-1390. [ Links ]
90. CLARK CM & GOODLAD GAJ - Actin synthesis and polymerization in the liver of fed and fasted rats bearing a Walker 256 carcinoma. Cancer Res 1981; 41:1973-1977. [ Links ]
91. NEUMANN CG, LAWLOR GJ, STIEHM ER et al. - Immunologic responses in malnourished children. Am J Clin Nutr 1975; 28:89-104. [ Links ]
92. LUNDHOLM K, BENNENGARD K, EDEN E et al. - Efflux of 3-methylhistidine from the leg in cancer patients who experience weight loss. Cancer Res 1982; 42:4807-4811. [ Links ]
93. LUNDHOLM K, EKMAN L, EDSTROOM S et al. - Protein synthesis in liver tissue under the influence of a methylcholanthrene-induced sarcoma in mice. Cancer Res 1979; 39:4657-4661. [ Links ]
94. ESPAT NJ, BODE B, LIND S, COPELAND EM et al. - Normalization of tumor-induced increase in hepatic amino acid transport after surgical resection. Ann Surg 1995; 221:50-58. [ Links ]
95. ESPAT NJ, COPELAND EM & SOUBA WW - Accelerated hepatic arginine transport in the tumor-bearing rat. Ann Surg Oncol 1994; 1:147-156. [ Links ]
96. FREDERIX EW, SOETERS PB, WOUTERS EF et al. - Effect of different tumor types on resting energy expenditure. Cancer Res 1991; 51: 6138-6141. [ Links ]
97. FALCONER JS, FEARON KCH, PLESTER CE et al. - Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg 1994; 219:325-331. [ Links ]
98. DEMPSEY DT, FEURER ID, KNOX LS et al. - Energy expenditure in malnourished gastrointestinal cancer patients. Cancer 1984; 53:1265-1273. [ Links ]
99. PEACOCK JL, INCULET RI, CORSEY R et al. - Resting energy expenditure and body cell mass alterations in non cachectic patients with sarcomas. Surgery 1987; 102:465-472. [ Links ]
100. MOLDAWER LL, ANDERSSON C, GELIN J et al. - Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol 1988; 254:450-456. [ Links ]
101. NORTON JA, MOLEY JF, GREEN MV et al. - Parabiotic transfer of cancer anorexia/cachexia in male rats. Cancer Res 1985; 45:5547-5552. [ Links ]
102. OLIFF A - The role of tumor necrosis factor (cachectin) in cachexia. - Cell 1988; 54:141-142. [ Links ]
103. BEUTLER B & CERAMI A - Cachectin and tumor necrosis factor as two sides of the same biological coin. Nature 1986; 320:584-588. [ Links ]
104. FLICK O & GIFFORD G - Pharmacokinetics of murine tumor necrosis factor. J Immunopharmacol 1986; 8(1):89-97. [ Links ]
105. SUGARMAN BJ, AGGARWAL BB, HASS PE et al. - Recombinant human tumor necrosis factor-alpha : Effects on proliferation of normal and transformed cells in vitro. Science 1985; 230:943-945. [ Links ]
106. VAN DAMME J, OPDENAKKER G, SIMPSON RJ et al. - Identification of the human 26-KD protein, interferon beta-2 (IFN beta-2), as B cell hybridoma/plasmacytoma growth factor induced by interleukin 1 and tumor necrosis factor. J Exp Med 1987; 165: 914-919. [ Links ]
107. LEIBOVICH SJ, POLVERINIO PJ, SHEPARD HM et al. - Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature 1987; 329:630-632. [ Links ]
108. MAHONY SM & TISDALE MJ - Role of prostaglandins in tumor necrosis factor induced weight loss. Br J Cancer 1989; 60: 51-55. [ Links ]
109. MICHIE HR, SHERMAN ML, SPRIGGS DR et al. - Chronic TNF infusion causes anemia and not accelerated nitrogen loss. Ann Surg 1989; 104:280-286. [ Links ]
110. DARLING G, FRAKER DL, JENSEN JC et al. - Cachectic effects of recombinant tumor necrosis factor in rats. Cancer Res 1990; 50:4008-4013. [ Links ]
