Míriam Toledo

The role of cytokines in cancer cachexia.

Purpose of reviewThe present investigation is devoted to uncovering the different signaling pathways – particularly transcriptional factors – involved in muscle wasting. Recent findingsAlthough 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. In this review we describe recent findings about the tumor necrosis factor (TNF)-α, interleukin (IL)-6, TWEAK and myostatin actions in cancer cachexia models. SummaryThe main aim of the present review is to summarize and evaluate the different molecular mechanisms and catabolic mediators (mainly cytokines) involved in cancer cachexia since they may represent targets for future promising clinical investigations.

The cachexia score (CASCO): a new tool for staging cachectic cancer patients

BackgroundAccording to a recent consensus, the cachectic syndrome is defined as: “… a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, insulin resistance, and increased muscle protein breakdown are frequently associated with cachexia.” Although this definition is accompanied by diagnostic criteria, it does not consider the problem of staging. Stratification of patients is important when considering therapy. The very first stage of the wasting syndrome does not necessarily involve body weight loss—a state known as pre-cachexia.Methods and ResultsThe aim of the present score was to overcome the problem of patient staging in cancer. This score considers five main different factors: body weight and lean body mass loss; anorexia; inflammatory, immunological, and metabolic disturbances; physical performance; and quality of life. The scoring scale goes from 0 to 100: mild cachexia (less than 25), moderate (more than 26 and less than 50), severe (more than 51 and less than 75), and terminal phase (more than 76 and up to 100). The score also takes into consideration the condition known as pre-cachexia.ConclusionThe present score will facilitate cachexia staging and will therefore allow for a more adequate therapy.

Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance.

BackgroundCachexia is a multiorganic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation.MethodsThe aim of this investigation was to examine the effect of the soluble receptor antagonist of myostatin (sActRIIB) in cachectic tumor-bearing animals analyzing changes in muscle proteolysis and in quality of life.ResultsAdministration of sActRIIB resulted in an improvement in body and muscle weights. Administration of the soluble receptor antagonist of myostatin also resulted in an improvement in the muscle force.ConclusionsThese results suggest that blocking myostatin pathway could be a promising therapeutic strategy for the treatment of cancer cachexia.

Combined approach to counteract experimental cancer cachexia: eicosapentaenoic acid and training exercise

BackgroundCancer cachexia is a syndrome characterized by loss of skeletal muscle protein, depletion of lipid stores, anorexia, weakness, and perturbations of the hormonal homeostasis. Despite several therapeutic approaches described in the past, effective interventions countering cancer cachexia are still lacking.MethodsThe present work was aimed to verify the ability of eicosapentaenoic acid (EPA) to prevent the muscle depletion in Lewis lung carcinoma-bearing mice and to test the ability of endurance exercise training to increase the EPA effect.ResultsEPA alone did not prevent the muscle loss induced by tumor growth while the combination with exercise induced a partial rescue of muscle strength and mass. Moreover, the association of EPA and exercise reduced the dramatic PAX-7 accumulation and stimulated the increase of PCG-1 protein.ConclusionsOverall, the present data suggest that exercise is an effective tool that should be added for combined therapeutic approaches against cancer cachexia.

Cachexia: a problem of energetic inefficiency

An alteration of energy balance is the immediate cause of the so-called cachexia. Although alterations of energy intake are often associated with cachexia, it has lately became clear that an increased energy expenditure is the main cause of wasting associated with different types of pathological conditions, such as cancer, infections or chronic heart failure among others. Different types of molecular mechanisms contribute to energy expenditure and, therefore, involuntary body weight loss; among them, adenosine triphosphate (ATP) consumption by sarcoplasmic reticulum Ca2+ pumps could represent a key mechanism. In other cases, an increase in energy inefficiency will further contribute to energy imbalance.

Interleukin-15 Affects Differentiation and Apoptosis in Adipocytes: Implications in Obesity

Interleukin-15 (IL-15) is an anabolic factor for skeletal muscle and several reports have described its important role as a regulator of energy homeostasis. In this study, we analyzed the effects of IL-15 on adipocyte differentiation using the 3T3-L1 preadipose cell line. The data show that IL-15 tends to reduce the rate of adipocyte proliferation, induces apoptosis, and partially stops differentiation. The signaling molecules behind these actions of the cytokine on adipose cells are: p42/p44 MAPK (which seem to be associated with the reduced rate of proliferation induced by the cytokine), STAT5 (which is related to the actions of IL-15 on differentiation), and SAPK/JNK (which are related to the increased apoptosis induced by IL-15). In conclusion, using the 3T3-L1 adipocyte cell line, the results presented here show that IL-15 exerts important effects on differentiation, proliferation and apoptosis. Altogether, the results presented here reinforce the idea that IL-15 is an important mediator that regulates adipose size and, therefore, the role of the cytokine in affecting body weight and obesity deserves additional studies.

