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PubMed1996

Food intake and body composition in cancer cachexia.

As a complex syndrome, cachexia has different clinical manifestations; anorexia appears to be one of the most frequent findings, together with weight loss. Anorexia is the cause and partly the consequence of metabolic changes and of progressive undernourishment. In cancer cachexia, weight loss is associated with a marked decrease of food intake and severe alteration of body composition. Malnourished cancer patients show a marked loss of adipose tissue and protein mass with BIA evidence of decreased body cell mass and expansion of extracellular water. The mechanisms of anorexia and cachexia are still a matter of debate, but the possible involvement of cytokines in the pathogenesis of this syndrome has opened up new possibilities for its understanding and treatment. As a result of the multifactorial etiology of cancer cachexia/anorexia, therapies that stimulate appetite and promote greater food intake, coupled with factors that influence metabolism and cytokine production may be an optimal therapeutic strategy. Of particular interest appears to be the possible role played by fish oil in antagonizing the negative effects of cytokines. Future research in this field will help clinicians develop new methods to treat patients who have disease-induced starvation and wasting.

Adult↗
PubMed2005

Muscle wasting in cardiac cachexia.

Cardiac cachexia is a serious complication of chronic heart failure which is characterized by complex changes that overall lead to a catabolic/anabolic imbalance resulting in body wasting and a poor prognosis. The wasting process affects all body components, but particularly the skeletal musculature, causing extreme fatigue and weakness, especially in cachectic heart failure patients. Available evidence suggests that several pathophysiologic pathways play a role in the muscle wasting process. Metabolic, neurohormonal, and immune abnormalities lead to an altered regulation of proliferation, differentiation, apoptosis, and metabolism in skeletal muscle, finally resulting in deterioration of the underlying cause with symptomatic exercise intolerance. Possible treatment strategies against muscle wasting and cachexia in chronic heart failure are also described here. As there is no validated therapy for cardiac cachexia yet, further research is necessary to find more therapeutic options for the wasting process.

Cachexia↗
PubMed2005

Effect of cancer cachexia on the activity of tripeptidyl-peptidase II in skeletal muscle.

The ubiquitin-proteasome proteolytic pathway plays a major role in degradation of myofibrillar proteins in skeletal muscle during cancer cachexia. The end-product of this pathway is oligopeptides and these are degraded by the extralysomal peptidase tripeptidyl-peptidase II (TPPII) together with various aminopeptidases to form tripeptides and amino acids. To investigate if a relationship exists between the activity of the proteasome and TPPII, functional activities have been measured in gastrocnemius muscle of mice bearing the MAC16 tumour, and with varying extents of weight loss. TPPII activity was quantitated using the specific substrate Ala-Ala-Phe-7-amido-4-methylcoumarin, while proteasome activity was determined as the 'chymotrypsin-like' enzyme activity. Both proteasome proteolytic activity and TPPII activity increased in parallel with increasing weight loss, reaching a maximum at 16% weight loss, after which there was a progressive decrease in activity for both proteases with increasing weight loss. In murine myotubes, proteolysis-inducing factor, which is a sulphated glycoprotein produced by cachexia-inducing tumours, induced an increase in activity of both proteasome and TPPII, with an identical dose-response curve, and both activities were inhibited by eicosapentaenoic acid. These results suggest that the activities of both the proteasome and TPPII are regulated in a parallel manner in cancer cachexia, and that both are induced by the same factor and probably have the same intracellular signalling pathways and transcription factors.

Aminopeptidases↗
PubMed2005

Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia.

Cachexia contributes to nearly a third of all cancer deaths, yet the mechanisms underlying skeletal muscle wasting in this syndrome remain poorly defined. We report that tumor-induced alterations in the muscular dystrophy-associated dystrophin glycoprotein complex (DGC) represent a key early event in cachexia. Muscles from tumor-bearing mice exhibited membrane abnormalities accompanied by reduced levels of dystrophin and increased glycosylation on DGC proteins. Wasting was accentuated in tumor mdx mice lacking a DGC but spared in dystrophin transgenic mice that blocked induction of muscle E3 ubiquitin ligases. Furthermore, DGC deregulation correlated positively with cachexia in patients with gastrointestinal cancers. Based on these results, we propose that, similar to muscular dystrophy, DGC dysfunction plays a critical role in cancer-induced wasting.

Adult↗
PubMedDate not supplied

Effects of simvastatin administration in an experimental model of cancer cachexia.

