Sílvia Busquets

Cancer cachexia: understanding the molecular basis

Cancer cachexia is a devastating, multifactorial and often irreversible syndrome that affects around 50–80% of cancer patients, depending on the tumour type, and that leads to substantial weight loss, primarily from loss of skeletal muscle and body fat. Since cachexia may account for up to 20% of cancer deaths, understanding the underlying molecular mechanisms is essential. The occurrence of cachexia in cancer patients is dependent on the patient response to tumour progression, including the activation of the inflammatory response and energetic inefficiency involving the mitochondria. Interestingly, crosstalk between different cell types ultimately seems to result in muscle wasting. Some of the recent progress in understanding the molecular mechanisms of cachexia may lead to new therapeutic approaches.

Effects of Water Stress on Respiration in Soybean Leaves

The effect of water stress on respiration and mitochondrial electron transport has been studied in soybean (Glycine max) leaves, using the oxygen-isotope-fractionation technique. Treatments with three levels of water stress were applied by irrigation to replace 100%, 50%, and 0% of daily water use by transpiration. The levels of water stress were characterized in terms of light-saturated stomatal conductance (gs): well irrigated (gs > 0.2 mol H2O m−2 s−1), mildly water stressed (gs between 0.1 and 0.2 mol H2O m−2 s−1), and severely water stressed (gs < 0.1 mol H2O m−2 s−1). Although net photosynthesis decreased by 40% and 70% under mild and severe water stress, respectively, the total respiratory oxygen uptake (Vt) was not significantly different at any water-stress level. However, severe water stress caused a significant shift of electrons from the cytochrome to the alternative pathway. The electron partitioning through the alternative pathway increased from 10% to 12% under well-watered or mild water-stress conditions to near 40% under severe water stress. Consequently, the calculated rate of mitochondrial ATP synthesis decreased by 32% under severe water stress. Unlike many other stresses, water stress did not affect the levels of mitochondrial alternative oxidase protein. This suggests a biochemical regulation (other than protein synthesis) that causes this mitochondrial electron shift.

Anticachectic effects of formoterol: a drug for potential treatment of muscle wasting.

In cancer cachexia both cardiac and skeletal muscle suffer an important protein mobilization as a result of increased proteolysis. Administration of the β2-agonist formoterol to both rats and mice bearing highly cachectic tumors resulted in an important reversal of the muscle-wasting process. The anti-wasting effects of the drug were based on both an activation of the rate of protein synthesis and an inhibition of the rate of muscle proteolysis. Northern blot analysis revealed that formoterol treatment resulted in a decrease in the mRNA content of ubiquitin and proteasome subunits in gastrocnemius muscles; this, together with the decreased proteasome activity observed, suggest that the main anti-proteolytic action of the drug may be based on an inhibition of the ATP-ubiquitin-dependent proteolytic system. Interestingly, the β2-agonist was also able to diminish the increased rate of muscle apoptosis (measured as DNA laddering as well as caspase-3 activity) present in tumor-bearing animals. The present results indicate that formoterol exerted a selective, powerful protective action on heart and skeletal muscle by antagonizing the enhanced protein degradation that characterizes cancer cachexia, and it could be revealed as a potential therapeutic tool in pathologic states wherein muscle protein hypercatabolism is a critical feature such as cancer cachexia or other wasting diseases.

Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats.

Tissue protein hypercatabolism (TPH) is an important feature in cancer cachexia, particularly with regard to the skeletal muscle. The Yoshida AH-130 rat ascites hepatoma is a model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle wasting, primarily due to TPH. The present study was aimed at investigating if IL-15, which is known to favour muscle fibre hypertrophy, could antagonize the enhanced muscle protein breakdown in this cancer cachexia model. Indeed, IL-15 treatment partly inhibited skeletal muscle wasting in AH-130-bearing rats by decreasing (8-fold) protein degradative rates (as measured by14C-bicarbonate pre-loading of muscle proteins) to values even lower than those observed in non-tumour-bearing animals. These alterations in protein breakdown rates were associated with an inhibition of the ATP-ubiquitin-dependent proteolytic pathway (35% and 41% for 2.4 and 1.2 kb ubiquitin mRNA, and 57% for the C8 proteasome subunit, respectively). The cytokine did not modify the plasma levels of corticosterone and insulin in the tumour hosts. The present data give new insights into the mechanisms by which IL-15 exerts its preventive effect on muscle protein wasting and seem to warrant the implementation of experimental protocols involving the use of the cytokine in the treatment of pathological states characterized by TPH, particularly in skeletal muscle, such as in the present model of cancer cachexia.

Journey from cachexia to obesity by TNF.

Tumor necrosis factor‐α (TNF‐α) is a cytokine involved in the physiological and metabolic abnormalities found in cachectic states. Until very recently, it was inconceivable to think of TNF‐α in obesity. However, recent studies have shown that TNF‐α 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‐α in these two opposite metabolic situations: obesity and cachexia. It is suggested that TNF‐α 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.—Argilés, J. M., López‐Soriano, J., Busquets, S., López‐Soriano, F. J. Journey from cachexia to obesity by TNF. FASEB J. 11, 743–751 (1997)

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.

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.

Cytokines in the pathogenesis of cancer cachexia.

Purpose of review The aim of the present review is to summarize and update the role of different cytokines in the pathogenesis of cancer cachexia and to provide therapeutic strategies based on cytokine action. Recent findings Cancer cachexia is a syndrome characterized by a marked weight loss, anorexia, asthenia and anemia. The cachectic state is invariably associated with the presence and growth of the tumor and leads to a malnutrition status due to the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumor 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. Different cytokines are clearly implicated in this process, possibly being responsible for anorexia, hypermetabolism and many other metabolic abnormalities, such as muscle proteolysis and apoptosis. Summary 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. A lot of progress has been made, however, in understanding the role of different cytokines ‐ tumor necrosis factor and IL‐6 in particular ‐ in muscle wasting associated with cancer cachexia, perhaps the most paradigmatic feature of this complex syndrome.

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.

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.