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PubMed2006

Cytokines as mediators and targets for cancer cachexia.

The cachexia syndrome, characterized by a marked weight loss, anorexia, asthenia and anaemia, is invariably associated with the growth of a tumour and leads to a malnutrition status caused by the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host results in a state of accelerated catabolism, which promotes severe metabolic disturbances in the patient. The search for the cachectic factor(s) started a long time ago, and many scientific and economic efforts have been devoted to its discovery, but we are still a long way from a complete answer. The present review aims to evaluate the different molecular mechanisms and catabolic mediators (both humoural and tumoural) that are involved in cancer cachexia and to discuss their potential as targets for future clinical investigations.

Cachexia↗

PubMed1993

Is the pharmacological treatment of cancer cachexia possible?

Cancer cachexia is highly prevalent in patients with advanced cancer. Its main clinical manifestation is profound anorexia. Progestational drugs have shown meaningful effects on appetite, food intake, and nutritional status in patients with advanced cancer and AIDS, and could be useful in managing anorexia. Corticosteroids also seem to produce increased appetite, but these effects are short-lived. Cyproheptadine, hydrazine sulfate, and cannabinoids also are being studied in the management of cancer-induced anorexia, but their role has not yet been clearly established. Future research should evaluate how the different drugs affect specific symptoms associated with cachexia.

Adrenal Cortex Hormones↗

PubMed1997

[Tumor cachexia--a special entity and therapeutic sequelae].

Cancer cachexia as a syndrome of generalized host tissue wasting results from interactions of tumor, host and tumor-directed treatment. Cancer cachexia may be associated with all terminal cancer stages and is not tumor-specific. Weight loss, functional impairment and deterioration of the quality of life require palliation. A therapeutic algorithm based on therapeutic standards is proposed: appropriate use of parenteral and enteral nutrition, of progesterone analogues and of metoclopramide. Innovative concepts that may enable prophylactic rather than therapeutic interventions are currently under investigation.

Cachexia↗

PubMed2003

Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress.

This study assessed in a wide population of advanced cancer patients the biological parameters relevant to cancer cachexia, such as serum levels of proinflammatory cytokines (IL-1beta, IL-6, TNFalpha), IL-2, acute-phase proteins (C-reactive protein and fibrinogen), leptin, and relevant to oxidative stress (OS), such as ROS, body antioxidant enzymes GPx and SOD. We also studied the ability of effective antioxidant agents alpha-lipoic acid (ALA), N-acetyl cysteine (NAC), and amifostine (AMI) added into culture to induce lymphocyte progression through the cell cycle, namely to enter into S phase. Additionally, we assessed the most significant clinical indexes of nutritional status such as body mass index and disease progression such as stage and ECOG-PS in the same cancer patient population. Cell cycle analysis of cultured unstimulated or PHA-stimulated PBMCs isolated from 120 cancer patients and 60 controls, with or without ALA, NAC, or AMI, was studied. The biological parameters relevant to cancer cachexia and OS were also studied. The addition of antioxidants ALA, NAC and AMI, enhanced significantly the progression through the cell cycle, namely from G0/G1 to S phase, of PBMCs isolated from cancer patients (+132%, +150% and +141%, respectively). The percentage of PHA-stimulated PBMCs of cancer patients entering S phase, which was significantly lower than that of controls, increased significantly to more than physiological level after coculture with antioxidants. ROS levels were significantly higher and GPx and SOD activities significantly lower in cancer patients than controls. Serum levels of IL-1 beta, IL-6, and TNFalpha were significantly higher and serum levels of IL-2 and leptin significantly lower in cancer patients than controls. Serum levels of C-reactive protein and fibrinogen were significantly higher in cancer patients than controls. A significant correlation was found in laboratory parameters only between serum levels of leptin and body mass index. Patients with advanced cancer thus exhibit both a high-grade OS and a chronic inflammatory condition. Antioxidant agents ALA, NAC, and AMI enhanced significantly the PBMCs progression through the cell cycle, thus providing evidence of their potential role in the functional restoration of the immune system in advanced cancer patients. Our data warrant further investigation with adequate clinical trials.

Adult↗

PubMed2004

Adipose tissue in Walker 256 tumour-induced cachexia: possible association between decreased leptin concentration and mononuclear cell infiltration.

