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PubMed2001

Role of cytokines in cancer cachexia in a murine model of intracerebral injection of human tumours.

To study the role of cytokines that are relevant in cancer cachexia syndrome due to intracerebral tumours, mice were injected with human A431 epidermoid carcinoma, OVCAR3 ovarian carcinoma and GBLF glioma cells comparing intracerebral (i.c.) and systemic (i.p. or s.c.) routes of implantation. Anorexia and weight loss developed within 7-10 days in mice injected i.c. with A431 or OVCAR3 cells well before a large tumour developed, while i.c.-injected GBLF cells did not induce cachexia until day 20, when the tumour was large. By contrast, mice injected i.p. or s.c. developed tumours without evidence of anorexia. Thus, intracerebrally-growing A431 and OVCAR3 resulted in cancer cachexia independent of tumour mass, and we investigated their cytokine pattern. Serum levels of murine and human cytokines are not predictive of cancer cachexia development. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis revealed in the brain of i.c.-injected A431 tumour-bearing mice expression of human interleukin-(IL-)1alpha, IL-1beta and LIF in all samples and IL-6 in two of four samples while in i.c.-injected OVCAR3 tumour-bearing animals IL-6, and LIF were detected in all samples and tumour necrosis factor-alpha (TNFalpha) in two of four samples. Only LIF was expressed in brains of mice injected with GBLF cells. Murine IL-6 was increased only in the brains of A431-bearing mice. Only mice injected i.c. simultaneously with a monoclonal antibody (mAb) directed against the murine IL-6 receptor and OVCAR3 cells, but not those with mAb and A431 cells, showed a significant increase in survival time with a partial and temporary attenuation of cachexia symptoms. These results suggest that IL-6 in OVCAR3 model may be important cachectogenic factor when centrally released by even a limited number of tumour cells.

Animals↗
PubMed1996

Are cytokines possible mediators of cancer cachexia?

The possible role of cytokines in the development of cancer cachexia was reviewed from the literature. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, interferon (IFN)-gamma and leukemia inhibitory factor (LIF) can elicit many but not all host changes seen in cancer cachexia, including loss of appetite, loss of body weight, and the induction of acute-phase protein synthesis. However, these cytokines are not always demonstrated in the circulation of the cancer patients. The inability to detect circulating cytokines may be due to their low rate of production, their short half-life and rapid clearance from plasma, or their mode of action (autocrine or paracrine). Different cytokines are induced to stimulate the same response. This is very different from hormonal regulation, where a hormone acts on a cell directly through a specific receptor without depending on other mediators. Specific antibodies including anti-IFN-gamma, anti-TNF and anti-IL-6 antibodies, as well as the cyclooxygenase inhibitor indomethacin, have been used to reverse cancer cachexia. Overlapping physiologic activities make it unlikely that a single substance is the sole cause of cancer cachexia. It is hoped that further investigation on other cytokines and their possible relationships with hormones will help to clarify the mechanisms of cancer cachexia in the near future.

Cachexia↗
PubMed2005

Cachexia in chronic heart failure: prognostic implications and novel therapeutic approaches.

Cachexia in patients with chronic heart failure (CHF) has been recognized for a long time; however, it has not received much attention until recently. Cardiac cachexia, a common and serious complication of CHF, is associated with very poor prognosis. Several studies have demonstrated that increased neurohormonal and immune abnormalities may play a crucial role in the pathophysiology of cardiac cachexia. Hormonal and catabolic/anabolic imbalances of the body are likely to be responsible for the development of cachexia in CHF. Recently, ghrelin, a novel growth hormone-releasing peptide, has been widely noticed to have potential in the treatment of severe CHF and cardiac cachexia. However, further research will be necessary to identify the exact pathways involved and to find the best therapeutic strategies of using ghrelin to fight the wasting process.

Cachexia↗
PubMed2004

Cachexia induced by Walker 256 tumor growth causes rat lymphocyte death.

