Mechanisms and treatment of cancer cachexia.

According to a recent consensus, cachexia is a complex metabolic syndrome associated with underlying illness and characterised by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss. Cachexia occurs in the majority of terminal cancer patients and it is responsible for the deaths of 22% of cancer patients. Although body weight is, indeed, an important factor to be taken into consideration in any cachexia treatment, body composition, physical performance and quality of life should be monitored. From the results presented here, one can speculate that a single therapy may not be completely successful in the treatment of cachexia. From this point of view, treatments involving different combinations are more likely to be successful. The objectives of any therapeutical combination are two: an anticatabolic aim directed towards both fat and muscle catabolism and an anabolic objective leading to the synthesis of macromolecules such as contractile proteins.

[Pathophysiology of neoplasic cachexia]. / Fisiopatología de la caquexia neoplásica.

The regulation of food intake is mediated by different psicological, gastrointestinal metabolic, nutritional and endocrine mechanisms. The cancer patient suffers from anorexia which results in early saciety and a reduction of appetite. Sometimes, the causes of the anorectic response are derived from the antitumoral treatment (chemotherapy, radiotherapy or immunotherapy), in some cases vomiting resulting in altered food intake. Alterations in the food taste and smell perception in addition to psychological dearrangements might also lead to the anorexia. Sometimes the tumour may play a direct effect when it is localised in either the hypothalamus or the digestive apparatus. However, in the majority of cases the origin of the anorexia associated with cancer cachexia seems to be due to the metabolic alterations induced by tumour burden. Different factors of both humoral and tumoral origin play a role in cancer anorexia. For instance, tumour necrosis factor (TNF-), a cytokine responsible for a great part of the metabolic alterations characteristic of cancer cachexia seems to be involved. In conclusion, the cancer anorexia seems to be more an effect than the cause of the weight loss and in fact the decrease in food intake might take place after weight loss is evident. In any case, the malnutrition associated with a decrease of food intake worsens the cachectic state, favouring a kind of a positive feed-back mechanism that finally leads to the patient's death.

Muscle wasting in cancer and ageing: cachexia versus sarcopenia.

Muscle wasting during cancer and ageing share many common metabolic pathways and mediators. Due to the size of the population involved, both cancer cachexia and ageing sarcopenia may represent targets for future promising clinical investigations. Cancer cachexia is a syndrome characterized by a marked weight loss, anorexia, asthenia and anemia. In fact, many patients who die with advanced cancer suffer from cachexia. The degree of cachexia is inversely correlated with the survival time of the patient and it always implies a poor prognosis. In recent years, age-related diseases and disabilities have become of major health interest and importance. This holds particularly for muscle wasting, also known as sarcopenia that decreases the quality of life of the geriatric population, increasing morbidity and decreasing life expectancy. The cachectic factors (associated with both depletion of fat stores and muscular tissue) can be divided into two categories: of tumour origin and humoural factors. In conclusion, more research should be devoted to the understanding of muscle wasting mediators, both in cancer and ageing, in particular the identification of common mediators may prove as a good therapeutic strategy for both prevention and treatment of wasting both in disease and during healthy ageing.

Calpain-3 gene expression is decreased during experimental cancer cachexia.

The Yoshida AH-130 rat ascites hepatoma is a model system for studying the mechanisms involved in the protein hypercatabolism associated with cancer cachexia. The present study was aimed at investigating if the calpain-3 gene expression in skeletal muscle was affected by tumor growth. The results presented clearly show that calpain-3 gene expression is considerably reduced in experimental cancer cachexia, while there is a reciprocal change in the expression of the ubiquitin-dependent proteolytic system and in the ubiquitous m-calpain. The results, observed during cancer cachexia, suggest a potential counterregulatory role of calpain-3 in muscle proteolysis.

Increased uncoupling protein-2 gene expression in brain of lipopolysaccharide-injected mice: role of tumour necrosis factor-alpha?