OBJECTIVE: We evaluated whether statins, in view of their anti-inflammatory properties, may effectively prevent the onset or modulate the severity of muscle wasting during cancer cachexia. METHODS: Simvastatin was administered to rats bearing the Yoshida AH-130 ascites hepatoma, a well-studied cytokine-dependent experimental model of cancer cachexia. RESULTS: Quite surprisingly, the drug negatively affected the wasting pattern induced by the AH-130 hepatoma. In fact, the administration of simvastatin to tumor hosts induced a further weight reduction of all the tissues examined except for the soleus, in the absence of significant effects of simvastatin on tumor growth or on food intake. No effects were observed after simvastatin administration in control animals, with the exception of a significant (P < 0.05) reduction in heart weight. CONCLUSIONS: Simvastatin administration, although capable of negatively modulating the inflammatory response, did not prevent muscle wasting in this experimental model of cancer cachexia. Moreover, the further muscle loss observed in simvastatin-treated tumor-bearing animals suggests that a note of caution should be introduced in treating cancer patients with statins in view of the possible occurrence of harmful side effects.

Animals↗
PubMed2003

Interleukin-1 alpha promotes tumor growth and cachexia in MCF-7 xenograft model of breast cancer.

Progression of breast cancer involves cross-talk between epithelial and stromal cells. This cross-talk is mediated by growth factors and cytokines secreted by both cancer and stromal cells. We previously reported expression of interleukin (IL)-1 alpha in a subset of breast cancers and demonstrated that IL-1 alpha is an autocrine and paracrine inducer of prometastatic genes in in vitro systems. To understand the role of IL-1 alpha in breast cancer progression in vivo, we studied the growth of MCF-7 breast cancer cells overexpressing a secreted form of IL-1 alpha (MCF-7IL-1 alpha) in nude mice. MCF-7IL-1 alpha cells formed rapidly growing estrogen-dependent tumors compared to parental cells. Interestingly, IL-1 alpha expression alone was not sufficient for metastasis in vivo although in vitro studies showed induction of several prometastatic genes and matrix metalloproteinase activity in response to cross-talk between IL-1 alpha-expressing cancer cells and fibroblasts. Animals implanted with MCF-7IL-1 alpha cells were cachetic, which correlated with increased leptin serum levels but not other known cachexia-inducing cytokines such as IL-6, tumor necrosis factor, or interferon gamma. Serum triglycerides, but not blood glucose were lower in animals with MCF-7IL-1 alpha cell-derived tumors compared to animals with control cell-derived tumors. Cachexia was associated with atrophy of epidermal and adnexal structures of skin; a similar phenotype is reported in triglyceride-deficient mice and in ob/ob mice injected with leptin. Mouse leptin-specific transcripts could be detected only in MCF-7IL-1 alpha cell-derived tumors, which suggests that IL-1 alpha increases leptin expression in stromal cells recruited into the tumor microenvironment. Despite increased serum leptin levels, animals with MCF-7IL-1 alpha cell-derived tumors were not anorexic suggesting only peripheral action of tumor-derived leptin, which principally targets lipid metabolism. Taken together, these results suggest that cancer cell-derived cytokines, such as IL-1 alpha, induce cachexia by affecting leptin-dependent metabolic pathways.

Animals↗
PubMed1989

Purification of a lipoprotein lipase-inhibiting protein produced by a melanoma cell line associated with cancer cachexia.

A human melanoma cell line, SEKI, induces severe cachexia in tumor-bearing nude mice. A factor with the ability to inhibit lipoprotein lipase (LPL) was isolated from the conditioned medium of this cell line. This factor was 40-K-dalton protein, and designated temporarily as melanoma-derived LPL inhibitor (MLPLI). Amino acid sequencing revealed that the amino-terminal portion consists of SPLPITPV-AT--IR-P. Unexpectedly, the sequence, as far as determined, was identical to those of leukemia inhibitory factor (LIF), suggesting that MLPLI is a protein closely related to LIF. The findings that MLPLI inhibits LPL activity and that MLPLI is produced by human cancer cells inducing cancer cachexia also suggest that this protein is a candidate for the factor responsible for cancer cachexia.

Amino Acid Sequence↗
PubMed2002

[Megestrol acetate: a systematic review usefulness about the weight gain in neoplastic patients with cachexia].