Death induction by Walker 256 tumor cachexia in non-tumor-infiltrating lymphocytes was investigated. Lymphocytes from cachectic tumor-bearing rats presented a higher proportion of cells with ruptured membranes, indicating necrotic cell death. The cachexia induced by Walker 256 tumor also increased by 3.6-fold the percentage of cells with fragmented DNA, suggestive of apoptotic cell death. The mitochondria involvement was examined by analysis of mitochondria transmembrane potential using rhodamine 123. Lymphocytes from cachectic tumor-bearing rats presented a more pronounced depolarization of mitochondrial transmembrane potential in comparison with cells from the control group. The expression of important proapoptotic (Bcl-xs, Bax, p53, caspase-3) and antiapoptotic genes (Bcl-2 and Bcl-xL) was also altered by tumor cachexia. These results suggest that the immunosuppression induced by Walker 256 tumor cachexia is at least in part a result of lymphocyte death. Evidence was found for the involvement of mitochondria and important proapoptotic genes in the process of lymphocyte death by Walker 256 tumor cachexia.

Animals↗
PubMed2006

Metabolic and immunologic derangements in cardiac cachexia: where to from here?

The onset of cardiac cachexia is characterized by a defined severe weight loss in patients with advanced chronic heart failure and it predicts an increased mortality in these patients. Recent studies with potential therapeutics investigated the effects and efficiency of beta-blockers, ghrelin, or ghrelin-agonists in cachexia. These and other new studies, like the influence of heart transplantation on cardiac cachexia, give prospect into potential therapeutic options in the future. General aim of the treatment strategy is to prevent the onset and retard the progress of cachexia. This could be achieved by modifying the metabolic, neurohormonal and immune system abnormalities, e.g. with beta-blockers and angiotensin-converting enzyme inhibitors. However, these alterations interact in a complex pathophysiological process, which is supposed to end in a vicious circle and thereby the wasting process is further promoted. To interrupt this, an early start of therapy is important to decelerate the development of cardiac cachexia. Many further investigations are needed to find out more about the pathophysiological pathways, to confirm the previous results, and to evaluate new therapeutics.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Molecular mechanisms involved in muscle wasting in cancer and ageing: cachexia versus sarcopenia.

The aim of the present review is to summarize and evaluate the different mechanisms and catabolic mediators involved in cancer cachexia and ageing sarcopenia since they 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. Unfortunately, at the clinical level, cachexia is not treated until the patient suffers from a considerable weight loss and wasting. At this point, the cachectic syndrome is almost irreversible. The cachectic state is often associated with the presence and growth of the tumour and leads to a malnutrition status due to the induction of anorexia. 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 strategies for both prevention and treatment of wasting both in disease and during healthy ageing.

Aging↗
PubMed1996

Mechanisms of cachexia induced by T-cell leukemia in the rat.

Body wasting (cachexia) is a common feature of cancer and a major cause of morbidity and mortality. The mechanisms underlying cachexia are largely unknown, and studies in experimental animals have focused mainly on solid tumors. Therefore, the objective of the present study was to quantify and investigate cachexia in experimentally induced T-cell leukemia in the rat. Induction of leukemia by serial passage (injection of cervical lymph node suspension) resulted in a rapid increase in white blood cell (WBC count, hypertrophy of the spleen (by day 11), and severe morbidity within 17 to 18 days. Body weight gain and food intake declined steadily in leukemic animals from day 12, although weight loss was significantly greater in pair-fed, nonleukemic animals. However, leukemic rats had a lower body fat content and higher water content than pair-fed animals on day 18, so the measurement of body weight significantly underestimated the severity of cachexia. Resting oxygen consumption (VO2), measured during the light phase, declined in pair-fed animals from day 13, but was elevated in leukemic rats on days 12 to 18 by 25% (P < .05, one-way ANOVA) compared with pair-fed rats and by 7% (P < .05, one-way ANOVA) relative to free-feeding controls. Hypermetabolism was associated with an increase in brown adipose tissue (BAT) activity (74% and 89%, respectively, P < .05, one-way ANOVA) in leukemic rats compared with control and pair-fed groups. Effects of leukemia on VO2 and BAT were prevented by administration of the adrenergic antagonist, propranolol. These results indicate that T-cell leukemia in the rat results in rapid and severe cachexia, which is largely due to marked hypophagia, but is also accompanied by inappropriately high rates of energy expenditure that are mediated by sympathetic activation of BAT thermogenesis.

Adipose Tissue, Brown↗
PubMed1998

Suppression of carcass weight loss in cachexia in rats bearing Leydig cell tumor by the novel compound NO-1886, a lipoprotein lipase activator.