In order to understand the role of brain localized uncoupling proteins, we have examined the UCP2 and BMCP-1 gene expression in mice brain in two different catabolic states: administration of lipopolysaccharide (LPS) (2.5 mg/kg, i.p.) and tumour burden. Administration of LPS resulted in an increased UCP2 gene expression both in brain (208%) and cerebellum (77%). An increase in UCP2 gene expression was also observed after LPS treatment in double knockout mice for tumour necrosis factor-alpha (TNF) receptors 1 and 2 (75% in brain and 33% in cerebellum). Tumour growth also resulted in increased brain UCP2 gene expression (80%) in mice bearing the Lewis lung carcinoma as compared with the non-tumour-bearing controls. No changes were observed in BMCP-1 mRNA levels of either LPS-injected or tumour-bearing mice. From the results presented it may be suggested that: (a) the brain may contribute significantly to the increase in energy expenditure associated with hypermetabolic states such as fever and tumour burden, and (b) the regulation of UCP2 gene expression in brain does not seem to be influenced by TNF; therefore the action of other cytokines cannot be discarded.

Interleukin-15 mediates reciprocal regulation of adipose and muscle mass: a potential role in body weight control.

Interleukin (IL)-15 is a cytokine which is highly expressed in skeletal muscle. Cell culture studies have indicated that IL-15 may have an important role in muscle fiber growth and anabolism. However, data concerning the metabolic effects of this cytokine in vivo are lacking. In the present study, IL-15 was administered to adult rats for 7 days. While IL-15 did not cause changes in either muscle mass or muscle protein content, it induced significant changes in the fractional rates of both muscle protein synthesis and degradation, with no net changes in protein accumulation. Additionally, IL-15 administration resulted in a 33% decrease in white adipose tissue mass and a 20% decrease in circulating triacylglycerols; this was associated with a 47% lower hepatic lipogenic rate and a 36% lower plasma VLDL triacylglycerol content. The decrease in white fat induced by IL-15 was in adipose tissue. No changes were observed in the rate of lipolysis as a result of cytokine administration. These findings indicate that IL-15 has significant effects on both protein and lipid metabolism, and suggest that this cytokine may participate in reciprocal regulation of muscle and adipose tissue mass.

Skeletal muscle UCP2 and UCP3 gene expression in a rat cancer cachexia model.

Rats bearing the Yoshida AH-130 ascites hepatoma showed an increased expression of both uncoupling protein-2 (UCP2) (194%) and UCP3 (189%) mRNA levels in skeletal muscle 7 days after tumour inoculation. Interestingly, an even greater increase was observed in mRNA for both UCP2 (278%) and UCP3 (797%) in the pair-fed animals, suggesting that the increase in gene expression was the result of the anorexia associated with tumour burden. The results constitute the first report of UCP2 and UCP3 gene expression during cancer cachexia and agree to their possible role in the increase of energy expenditure associated with tumour growth.

In the rat, tumor necrosis factor alpha administration results in an increase in both UCP2 and UCP3 mRNAs in skeletal muscle: a possible mechanism for cytokine-induced thermogenesis?

Since the discovery of the new members of the UCP (uncoupling protein) family, UCP2 and UCP3, very few studies have dealt with the regulation of their expression. Bearing this in mind, administration of a single intravenous injection of TNF-alpha (100 microg/kg body weight) to rats resulted in a significant increase in UCP2 (242%) and UCP3 (113%) gene expression in skeletal muscle. The results suggest a possible role for UCP2 and UCP3 in the increase of energy expenditure associated with cytokine treatment.

Hyperlipemia: a role in regulating UCP3 gene expression in skeletal muscle during cancer cachexia?

Rats bearing the Yoshida AH-130 ascites hepatoma showed an increased expression of both uncoupling protein-2 (UCP2) (two-fold) and UCP3 (three- to four-fold) in skeletal muscle (both soleus and gastrocnemius). The increase in mRNA content was associated with increased circulating concentrations of fatty acids (two-fold), triglyceride (two-fold) and cholesterol (1.9-fold). Administration of nicotinic acid to tumor-bearing rats abolishes the hyperlipidemic increase associated with tumor burden. The vitamin treatment also resulted in a decreased UCP3 gene expression in soleus muscle but not in gastrocnemius. It is concluded that circulating fatty acids may be involved in the regulation of UCP3 gene expression in aerobic muscles during experimental cancer cachexia. Since the UCP3 protein could have a role in energy expenditure, it may be suggested that hypolipidemic agents may have a beneficial role in the treatment of the cachectic syndrome.