BACKGROUND: The clinical efficacy of megestrol acetate in the treatment of cachexia in cancer patients has not been clearly demonstrated. A systematic review and meta-analysis have been performed to ascertain its effectiveness on weight gain in patients with cancer-associated cachexia. MATERIAL AND METHOD: A systematic review of randomized clinical trials comparing megestrol acetate with placebo in cancer patients was performed. The outcome measure used was weight gain expressed as the difference in weight at the outset compared with that at the end of treatment. Trials analyzed were those that allowed for this calculation, or those whose authors provided information for the above calculation. RESULTS: Patients treated with placebo had an average weight loss of 1.090 kg (CI 95%, 1.620 to 0.561), whereas patients treated with megestrol acetate gained an average 0.423 kg (CI 95%, 0.078-0.769). A weight gain of 0.448 kg (CI 95%, 0.021-0.874) was observed with acetate megestrol doses # 240 mg. No statistically significant effect was observed when using higher doses: 0.358 kg (CI 95%, 0.135-0.85). CONCLUSIONS: Megestrol acetate doses equal to or lower than 240 mg/day lead to slight weight gain in patients with cancer-associated cachexia. The majority of studies have a low methodological quality. Further, well-designed studies comparing megestrol acetate with placebo are warranted.

Cachexia↗
PubMed2002

Regulation of lipolysis: natriuretic peptides and the development of cachexia.

The development of cachexia is commonly seen in many pathological states and is associated with a markedly impaired prognosis. Loss of fat tissue appears to be of particular pathophysiological importance in this setting. Lipolysis is closely regulated in health; the major established pathways involving catecholamines (stimulation of lipolysis) and insulin (inhibition of lipolysis). The wasting process in cachexia is associated with marked metabolic dysfunction, and loss of this tight regulatory control. Natriuretic peptides are a family of related peptides with important vasodilatory, natriuretic and diuretic properties. It has recently been shown that natriuretic peptides are also potent stimuli for lipolysis in humans. In this respect, atrial and brain natriuretic peptide appear to have the greatest lipolytic effect, and are similar in potency to catecholamines. Elevated levels of circulating natriuretic peptides are found in several pathological states, and generally reflect disease severity. This article will provide a concise review of the regulation of lipolysis in humans, concentrating on the role of the natriuretic peptides. The relevance of natriuretic peptides to the development of cachexia will be discussed.

Adipose Tissue↗
PubMed2002

Cytokines, apoptosis and cachexia: the potential for TNF antagonism.

The cachexia syndrome is characterised by progressive weight loss and depletion of lean body mass and has long been recognised as a poor prognostic sign. Whilst the clinical features of the wasting process are readily apparent, its pathogenesis is complex and poorly understood. There is increasing evidence that the immune system, in particular inflammatory cytokines, may play an important role in the development of cachexia. The cytokine considered to be the most relevant to this process is tumor necrosis factor alpha (TNF), although other mediators such as interleukin (IL) 1, IL-6 and interferon gamma have also been implicated. Apoptosis represents a potential pathway by which wasting can occur in chronic diseases. Cytokines and their corresponding receptors are known to be important regulators of cell death. Apoptosis has been demonstrated in the skeletal muscle of patients with chronic heart failure (CHF) and is thought to be partly responsible for the significant impairment of functional work capacity associated with this condition. An understanding of the mechanisms that regulate muscle protein breakdown is essential for the development of strategies for treating or even preventing muscle cachexia in patients. It is the aim of this article to review the role of inflammatory cytokines, particularly TNF, in the pathogenesis of wasting and also the potential for anti-cytokine therapy. Although this review will concentrate predominantly on the syndrome of CHF, other chronic illnesses such as liver disease, cancer, and sepsis will also be discussed.

Apoptosis↗
PubMed2000

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.

Animals↗
PubMed1996

The role of tumor necrosis factor-alpha in the pathogenesis of anorexia and bulimia nervosa, cancer cachexia and obesity.