Differences in food intake of tumour‐bearing cachectic mice are associated with hypothalamic serotonin signalling

Anorexia is a common symptom among cancer patients and contributes to malnutrition and strongly impinges on quality of life. Cancer‐induced anorexia is thought to be caused by an inability of food intake‐regulating systems in the hypothalamus to respond adequately to negative energy balance during tumour growth. Here, we show that this impaired response of food‐intake control is likely to be mediated by altered serotonin signalling and by failure in post‐transcriptional neuropeptide Y (NPY) regulation.

Megestrol acetate: its impact on muscle protein metabolism supports its use in cancer cachexia.

BACKGROUND & AIMS Cachexia is a multiorganic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation, being often associated with anorexia. The aim of the present investigation was to examine the effect of megestrol acetate (MA) in cachectic tumour-bearing animals analyzing changes in muscle proteolysis and in parameters related with quality of life. METHODS The effects of MA (100mg/kg) were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). RESULTS Administration of MA to tumour-bearing rats resulted in an important reversal of the muscle wasting process, as reflected by individual muscle weights. MA also decreased the rate of protein degradation in incubated isolated skeletal muscles. Real-time PCR analysis revealed that MA treatment resulted in a decrease in ubiquitin, E2 and atrogin-1 mRNA content in muscles, therefore suggesting that the main anti-proteolytic action of the drug may be based on an inhibition of the ATP-ubiquitin-dependent proteolytic system. The drug also improves appetite, weight loss, total physical activity and grip force. CONCLUSIONS The results indicate that treatment with megestrol acetate increases appetite, weight loss, physical performance and muscle force in tumour-bearing rats suggesting that MA is a good candidate for muscle wasting treatment.

l-Carnitine: An adequate supplement for a multi-targeted anti-wasting therapy in cancer

BACKGROUND & AIMS Tumour growth is associated with weight loss resulting from both adipose and muscle wasting. METHODS Administration of L-carnitine (1 g/kg body weight) to rats bearing the AH-130 Yoshida ascites hepatoma, a highly cachectic rat tumour. RESULTS The treatment results in a significant improvement of food intake and in muscle weight (gastrocnemius, EDL and soleus). These beneficial effects are directly related to improved physical performance (total physical activity, mean movement velocity and total travelled distance). Administration of L-carnitine decreases proteasome activity and the expression of genes related with this activity, such as ubiquitin, C8 proteasome subunit and MuRF-1. Interestingly, L-carnitine treatment also decreases caspase-3 mRNA content therefore suggesting a modulation of apoptosis. Moreover, addition of 50 μM of L-carnitine to isolated EDL muscles results in a significant decrease in the proteolytic rate suggesting a direct effect. CONCLUSIONS It can be concluded that L-carnitine supplementation may be a good approach for a multi-targeted therapy for the treatment of cancer-related cachexia.

Combination of exercise training and erythropoietin prevents cancer-induced muscle alterations

Cancer cachexia is a syndrome characterized by loss of skeletal muscle mass, inflammation, anorexia and anemia, contributing to patient fatigue and reduced quality of life. In addition to nutritional approaches, exercise training (EX) has been proposed as a suitable tool to manage cachexia. In the present work the effect of mild exercise training, coupled to erythropoietin (EPO) administration to prevent anemia, has been tested in tumor-bearing mice. In the C26 hosts, acute exercise does not prevent and even worsens muscle wasting. Such pattern is prevented by EPO co-administration or by the adoption of a chronic exercise protocol. EX and EPO co-treatment spares oxidative myofibers from atrophy and counteracts the oxidative to glycolytic shift, inducing PGC-1α. LLC hosts are responsive to exercise and their treatment with the EX-EPO combination prevents the loss of muscle strength and the onset of mitochondrial ultrastructural alterations, while increases muscle oxidative capacity and intracellular ATP content, likely depending on PGC-1α induction and mitophagy promotion. Consistently, muscle-specific PGC-1α overexpression prevents LLC-induced muscle atrophy and Atrogin-1 hyperexpression. Overall, the present data suggest that low intensisty exercise can be an effective tool to be included in combined therapeutic approaches against cancer cachexia, provided that anemia is coincidently treated in order to enhance the beneficial action of exercise.