The adipose tissue (AT) is severely affected by cachexia, a paraneoplastic syndrome, which increases the morbidity and mortality of cancer. There is, however, a heterogeneous response to the condition, according to the AT depot. As plasma leptin concentration has been often reported to vary in cachexia, we have measured (species specific radioimmunoassay) the local concentration of leptin in three AT depots: retroperitoneal (RPAT), epididymal (EAT) and mesenteric (MES) of Walker 256 tumour-bearing rats. A reduced concentration of leptin ( P<0.0001) was found in all the depots and in the plasma of the cachectic rats, compared with controls already from day 4 after tumour cell injection. The presence of a cell infiltrate was observed in all AT obtained from the tumour-bearing animals. Ultrastructural analysis, along with immunocytochemistry for RT1B (indicating the presence of MHCII) and using antibody against mononuclear phagocytes, showed the cells to be macrophages. The profile of TNFalpha and PGE2 secretion by the infiltrate was investigated (commercial kits). There was increased production of both factors by the cells of all AT ( P<0.05) compared with peritoneal macrophages obtained from the cachectic rats, while the cells isolated from MES showed the highest synthesis of TNFalpha. The results suggest a possible modulation of the chronic locally produced TNFalpha and PGE2 upon leptin synthesis by the AT of the cachectic rats.

Adipose Tissue↗

PubMed2006

Anorexia-Cachexia syndrome in cancer: implications of the ubiquitin-proteasome pathway.

INTRODUCTION: Malnutrition is a common problem in cancer patients. Its incidence varies according to disease stage (between 15 and 90%) and is considered a possible prognostic factor for therapeutic response and survival. It is also one of the causes contributing to the increase in morbidity and mortality in patients. Tumor cachexia is defined as a nutritional defect caused by tumor growth in the patient and presents as a significant weight loss. This weight loss is mainly caused by a degradation of skeletal muscle proteins. CONCLUSION: The ubiquitin-proteasome system is the most important pathway of protein degradation. As a regulatory system governing protein half-life, it is involved in the regulation of the cell cycle, signal transmission, immune system response, apoptosis, and oncogenesis. Knowledge of the molecular pathways involved in the induction of cancer-associated cachexia will favor a more rational approach to its treatment as well as possible quality of life and survival benefit for the patient.

Anorexia↗

PubMed2000

Modern management of the cancer anorexia-cachexia syndrome.

The cancer anorexia-cachexia syndrome is common, occurring in 80% of patients with advanced-stage cancer, and it is one of the most frequent causes of death in patients with cancer. It is a complex problem involving abnormalities in protein, carbohydrate, and fat metabolism. Tumors have both direct and indirect effects that result in anorexia and weight loss. The disease burden does not necessarily correlate with the degree of cachexia. In addition to the physical manifestations, the resulting abnormalities have a significant psychologic effect on patients and their families. Although there is no treatment to reverse the process, pharmacologic and nonpharmacologic measures can enhance food intake and improve quality of life.

Anorexia↗

PubMed2001

Modern management of the cancer anorexia-cachexia syndrome.

Anorexia↗

PubMed1991

Inhibition of tumour-induced lipolysis in vitro and cachexia and tumour growth in vivo by eicosapentaenoic acid.

Stimulation of lipolysis in murine adipocytes in response to a lipid-mobilizing factor produced by a cachexia-inducing murine adenocarcinoma was inhibited by eicosapentaenoic acid (EPA) with a Ki value of 104 microM. The inhibitory effect was strictly structurally specific, since other related fatty acids of both the (n-3) and (n-6) series were ineffective as inhibitors of the lipolytic process. Induction of lipolysis by both salbutamol and ACTH was also inhibited by EPA, suggesting that the effect is exerted on a step central to the process of lipolysis. Lipolysis induced with the tumour lipid-mobilizing factor was associated with a prolonged elevation of the intracellular level of cyclic AMP in adipocytes, in contrast with ACTH and salbutamol. The elevation of adipocyte cyclic AMP in response to the tumour lipid-mobilizing factor and lipolytic hormones was inhibited by EPA. In vivo, administration of pure EPA to weight losing mice bearing the MAC16 adenocarcinoma completely prevented weight loss and tumour growth rate. In contrast both the other (n-3) fatty acid present in fish oil, docosahexaenoic acid (DHA), and linoleic acid were ineffective in inhibiting weight loss or the growth of the MAC16 tumour. This suggests that inhibition of tumour lipolytic activity accounts for the anticachectic effect of EPA, and that a correlation may exist between the inhibition of cachexia and the inhibition of tumour growth.

Adenocarcinoma↗

PubMed1985

Tumour-host metabolic interaction and cachexia.

Cachexia is a terminal metabolic problem observed in a wide variety of tumours. In this article I propose that the syndrome is a direct consequence of the common feature to all malignant tumours: growth. I suggest that the requirement for essential amino acids can be used as the unifying principle that links the tumour to the two main components of cachexia: muscle wastage and anorexia. This underlying factor is usually clouded by the overlapping of individual tumour characteristics.

Amino Acids↗

PubMed1989

Altered macrophage activity and tumor necrosis factor: tumor necrosis and host cachexia.