Lack of effect of the cytokine suppressive agent FR167653 on tumour growth and cachexia in rats bearing the Yoshida AH-130 ascites hepatoma.

Daily s.c. administration of 6 mg/kg of FR167653 (an inhibitor of the synthesis of interleukin-1 and tumour necrosis factor-alpha) to rats bearing the ascites hepatoma Yoshida AH-130 (a highly cachectic tumour) did not prevent either the anorexia or the massive weight loss - affecting both adipose tissue and skeletal muscle - present in the cachectic animals. The compound did not affect the circulating levels of triacylglycerols or other metabolites such as glucose or lactate. Nor did the administration of FR167653 influence tumour growth. It is concluded that the drug is unable to reverse the cachectic state in this particular experimental tumour model.

Curcumin, a natural product present in turmeric, decreases tumor growth but does not behave as an anticachectic compound in a rat model.

Systemic administration of curcumin [1,7-bis(4-hydroxy-3-methoxyphenil)1,6-heptadiene-3,5-dione] (20 microg/kg body weight) for 6 consecutive days to rats bearing the highly cachectic Yoshida AH-130 ascites hepatoma resulted in an important inhibition of tumor growth (31% of total cell number). Interestingly, curcumin was also able to reduce (24%) in vitro tumor cell content at concentrations as low as 0.5 microM without promoting any apoptotic events. Although systemic administration of curcumin has previously been shown to facilitate muscle regeneration, administration of the compound to tumor-bearing rats did not result in any changes in muscle wasting, when compared with the non-treated tumor-bearing animals. Indeed, both the weight and protein content of the gastrocnemius muscle significantly decreased as a result of tumor growth and curcumin was unable to reverse this tendency. It is concluded that curcumin, in spite of having clear antitumoral effects, has little potential as an anticachectic drug in the tumor model used in the present study.

Different cytokines modulate ubiquitin gene expression in rat skeletal muscle.

Intravenous administration of different cytokines caused important changes in the expression of ubiquitin genes in skeletal muscle. Tumour necrosis factor-alpha caused a 2.2- and 1.9-fold increase in the expression of the 2.4 and 1.2 kb transcripts, respectively. Administration of interferon-gamma also caused a 2.2- and 1.8-fold increase in the 2.4 and 1.2 kb transcripts, respectively. While administration of leukaemia inhibitory factor and interleukin-6 resulted in no changes in ubiquitin gene expression, interleukin-1 administration also caused an increase in both ubiquitin gene transcripts (2.8- and 1.9-fold for the 2.4 and 1.2 kb transcripts, respectively). The results suggest that some of the cytokine effects on the ubiquitin system gene expression could be related to the enhanced skeletal muscle proteolysis found during cancer cachexia and other pathological states.

Mechanism for the increased skeletal muscle protein degradation in the obese Zucker rat.

Obese (fa/fa) Zucker rats showed a decreased protein content in skeletal muscle compared with their lean counterparts. This was associated with both a decrease in the fractional rate of protein synthesis and an enhanced fractional rate of protein degradation in skeletal muscle, as studied by pre-loading body proteins with (14)C-bicarbonate. The increased protein degradation could be the result of the clearly enhanced expression for several transcripts of the ubiquitin genes in skeletal muscle. The results suggest that the increased protein degradation in the skeletal muscle of the obese animals may be due to increased activity of the ubiquitin-dependent proteolytic system.

Short-term effects of leptin on skeletal muscle protein metabolism in the rat.

We have examined the short-term effects of leptin on protein metabolism in the rat. Indeed, an intravenous leptin administration (100 microg/kg body weight), which resulted in no changes in circulating insulin in the time interval studied, induced a decrease in the incorporation of (14)C-leucine to (14)C-skeletal muscle protein. No changes were observed in relation to muscle protein degradation (either measured in vivo following isotope preloading or in vitro as tyrosine released into the incubation medium) and gene expression associated with the different proteolytic systems (cathepsin B, m-calpain and ubiquitin-proteasome system). The effects of leptin on amino acid incorporation into muscle protein do not seem to be direct because incubation of isolated EDL muscles in the presence of 10 microg/ml of leptin did not modify either the protein incorporation or the oxidation of (14)C-leucine. It may, therefore, be suggested that leptin is able to influence protein synthesis in skeletal muscle through the action of an unknown mediator.