The Leydig cell tumor has been reported to produce tumor necrosis factor (TNF) and induce cachexia in rats. TNF is thought to reduce lipoprotein lipase (LPL) activity, decrease fat deposits, induce emaciation, and worsen cachexia. Therefore, we thought emaciation might be prevented and thus cachexia improved by increasing LPL activity. We administered NO-1886, a lipoprotein lipase activator, to rats bearing Leydig cell tumor and observed its effect on improving the cachexia induced by the tumor. In Leydig cell tumor-bearing rats, the emaciation progressed after tumor inoculation and the general condition worsened daily. Plasma levels of total protein, albumin, and glucose, which are biological parameters of malnutrition, were found to decrease soon after tumor inoculation in tumor-bearing rats. In contrast, rats given NO-1886 showed less malnutrition than tumor-bearing rats. LPL activity of rat adipose tissue was decreased, the weight of adipose tissue was decreased, carcass weight was reduced, and food consumption was decreased after Leydig cell tumor inoculation. NO-1886 increased adipose tissue LPL activity and suppressed the decrease in the weight of adipose tissue, carcass weight, and food consumption due to cachexia without influencing tumor growth. The present results suggest that the novel compound NO-1886 may suppress carcass weight loss in rats bearing Leydig cell tumor by suppressing the decrease in food consumption and LPL activity.

Adipose Tissue↗
PubMed2002

Cardiac cachexia in early literature: a review of research prior to Medline.

Cachexia has been known to physicians since ancient Greek times as a 'signum mali ominis' in various diseases indicating end stage disease and poor quality of life. Cardiac cachexia is recently receiving growing attention as modern treatment options prevent early death from cardiac events and more patients live with chronic compensated heart failure. Nevertheless, observation and clinical documentation of this condition go back as long as medical science itself. Pioneering studies on the reasons and mechanisms of cachexia were performed several decades ago. These studies provide fundamental insights and guidance towards a better understanding of cachexia. This review presents an overview of early thoughts and milestone studies on metabolic abnormalities and cachexia in chronic heart failure.

Cachexia↗
PubMed2002

Origin of symptoms in patients with cachexia with special reference to weakness and shortness of breath.

Cachexia is a complication of many disorders. It is associated with an extremely poor prognosis and many symptoms. The wasting process affects particularly skeletal muscle causing extreme fatigue and weakness. In many underlying conditions associated with cachexia, the patient also suffers an often unexplained severe dyspnoea along with weakness, asthenia and exhaustion. There appears to be marked similarities in the cause of dyspnoea and fatigue between different cachectic conditions. Using the example of cardiac cachexia, this article reviews the evidence linking skeletal muscle reflex inputs to ventilatory control and exaggerated chemoreflex responses as candidates for the heightened perception of dyspnoea which cannot be explained by heart or lung dysfunction in many patients. Evidence is reviewed that similar processes may occur in other cachexias, especially those complicating cancer, AIDS, chronic liver disease, and chronic lung disease. Potential novel therapeutic strategies to combat these cachexia symptoms are reviewed.

Cachexia↗
PubMed1989

Factors affecting postoperative ventilatory support in patients with cardiac cachexia.

Factors affecting early v late weaning from ventilatory support after cardiac surgery were retrospectively compared in 15 patients with cardiac cachexia. These patients were divided into two groups based on the duration of postoperative ventilatory support, group I (n = 7) less than two days (22 +/- 8 hours) and group II (n = 8) over three days (140 +/- 125 hours). Findings in 14 randomly selected patients without cardiac cachexia who underwent cardiac valve replacement were also examined. Comparisons were made between the groups in regards to the following parameters: (1) preoperatively: anthropometric, biochemical, and immunologic parameters of nutritional status, hepatic function, cardiothoracic ratio (CTR) on chest x-ray, and data from cardiac catheterization; (2) intraoperatively and postoperatively: anesthetic drugs, duration of surgery, cardiopulmonary bypass (CPB), aortic cross-clamp, and postoperative use of inotropes. The anthropometric measurements, cell-mediated immunity, and hepatic function were significantly decreased in all patients with cachexia, but with no significant differences between the groups. Serum transferrin levels, which increased in patients with cachexia, showed no significant difference between the groups. The levels of serum albumin were significantly lower in cachectic patients than in patients without cachexia; they were significantly higher in group II than in group I. The durations of surgery and CPB were significantly longer in group II, but there was no significant difference in the duration of aortic clamping between the groups. The postoperative use of inotropes was higher in group II. These results indicate that group II patients were nutritionally as well sustained as group I. However, they had less satisfactory cardiac function, and therefore required a longer duration of postoperative ventilatory support.