In this paper a new immunological model of anorexia and bulimia nervosa will be presented in which the inflammatory cytokines are conceived as the fundamental regulators of body metabolism. This conception differs from the conventional view in which the inflammatory cytokines are perceived primarily as peptide molecules utilized by the immune system to control infection, inflammation and tissue or neuronal damage. Given that the inflammatory cytokines are also fundamental regulators of body metabolism, when they become dysregulated they create physiological chaos which results in the development of a number of autoimmune, metabolic and psychiatric disorders. In this proposed immunological model of anorexia and bulimia nervosa, elevated tumor necrosis factor-alpha features as the primary cause of these conditions. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia in terms of the causal role the cytokines, neuropeptides and neurotransmitters play in the manifestation of shared symptoms. These shared symptoms include elevated tumour necrosis factor-alpha, down-regulated interleukin-2 and interleukin-4 and depletion of lean body mass. Furthermore, the following neuropeptides are dysregulated in both anorexia nervosa and cancer cachexia: vasoactive intestinal peptide, cholecystokinin, corticotropin-releasing factor, neuropeptide Y, peptide YY and beta-endorphin. In addition, in anorexia and bulimia nervosa, secretion of the neurotransmitter serotonin is inhibited while norepinephrine is enhanced. It will be argued that the causal interplay between the cytokines, neuropeptides and neurotransmitters initiates a cascade of biochemical events which may result in either anorexia or bulimia nervosa, or cancer cachexia. The extent to which these inflammatory cytokines, neuropeptides and neurotransmitters are causally efficacious in the pathogenesis of other autoimmune disorders, such as diabetes mellitus and rheumatoid arthritis, will also be addressed.

Anorexia Nervosa↗
PubMed2000

Metabolic abnormalities in cachexia and anorexia.

An increased glucose requirement by many solid tumors produces an increased metabolic demand on the liver, resulting in an increased energy expenditure. In addition, several cytokines and tumor catabolic products have been suggested as being responsible for the depletion of adipose tissue and skeletal-muscle mass in cachexia. A sulphated glycoprotein of molecular mass 24 kDa, produced by cachexia-inducing tumors and present in the urine of cancer patients actively losing weight, has been shown to be capable of inducing direct muscle catabolism in vitro and a state of cachexia in vivo, with specific loss of the non-fat carcass mass. In vitro studies have shown the bioactivity of this proteolysis-inducing factor to be attenuated by the polyunsaturated fatty acid, eicosapentaenoic acid. Preliminary clinical studies have shown that eicosapentaenoic acid stabilizes body weight and protein and fat reserves in patients with pancreatic carcinoma. Further trials are required to confirm the efficacy of eicosapentaenoic acid and to determine the anticachectic activity in other types of cancer.

Anorexia↗
PubMed1999

Cancer cachexia.

Cachexia is a common cause of morbidity and mortality in patients with advanced cancer. It is characterised by numerous metabolic abnormalities including inefficient substrate utilisation, alterations in the balance of energy intake and expenditure and the acute-phase protein response. These changes seem to be driven by pro-inflammatory cytokines, alterations of the neuro-endocrine axis and tumour-derived catabolic factors. This results in the loss of both fat and lean tissue. Trials of conventional nutritional supplements in patients with cancer cachexia have failed to show any benefit in terms of weight gain or quality of life and this may be because the ongoing metabolic abnormalities prevent the efficient use of additional calories supplied. A variety of pharmacological agents have been studied in an attempt to normalise these metabolic changes with only limited success. However, it is possible that the combination of an agent to normalise the metabolic milieu along with the provision of additional nutritional support may have the potential to reverse cachexia in advanced cancer.

Anti-Inflammatory Agents↗
PubMed2003

Partial reversal of cachexia by beta-adrenergic receptor blocker therapy in patients with chronic heart failure.

BACKGROUND: Cachexia is a common problem in chronic heart failure (CHF) that may be partly mediated by activation of the sympathetic nervous system. The effects of beta-adrenergic receptor blocker (BB) therapy on body weight in cachectic and noncachectic subjects with CHF has not been previously reported. METHODS AND RESULTS: Body weight and plasma norepinephrine, leptin, and insulin levels were measured in 27 subjects with CHF before and after 6 months of beta-adrenergic receptor blockade with carvedilol or long-acting metoprolol. Before BB therapy, baseline weight, plasma leptin, and plasma insulin levels did not differ between cachectic and noncachectic subjects. Baseline plasma norepinephrine levels were increased in cachectic subjects when compared with noncachectic subjects (930+/-248 pg/mL versus 503+/-109 pg/mL, P=.063). After 6 months of BB therapy, subjects with baseline cachexia demonstrated significantly greater weight gain (+5.2+/-9.6 versus +0.8+/-5.0 kg, P=.027), greater increase in plasma leptin levels (+3.7+/-3.9 versus +1.2+/-4.3 ng/mL, P=.030), and greater decrease in plasma norepinephrine levels (-374+/-261 versus -41+/-122 pg/mL, P=.012) when compared with noncachectic subjects. CONCLUSIONS: Six months of BB therapy with carvedilol or long-acting metoprolol is associated with differential effects on body weight and hormonal levels in cachectic and noncachectic subjects with CHF. Further work is needed to determine the role the sympathetic nervous system in the pathogenesis of cachexia in patients with CHF.