Tumor necrosis factor (TNF) may be a mediator of cancer cachexia. This study evaluates the activity of macrophages from non-tumor-bearing (NTB) and tumor-bearing (TB) rats by measuring TNF production in response to endotoxin (LPS), both in vitro and in vivo, and correlates macrophage activity with tumor burden and parameters of host cachexia. Isolated macrophages from rats with small tumors, normal food intake, and weight gain secreted more TNF in response to 10 micrograms/ml LPS than macrophages from control NTB rats and behaved similar to activated macrophages from rats previously treated with thioglycollate. Heightened macrophage activity (increased production of TNF in response to LPS) in TB rats increased further as tumor burden increased (r = 0.889, P less than 0.001). Tumor resection reversed the heightened macrophage activity as LPS-induced levels of TNF secreted by macrophages from resected TB rats were not different from those of sham-operated NTB control rats. TB rats had serum levels of TNF activity following an iv bolus of 10 mg/kg LPS greater than those of NTB rats (P less than 0.05). In addition, peak serum TNF activity levels following iv LPS increased directly as tumor burden increased (r = 0.91, P less than 0.001). Supernatants from tissue cultures of the tumor (MCA sarcoma) failed to have any detectable TNF activity. However, large tumors in vivo had increased amounts of necrosis (78 +/- 8%), increased numbers of infiltrating macrophages, and increased levels of TNF (480 +/- 68 U/ml) compared to small tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Cancer cachexia is transmissible in plasma.

The cause of cancer cachexia is unclear. Tumors may be competing with the host for ingested nutrients or may be releasing some factor that actively inhibits energy utilization. To explore these questions, plasma was sterilely collected and pooled from 103 terminally cachectic Fischer 344 rats implanted with an experimental sarcoma. Control plasma was collected in similar fashion from 138 nontumor-bearing rats (NTBP). Plasma from tumor-bearing rats (TBP) or NTBP was continuously infused in a randomized, blinded fashion for 4 days into 20 normal rats. During infusion, food intake and nitrogen excretion were measured daily. At sacrifice, body weight and organ masses were determined. Rats receiving TBP demonstrated an immediate and profound anorexia compared with those receiving NTBP. Total food intake during treatment was 31.2 +/- 3.3 (g +/- SEM) in the TBP group versus 48.2 +/- 2.8 in the NTBP group (P less than 0.001 by t test). Likewise, the total decline in body weight was greater in the TBP group as compared with the NTBP group (-35.2 +/- 3.4 versus -14.6 +/- 4.0, P less than 0.001). Mean daily nitrogen balance during treatment was negative in the rats receiving TBP (-14.5 +/- 20.1 mg +/- SEM) while remaining highly positive in the rats receiving NTBP (110.7 +/- 19.3, P less than 0.002). Finally, cardiac and gastrocnemius muscle masses were decreased, while hepatic mass was unaffected. These data demonstrate that the syndrome of cancer-associated cachexia is transmissible in plasma and therefore may be mediated by a circulating molecule or molecules. Identification and purification of the molecule(s) responsible for this effect would have obvious clinical benefits.

Animals↗

PubMed1986

Cancer cachexia and the rate of whole body lipolysis in man.

While malnutrition attending cancer cachexia may be associated with variable losses of body fat, lipid metabolism has been only minimally studied. To clarify potential aberrations of lipid metabolism in weight losing cancer patients, the whole body rate of lipolysis was determined in 9 cancer patients in the postabsorptive state and compared to that in 5 normal subjects. A primed-three stage infusion of glycerol was used to measure plasma glycerol clearance and turnover. A positive correlation between glycerol turnover and plasma concentration was demonstrated in both cancer patients (r = 0.72) and in normal subjects (r = 0.81). Glycerol turnover rate in cancer patients (2.05 +/- 0.14 mumol X kg-1 X min-1) was not different from that in normals (2.31 +/- 0.50); while glycerol clearance in cancer patients (1.72 +/- 0.13 L/min) was significantly lower (P less than 0.025) by 32% than that in normals. This study demonstrates that the whole body lipolytic rate in cancer patients is not different from healthy normals. As a consequence, the loss of body fat in patients with cancer cachexia may be due to a reduced rate of lipogenesis rather than augmented lipolysis as is observed in nonmalignant malnutrition, starvation, or injury.

Adult↗

PubMed1987

Tumors secreting human TNF/cachectin induce cachexia in mice.