Blood Pressure↗
PubMed2001

Metabolic and nutritional disorders in cardiac cachexia.

Cardiac cachexia is divided into two types, i.e., the classic type, which occurs in patients with severe heart failure, and the nosocomial type, which develops in the postoperative state. Cardiac cachexia is due both to a decrease in nutrient intake (anorexia, malabsorption) and to specific metabolic alterations (hypercatabolism with increased energy expenditure, response to hypoxia, inflammatory status, etc). Among the various mechanisms involved in the pathogenesis of cachexia, cellular hypoxia has long been recognized. The chronic activation of the endogenous neurohormonal system is another specific feature of such patients; a striking relationship was found between cardiac cachexia and hormonal levels which correlate better than the classical parameters of cardiac failure severity. Finally, inflammatory syndrome has been known to occur frequently in patients with cardiac cachexia. Several studies have shown that tumor necrosis factor-alpha was significantly increased in cachectic patients and that chronic activation of the systemic immune response might be a common and unifying factor.

Cachexia↗
PubMed2001

Cancer cachexia and its treatment with fish-oil-enriched nutritional supplementation.

OBJECTIVE: Cachexia is a common condition affecting those with advanced cancer. This review explores mechanisms of cachexia and possible treatments devised with these mechanisms in mind. METHODS: Selective review of the relevant scientific literature was performed with particular emphasis on studies performed by our group over the past 10 y involving patients with advanced pancreatic cancer. RESULTS: Cancer cachexia adversely affects patient quality of life and survival. It is characterized by a lack of a normal anabolic response to the provision of apparently adequate nutrition. It appears to result from a persistent response to illness stimulated by the cancer resulting in a proinflammatory cytokine and catabolic hormonal environment. Interventions that ignore this inflammatory milieu have had little success. More promising interventions have a broad antiinflammatory component such as nonsteroidal antiinflammatory drugs or fish oil. Preliminary studies of a combination of fish oil as an antiinflammatory agent with nutritional supplementation show promise in reversing weight loss with apparent gains in lean tissue and performance status in association with normalization of the metabolic environment in patients with advanced pancreatic cancer. CONCLUSIONS: Cancer cachexia produces a metabolic environment that prevents the appropriate use of supplied nutrition. Antiinflammatory agents such as fish oil in combination with nutritional supplementation may reverse aspects of cachexia.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Cancer cachexia: metabolic alterations and clinical manifestations.

Progressive wasting is common in many types of cancer and is one of the most important factors leading to the early death of cancer patients. Although anorexia frequently accompanies cachexia it has been difficult to establish a simple cause-and-effect relationship, and nutritional supplementation is not able to effectively reverse the process of cachexia. An increased resting energy expenditure may contribute to weight loss in some cancer patients and may explain the increased oxidation of fat. Futile energy-consuming cycles, such as the Cori cycle, may contribute to the increased energy demand. Unlike starvation, weight loss in cancer arises equally from loss of muscle and fat, and the process is characterized by an increased catabolism of skeletal muscle and a decrease in protein synthesis. Several experimental studies have suggested a role for the cytokines tumor necrosis factor alpha, interleukins-1 and -6, and interferon gamma as mediators of the process of cachexia, although conclusive data supporting a role in human disease are often lacking. Catabolic factors capable of direct breakdown of muscle and adipose tissue appear to be secreted by cachexia-inducing human tumors and may play an active role in the process of tissue degeneration. Pharmacologic intervention using antagonists to cachexia factors may be capable of reversing the wasting process.

Animals↗
PubMed1987

Cancer cachexia.