Adrenergic beta-Antagonists↗
PubMed2003

Cancer cachexia: the molecular mechanisms.

Cancer cachexia is a syndrome characterised by a marked weight loss, anorexia, asthenia and anaemia. In fact, many patients who die with advanced cancer suffer from cancer cachexia. The cachectic state is invariably associated with the presence and growth of the tumour and leads to a malnutrition status due to the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host leads to an accelerated starvation state which promotes severe metabolic disturbances in the host, including hypermetabolism which leads to an increased energetic inefficiency. Although, the search for the cachectic factor(s) started a long time ago, and although many scientific and economic efforts have been devoted to its discovery, we are still a long way from knowing the whole truth. The main aim of the present review is to summarise and evaluate the different catabolic mediators (both humoural and tumoural) involved in cancer cachexia since they may represent targets for future promising clinical investigations.

Animals↗
PubMed2001

The effects of enalapril-digoxin-diuretic combination therapy on nutritional and anthropometric indices in chronic congestive heart failure: preliminary findings in cardiac cachexia.

BACKGROUND: Body wasting is a clinical feature of a variety of chronic illnesses including congestive heart failure. The wasting associated with chronic congestive heart failure (cardiac cachexia) has recently been shown to portend a worse prognosis, and it is an independent predictor of mortality. The mechanisms underlying cardiac cachexia are multi-factorial, including metabolic, nutritional, neuroendocrine and immunological aberrations. There is, however, no direct evidence that current medical treatment reverses cachexia in chronic heart failure. METHODS: The effect of enalapril, digoxin and frusemide combination on clinical, biochemical and anthropometric indices were determined in eight cachectic Nigerians with chronic congestive heart failure [body mass index (BMI) 20.80+/-2.7 kg/m(2), left ventricular ejection fraction 29+/-4% and LV mass index 161+37 g/m(2)] at baseline, and again after 3 and 6 months of therapy. Ten age- and sex-matched healthy volunteers whose anthropometric data were concurrently measured served as controls. RESULTS: The anthropometric and clinical measurements were significantly (P<0.001) reduced in heart failure compared to the healthy controls. Congestive hepatomegaly significantly regressed from 161+/-20 mm to 123+/-13 mm after 6 months therapy (P<0.001 ANOVA). There was a significant increase in the sum of four skin fold thickness from 27.6+/-3.3 mm to 30.1+/-3.9 mm at 6 months (P<0.001 ANOVA) 95% confidence intervals for the difference being 1.42 to 3.4 mm. There was a significant increase in the mid-upper arm circumference (P<0.001 ANOVA) with a 95% confidence interval of 0.87-2.1 cm, and a similar trend for increased mid-thigh circumference (95% confidence limits 0.93-5.30 cm) was apparent. Plasma albumin and sodium increased significantly (P<0.05) from 30.1+/-3.8 g/l and 136+/-5.9 mmol/l to 32.9+/-2.5 g/l and 139+/-3.9 mmol/l, respectively. There was a positive and significant correlation between the treatment induced increases in plasma albumin and the increase in mid-upper arm circumference (y=0.25x+0.8, r=0.76, P=0.03 ANOVA) but not with the change in skin fold thickness. CONCLUSION: The preliminary results demonstrate increased subcutaneous fat (increased skin fold thickness), greater muscle bulk (increased mid-upper arm and thigh circumferences) together with a significant elevation in plasma albumin and the hematocrit, which reflect the anabolic state in patients treated with ACE inhibitor-digoxin-diuretic with congestive heart failure.

Adult↗
PubMed2000

Cachexia and asthenia in cancer patients.

Over the past 10 years, there have been major advances in the understanding of cancer cachexia and asthenia. These common complications of cancer are now thought to be the consequences of complex interactions between host, tumour, and psychosocial factors. Cachexia and asthenia commonly coexist, but they can occur independently of each other. Recently identified tumour-derived factors cause lipolysis and protein catabolism. Cytokines produced by the host in response to tumour presence cause metabolic abnormalities, which result in decreased protein and lipid synthesis, increased lipolysis, and anorexia. Many other factors contribute to asthenia, such as anaemia, autonomic failure, and muscular abnormalities. Future research should clarify optimum management. The way forward seems to lie in a multidimensional approach with combined therapy to manage both cancer cachexia and asthenia.

Asthenia↗