111. KAWAKAMI M & CERAMI A - Studies of endotoxin induced decrease in lipoprotein lipase activity. J Exp Med 1981; 154: 631-637. [ Links ]
112. FEINGOLD KR & GRUNFELD C - Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vitro. J Clin Invest 1987; 80:184-190. [ Links ]
113. SHERRY BA, GELIN J, FONG Y et al. - Anticachectin/ tumor necrosis factor-alpha antibodies attenuated development of cachexia in tumor models. FASEB J 1989; 3:1956-1962. [ Links ]
114. OLIFF A, DEFEO-JONES D, BOYER M et al. - Tumors secreting human TNF-cachectin induced cachexia in mice. Cell 1987; 50:555-563. [ Links ]
115. STOVROFF ML, FRAKER DL & NORTON JA - Cachectin activity in the serum of cachectic, tumor-bearing rats. Arch Surg 1989; 124:94-99. [ Links ]
116. LONNROTH C, MOLDAWER LL, GELIN J et al. - Tumor necrosis factor and interleukin 1 alpha production in cachectic, tumor-bearing mice. Int J Cancer 1990; 46:889-896. [ Links ]
117. FULTON AM - Inhibition of experimental metastasis with indomethacin; role of macrophages and natural killer cells. Prostagrandins 1988; 35:413-425. [ Links ]
118. BALKWILL F, BURK F, TALBERT D et al. - Evidence for tumor necrosis factor-cachectin production in cancer. Lancet 1987; 28: 1229-1232. [ Links ]
119. ADERKA D, FISHER S, LEVO Y et al. - Cachectin; tumor necrosis factor production by cancer patients. Lancet 1987; ii: 1190. [ Links ]
120. MOLDWER L, DROTT C & LUNDHOLM K - Monocytic production and plasma bioactivities of interleukin-1 and tumor-necrosis factor in human cancer. Eur J Clin Invest 1988; 18: 486-492. [ Links ]
121. SOCHER SH, MARTINEZ D, CRAIG JB et al. - Tumor necrosis factor not detectable in patients with clinical cachexia. J Natl Cancer Inst 1988; 80:595-598. [ Links ]
122. NORDAN RP, PUMPHREY JG & RUNDIKOFF S - Purification and NH3 terminal sequence of a plasmacytoma growth factor derived from the murine macrophage cell line P388D1. J Immunol 1987; 139:813-817. [ Links ]
123. HIRANO T, YASUKAWA K, HARADA H et al. - Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 1986; 324:73-76, 1986. [ Links ]
124. SCHREIBER G, TSYKLIN A, ALDRED AR et al. - The acute phase response in the rodent. Ann NY Acad Sci 1989; 557: 61-85. [ Links ]
125. MICHIE HR, GUILLOU PJ & WILMOREM DW - Tumour necrosis factor and bacterial sepsis. Br J Surg 1989; 76:670-671. [ Links ]
126. STRASSMANN G, FONG M, KENY JS et al. - Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 1992; 89:1681-1684. [ Links ]
127. BLACK K, GARRETT IR & MUNDY GR - Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thrombocytosis in tumor-bearing nude mice. Endocrinol 1991;128: 2657-2659. [ Links ]
128. GREEMBERG AS, NORDAN RP, MCINTOSH J et al. - Interleukin 6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L1 adipocytes: a possible role for interleukin 6 in cancer cachexia. Cancer Res 1992; 52:4113-4116. [ Links ]
129. TABIBZADEH SS, POUBOURIDIS AB, MAY LT S et al. - Interleukin-6 immunoreactivity in human tumors. Am J Pathol 1989; 135:427-433. [ Links ]
130. YONEDA T, NAKAI M, MORIYAMA K et al. - Neutralizing antibodies to human interleukin 6 reverse hypercalcemia associated with a human squamous carcinoma. Cancer Res 1993; 53:737-740. [ Links ]
131. NAYLOR MS, STAMP GWH & BALKWILL FR - Investigation of cytokine gene expression in human colorectal cancer. Cancer Res 1990; 50:4436-4440. [ Links ]
132. GRAU G, TAYLOR T, TROP M et al. - Tumor necrosis factor and disease in children with falciparum malaria. New Engl J Med 1989; 320:1586-1598. [ Links ]