Cancer cachexia is a complex syndrome that includes host tissue wasting, anorexia, asthenia, and abnormal host intermediary metabolism. It is present in approximately 50% of cancer patients during treatment and nearly 100% of treated cancer patients at death. Cachexia has a detrimental impact on cancer therapy. The central problem of cancer cachexia is that energy balance is not maintained, and the host has a relative hypophagia which results in host tissue wasting. The tumor by its nature and obligate growth can continue to consume glucose, amino acids, and lipids at the expense of the host. This produces abnormal host intermediary metabolism including elevated glucose production and recycling, decreased muscle protein synthesis, and increased muscle and fat breakdown. The exact mechanisms of cancer cachexia have been only partially elucidated. The identification of signal molecules like cachectin which mediate these changes may be on the horizon. Nutritional support can reverse some of the derangements seen with cachexia, and there is evidence that functional lean body mass or body cell mass can be restored in some (but not all) patients. However, nutritional support has not yet improved response to chemotherapy or radiation therapy, nor has it improved host tolerance of chemotherapy. It has improved operative mortality and morbidity in cachectic cancer patients undergoing major surgical procedures. Optimum host nutritional support appears to be dependent on high insulin concentrations in both humans and rats. Insulin and exercise may be methods to preserve host lean tissue and feed the host rather than the tumor. Future studies depend on better definition of tumor-bearing host metabolism, altering the relationship between neoplasm and host to preferentially feed the host, and making the neoplasm more susceptible to effective treatment.

Animals↗
PubMed2006

Therapy insight: Use of melanocortin antagonists in the treatment of cachexia in chronic disease.

Cachexia is a process that accompanies many chronic diseases, and consists of a combination of wasting of lean body mass, increased energy expenditure, and a paradoxical loss of appetite. Cachexia both worsens quality of life and negatively affects treatment of the underlying disease. Conditions as diverse as cancer, renal failure, and heart failure show a remarkable similarity in their associated cachexia, exhibiting changes in metabolism and endocrinology, including marked increases in levels of cytokines that accompany these diseases. So far, it has been difficult to treat disease-associated cachexia successfully. One treatment that has shown promise in animal trials, however, involves antagonism of the central melanocortin system, an anorexigenic pathway in the hypothalamus and brainstem. Humans who have genetic mutations involving pro-opiomelanocortin or the melanocortin 4 receptor in this pathway exhibit increased appetite and increased lean body mass. Recent research has shown that in rodent models of cancer and renal failure, administration of melanocortin 4 receptor antagonists results in an attenuation of symptoms of cachexia, including maintenance of appetite, lean body mass, and basal energy expenditure. Although this research needs to be substantiated in humans, it provides a promising direction for treating the wasting that is associated with a variety of disease states.

Animals↗
PubMed2005

Report of a Joint Cancer Research UK/Medical Research Council workshop on cancer cachexia research at the Royal College of Physicians, Tuesday, 2 December 2003.

A joint workshop held by Cancer Research UK and the Medical Research Council aimed to stimulate interest in further research into the area of cancer cachexia. The workshop was divided into four sessions: an overview of cancer cachexia, potential mechanisms involved and methodologies that might be used to understand cachexia, and also the experience of cachexia from other disease areas. The workshop identified a need to develop a multimodal therapeutic approach to cancer cachexia and a need to undertake more multidisciplinary research.

Cachexia↗
PubMed1999

Insights into the pathogenesis of chronic heart failure: immune activation and cachexia.

Body wasting, i.e, cardiac cachexia, is a complication of chronic heart failure (CHF). The authors have suggested that cardiac cachexia should be diagnosed when nonedematous weight loss of more than 7.5% of the premorbid normal weight occurs over a time period of more than 6 months. In an unselected CHF outpatient population, 16% of patients were found to be cachectic. The cachectic state is predictive of poor survival independently of age, functional class, ejection fraction, and exercise capacity. Patients with cardiac cachexia suffer from a general loss of fat, lean, and bone tissue. Cachectic CHF patients are weaker and fatigue earlier. The pathophysiologic causes of body wasting in patients with CHF remain unclear, but initial studies have suggested that humoral neuroendocrine and immunologic abnormalities may be of importance. Cachectic CHF patients show increased plasma levels of catecholamines, cortisol, and aldosterone. Several studies have shown that cardiac cachexia is linked to increased plasma levels of tumor necrosis factor alpha. The degree of body wasting is strongly correlated with neurohormonal and immune abnormalities. Some investigators have suggested that endotoxin may be important in triggering immune activation in CHF patients. Available studies suggest that cardiac cachexia is a multifactorial neuroendocrine and immunologic disorder that carries a poor prognosis. A complex catabolic-anabolic imbalance in different body systems may cause body wasting in patients with CHF.

Cachexia↗