Anorexia and weight loss are serious complications that adversely effect the prognosis of cancer patients. It has been suggested that TNF/cachectin may cause cachexia. To determine if TNF/cachectin can induce progressive weight loss in tumor-bearing animals, a clone of the human TNF/cachectin gene was isolated and inserted into a mammalian expression vector. This construct was transfected into CHO cells, and a cell line (CHO/TNF-20) that secretes TNF/cachectin was isolated. A cell line (CHO/CMV-Neo) that contains the same expression vector without the TNF/cachectin gene was also isolated. Nude mice injected intraperitoneally with CHO/TNF-20 cells died more quickly than mice injected with CHO/CMV-Neo cells. Eighty-seven percent of mice inoculated intramuscularly with CHO/TNF-20 cells developed severe cachexia and weight loss. All mice bearing CHO/CMV-Neo tumors maintained or increased their body weight. We conclude that mice bearing tumors that secrete TNF/cachectin develop progressive wasting and die more quickly than mice bearing control tumors.

Animals↗

PubMed1996

[Synthetic progestational hormones in the treatment of neoplastic cachexia].

Cachexia frequently occurs in cancer patients. Indeed, this syndrome affects about 50% of hospitalized patients. This clinical entity may be described by different characteristics: appetite and weight loss, several metabolic abnormalities, possible influence of cytokines, poor prognosis. During the last decade, several papers have shown the beneficial activity of medroxyprogesterone acetate (MPA) and megestrol acetate (MA) in cancer cachexia. Seven randomized trials emphasized their activity on patients weight and appetite. Megestrol acetate doses in those trials are different: from 160 mg/24 h to 1600 mg/24 h; this drug is similar to MPA in terms of clinical and pharmacological properties. Iatrogenic toxicity due to MA and MPA is mild, but numerous questions still subsist: optimal date of introduction during the course of the disease, posology, treatment duration and its impact on quality of life of cancer patients.

Cachexia↗

PubMed1990

Effects of spontaneous physical exercise on experimental cancer anorexia and cachexia.

The aim of this study was to evaluate whether spontaneous physical exercise can modify cancer anorexia and cachexia in tumour-bearing rats. Two transplantable experimental tumours were evaluated. Tumour-bearing Wistar Furth rats fed ad libitum and with free access to a running wheel had a delayed onset of anorexia compared with their non-exercised tumour-bearing controls, retained normal behaviour and were able to run the same daily distance as non-tumour controls until the onset of cachexia. Exercise resulted in a decreased carcass wet weight and lipid stores but in an increased carcass dry weight in the tumour-bearing animals. Despite increased food intake, physical exercise resulted in a reduced final tumour weight without any change in water content. Skeletal and cardiac muscle tissue did not show any difference in water content but there was an increased RNA/protein quotient in the exercising tumour-bearing animals. Thus the deleterious alterations induced by the malignancy on tumour host metabolism are not inevitable but can be modified by spontaneous physical exercise.

Animals↗

PubMed1991

Anti-interferon-gamma antibody treatment, growth of Lewis lung tumours in mice and tumour-associated cachexia.

C57BL/6N mice bearing Lewis lung tumours were treated with anti-gamma-interferon (IFN-gamma) monoclonal antibodies. Early, but not late, treatment inhibited tumour growth, suggesting that endogenous IFN-gamma promotes initial tumour cell proliferation. Tumour development was associated with failure to gain weight or with progressive weight loss. Anti-IFN-gamma given early or late counteracted this wasting syndrome, which indicates that IFN-gamma production subsists during tumour growth and is directly or indirectly responsible for tumour-associated cachexia. Studies of body composition in cachectic mice revealed fat tissue to be particularly affected. Fat loss was enhanced by IFN-gamma and antagonised by anti-IFN-gamma. Tumour-bearing mice were also hypersensitive to the lethal effect of endotoxin; anti-IFN-gamma was unable to mitigate this sensitisation, suggesting that IFN-gamma does not exert its cachexia-inducing effect through augmentation of the host response to an endogenous endotoxin source.

Animals↗

PubMed1995

Interleukin-1 receptor antagonist (IL-1ra) is unable to reverse cachexia in rats bearing an ascites hepatoma (Yoshida AH-130).

The mechanisms leading to the development of cancer cachexia are still poorly understood. Recently, cytokines such as interleukin 1 and tumour necrosis factor-alpha have been involved as mediators of the tissue wasting consequent to tumour growth. The rat ascites hepatoma Yoshida AH-130 is a highly anaplastic tumour that causes in the host an early and marked depletion of both the skeletal muscle and the adipose tissue, mainly accounted for by a hypercatabolic state. Profound hormonal alterations and the release of tumour necrosis factor-alpha and interleukin 1 by the tumour cells likely concur in forcing the metabolic balance towards the catabolic side [1]. In order to possibly achieve the correction of this wasting condition, the AH-130 bearing rats were administered a daily s.c. dose of interleukin 1 receptor antagonist (IL-1ra; 2 mg/kg). This factor, however, was completely ineffective in either inhibiting tumour proliferation or in preventing the consequent tissue depletion and protein hypercatabolism. These observations suggest that interleukin 1 is not important, at least in this model system, for either the development of cachexia or tumour growth.

Animals↗