133. SIMMS MA, TOPPO AM, KOSKELO EK et al. - Serum tumor necrosis factor does not correlate with changes in muscle volume in children with malignancies. Pediatr Hematol Oncol 1991; 8:69-75. [ Links ]
134. MULLIGAN HD, MAHONY SM, ROSS JA et al. - Weight loss in a murine cachexia model is not associated with the cytokine tumour necrosis factor-alpha or interleukin-6. Cancer Lett 1992; 65:239-243. [ Links ]
135. ROHDENBERG GL, BERNHARD A & KREHBIEL O - Surgical tolerance in cancer. JAMA 1919; 72:1528. [ Links ]
136. LUNDHOLM K, HOLM G & SCHERSTEN T - Glucose tolerance in relation to skeletal muscle enzyme activities in cancer patients. Scand J Clin Lab Invest 1978; 37:267. [ Links ]
137. KAHN CR - Insulin resistance, insulin insensitivity and insulin unresponsiveness; a necessary distinction. Metabolism 1978; 27:1893. [ Links ]
138. GLICKSMAN AS & RAWSON RW - Diabetes and altered carbohydrate metabolism in patients with cancer. Cancer 1956; 19:1127. [ Links ]
139. BURT ME, AOKI T, GORSCHBOTH CM et al. - Peripheral tissue metabolism in cancer-bearing man. Ann Surg 1983; 198:685-691. [ Links ]
140. BYERLEY LO, HEBER D, BERGMAN RN et al. - Insulin action and metabolism in patients with head and neck cancer. Cancer 1991; 67:2900-2006. [ Links ]
141. CERSOSIMO C, PISTERS PWT, PESOLA G et al. - The effects of graded dose of insulin on peripheral glucose uptake and lactate release in cancer cachexia. Surgery 1991; 109:459-467. [ Links ]
142. PERMET J, ADRIAN TE, PERJACOBSSON et al. - Is profound peripheral insulin resistance in patients with pancreatic cancer caused by a tumor associated factor? Am J Surg 1993; 165:61-66. [ Links ]
143. COPELAND GP, LEINSTER SJ, DAVIS JC et al. - Insulin resistance in patients with colorectal cancer. Br J Surg 1987; 74:1031-1035. [ Links ]
144. BENNEGARD K, LUNDGRFEN F & LUNDHOLM K - Mechanism of insulin resistance in cancer associated malnutrition. Clin Physiol 1986; 6:539. [ Links ]
145. RUSSEL; D, SHIKE M, MARLISS EB et al. - Effects of total parenteral nutrition and chemotherapy on the metabolic derangement in small cell lung cancer. Cancer Res 1984; 44:1706-1711. [ Links ]
146. NOGUCHI Y, NOMURA K, YOSHIKAWA T et al. - Role of insulin resistance in decreasing lipoprotein lipase activity in tumor-bearing rats. Surg Today 1996; 26:271-275. [ Links ]
147. SAUERWEIN HP, PESOLA GR, GODFRIED MR et al. - Insulin sensitivity in septic cancer-bearing patients. JPEN 1991; 15:653-658. [ Links ]
148. SVANINGER G, DROTT & LUNDHOLM K - Role of insulin in development of cancer cachexia in nongrowing sarcoma-bearing mice : special reference to muscle wasting. JNCI 1987; 78:943. [ Links ]
149. OJAMAA K, HEDO JA, ROBERTS Jr.CT et al. - Defects in human insulin receptor gene expression. Mol Endocrinol 1988; 2:242. [ Links ]
150. HARING HU, WHITE MF, KAHN CR et al. - Abnormality of insulin binding and receptor phosphorylation in an insulin resistant melanoma cell line. J Cell Biol 1984; 99:900-908. [ Links ]
151. KRETT NC, HEATON JH & GELEHRTER TD - Insulin resistance in H-35 rat hepatomacells is mediated by postreceptor mechanisms. Mol Cell Endocrinol 1983; 32:91. [ Links ]
Received for publication on the 27/07/00
From the Department of Surgery, Hospital das Clínicas, Faculty of Medicine, University of São Paulo (LIM 62), Department of Thoracic Surgery, Hospital do Cancer AC Camargo and Universidade Paulista.