The divergent effects of tumour necrosis factor-alpha on skeletal muscle: implications in wasting.

Tumour necrosis factor-alpha (TNF) is a pleiotropic cytokine that can have effects on many cell types, including skeletal muscle, the most abundant tissue (representing almost 45% of body weight), where many effects of this cytokine have been described. Thus, TNF receptors have been described in muscle tissue, and different investigations have revealed effects of the cytokine on membrane potential, glucose uptake and metabolism, amino acid transport and protein turnover. However, the results found are relatively divergent, therefore the main aim of the present review has been to clarify and reconcile some of the most contradictory studies concerning the effects of TNF on metabolism in skeletal muscle.

Direct effects of tumor necrosis factor alpha (TNF-alpha) on murine skeletal muscle cell lines. Bimodal effects on protein metabolism.

Incubation of murine C2C12 myotubes with tumour necrosis factor-alpha (TNF-alpha) leads to significant changes in protein content and turnover, suggesting that the cytokine exerts direct effects in skeletal muscle. The effects of the cytokine on protein content show a clear bimodal behaviour. At low concentrations (1 U/ml or less), TNF-alpha decreases both total and myofibrillar protein content, while at relatively high concentrations (100 U/ml or more), the effects are opposite and TNF-alpha increases the total and myofibrillar protein content in C2C12 myotubes. The mechanisms responsible for this latter, unexpected anabolic effect of the cytokine on muscle cells are related to a 40% increase in the rate of protein synthesis and to a significant decrease (14%) in the rate of protein degradation. At high concentrations, TNF-alpha decreased the expression of the mRNA of components of both the ATP- (ubiquitin, E2, C8) and Ca2+-dependent (m-calpain) proteolytic systems. The effects of TNF-alpha (10 U/ml or higher) on protein content of cultured murine myotubes (differentiated myogenic cells) were similar to those induced by insulin (1 or 5 microg/ml), but the effects of TNF-alpha and those of insulin were not additive. Experiments using inhibitors of the signalling pathways mediated by PI3K and MAP kinases (MAPKs) ERK1/2 and p38 suggest that insulin and TNF-alpha may share some intracellular signalling pathways involving MAPKs in the enhanced protein accretion observed in the muscle cell cultures.

Metabolic interrelationships between liver and skeletal muscle in pathological states.

The present review focuses on the metabolic interrelationships between liver and muscle in pathological states associated with catabolic conditions. Carbohydrate, fat and nitrogen metabolism between the parenchymal liver and skeletal muscle are considered and interrelated together with the possible mediators involved in pathological conditions.

Protein turnover in skeletal muscle of the diabetic rat: activation of ubiquitin-dependent proteolysis.

Induction of experimental insulin-deficiency by a single administration of streptozotocin to rats resulted in substantial changes in heart and skeletal muscle size and protein content. This was accompanied by a marked loss of total body (carcass) nitrogen and raised concentrations of circulating branched-chain amino acids. These changes were related to alterations in protein turnover in skeletal muscle. Thus, the diabetic animals showed changes in both the fractional protein rates of synthesis (decreased by 37%) and degradation (increased by 141%). The increased protein degradation observed in the muscle of the diabetic animals was associated only with an increase in the expression of the genes controlling ubiquitin-dependent proteolysis. It may be suggested that the hormonal changes associated with the diabetic state play an important role in the regulation of the activity of the ubiquitin-dependent proteolytic system in skeletal muscle, highlighting the major role of this system in the diabetes-related cachexia.

Journey from cachexia to obesity by TNF.

Tumor necrosis factor-alpha (TNF-alpha) is a cytokine involved in the physiological and metabolic abnormalities found in cachectic states. Until very recently, it was inconceivable to think of TNF-alpha in obesity. However, recent studies have shown that TNF-alpha can also play a key role in obesity, the cytokine being overexpressed in adipose tissue of obese rodents and humans. The aim of this review is to reconcile the role of TNF-alpha in these two opposite metabolic situations: obesity and cachexia. It is suggested that TNF-alpha may have a key role in the control of body mass in normal weight-controlled situations and that abnormalities in either its production (during cachexia) or action (during obesity) are responsible for the lack of control of body weight.