Cachexia Syndrome Research Articles

Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients.

Urine from cancer patients with weight loss showed the presence of an antigen of M(r) 24,000 detected with a monoclonal antibody formed by fusion of splenocytes from mice with cancer cachexia. The antigen was not present in the urine of normal subjects, patients with weight loss from conditions other than cancer or from cancer patients who were weight stable or with low weight loss (1 kg month(-1)). The antigen was present in the urine from subjects with carcinomas of the pancreas, breast, lung and ovary. The antigen was purified from urine using a combination of affinity chromatography with the mouse monoclonal antibody and reversed-phase high-performance liquid chromotography (HPLC). This procedure gave a 200,000-fold purification of the protein over that in the original urine extract and the material isolated was homogeneous, as determined by silver staining of gels. The N-terminal amino acid sequence showed no homology with any of the recognized cytokines. Administration of this material to mice caused a significant (P<0.005) reduction in body weight when compared with a control group receiving material purified in the same way from the urine of a normal subject. Weight loss occurred without a reduction in food and water intake and was prevented by prior administration of the mouse monoclonal antibody. Body composition analysis showed a decrease in both fat and non-fat carcass mass without a change in water content. The effects on body composition were reversed in mice treated with the monoclonal antibody. There was a decrease in protein synthesis and an increase in degradation in skeletal muscle. Protein degradation was associated with an increased prostaglandin E2 (PGE2) release. Both protein degradation and PGE2 release were significantly reduced in mice pretreated with the monoclonal antibody. These results show that the material of M(r) 24,000 present in the urine of cachectic cancer patients is capable of producing a syndrome of cachexia in mice.

NUTRITIONAL SUPPORT IN ADVANCED LUNG DISEASE: The Pulmonary Cachexia Syndrome

Patients with advanced lung disease (ALD) demonstrate changes in body composition characteristically manifested by a progressive loss of body weight. The mechanisms of this pulmonary cachexia syndrome are multifactorial, and treatment must be comprehensive in nature. This article addresses our current knowledge regarding the relationship between nutrition and ALD.

Proinflammatory cytokines, nutritional support, and the cachexia syndrome

BACKGROUND Protein calorie malnutrition remains endemic in hospitalized patients with both acute and chronic inflammation secondary to either cancer, chronic infectious processes, surgical injury, trauma, or burns. For the patients who cannot support themselves by enteral feeding, total parenteral nutrition remains an essential tool to minimize nitrogen losses and replete the depleted patient. However, in patients with active inflammation, nitrogen retention and lean tissue accretion are often impaired during total parenteral nutrition. Production of humoral factors, including proinflammatory cytokines, regulates many of the anabolic and catabolic processes that accompany inflammation. METHODS The investigators' experience with total parenteral nutrition and proinflammatory cytokines is reviewed. RESULTS Cytokines such as interleukin-1, tumor necrosis factor-α, and, in particular, interleukin-6 appear to play central roles in both the loss of skeletal muscle protein and the initiation of the acute phase response to inflammation, as well as in modulating the utilization of exogenously administered nutrients. CONCLUSIONS Although innovative second- and third-generation nutritional formulations for the acutely ill patient may represent one approach for improving the effectiveness of total parenteral nutrition, understanding the humoral response to inflammation and modifying cytokine actions pharmacologically may prove equally effective in improving the utility of exogenously administered nutrients. Future studies need to determine whether the effectiveness of exogenously administered nutrients in the patient with inflammation can be improved by efforts to modulate the proinflammatory cytokine response through cytokine inhibitors or antagonists. Cancer 1997; 79:1828-39. © 1997 American Cancer Society.

Proinflammatory cytokines, nutritional support, and the cachexia syndrome

Protein calorie malnutrition remains endemic in hospitalized patients with both acute and chronic inflammation secondary to either cancer, chronic infectious processes, surgical injury, trauma, or burns. For the patients who cannot support themselves by enteral feeding, total parenteral nutrition remains an essential tool to minimize nitrogen losses and replete the depleted patient. However, in patients with active inflammation, nitrogen retention and lean tissue accretion are often impaired during total parenteral nutrition. Production of humoral factors, including proinflammatory cytokines, regulates many of the anabolic and catabolic processes that accompany inflammation. The investigators' experience with total parenteral nutrition and proinflammatory cytokines is reviewed. Cytokines such as interleukin-1, tumor necrosis factor-alpha, and, in particular, interleukin-6 appear to play central roles in both the loss of skeletal muscle protein and the initiation of the acute phase response to inflammation, as well as in modulating the utilization of exogenously administered nutrients. Although innovative second- and third-generation nutritional formulations for the acutely ill patient may represent one approach for improving the effectiveness of total parenteral nutrition, understanding the humoral response to inflammation and modifying cytokine actions pharmacologically may prove equally effective in improving the utility of exogenously administered nutrients. Future studies need to determine whether the effectiveness of exogenously administered nutrients in the patient with inflammation can be improved by efforts to modulate the proinflammatory cytokine response through cytokine inhibitors or antagonists.

Hormonal treatment in advanced non-small cell lung cancer: fact or fiction?

In patients with advanced non-small cell lung cancer, cachexia is an important cause of morbidity and mortality. The pathogenic mechanism of this finding, usually referred to as "cancer anorexia and cachexia syndrome" (CACS), is complex and far from completely understood, but a disturbed equilibrium between possible food intake and metabolic needs seems to be fundamental. The literature data on the treatment options in advanced non-small cell lung cancer (NSCLC) with cachexia are reviewed. Based on the clinical studies on cancer cachexia, some recommendations for the therapeutic approach of this disorder in patients with advanced NSCLC can be given. Metoclopramide is easily administered, can alleviate gastric disturbances, but probably does not correct the catabolic spiral of CACS. There are not enough data to advise the use of parenteral nutritional support, hydrazine, cyproheptadine, tetrahydrocannabinol or nandrolone decanoate. Corticosteroids are useful in additional analgesia and fast palliation of very weak and debilitated patients in the final episode of their disease. Recent data in non-small cell lung cancer patients are in favour of the use of high-dose progestagens to improve both appetite and weight.

Toxohormones responsible for cancer cachexia syndrome in nude mice bearing human cancer cell lines.

Toxohormones are tumor-derived factors that induce cancer cachexia syndrome in tumor-bearing animals. Nude mice bearing tumors induced by eight human cancer cell lines with this activity were studied for cytokine production and expression of a newly identified gene, ob, which has the ability to control body weight. A melanoma cell line, SEKI, and a neuroepithelioma cell line, NAGAI, produced a large amount of the cytokine, leukemia-inhibitory factor (LIF). A uterine carcinoma cell line, Yumoto, produced a large amount of interleukin 6 (IL-6), and an oral cavity carcinoma cell line, OCC-1C, concomitantly produced LIF, IL-6, and IL-11. Reverse transcription polymerase chain reaction studies revealed that ob gene mRNA was not expressed in any of these cell lines, suggesting that the gene does not have a role as a tumor product responsible for cancer cachexia in this model. These findings suggest that in four of eight animal models in which cancer cachexia syndrome developed, LIF, IL-6, or possibly IL-11 produced by cancer cells may be toxohormones, but in the remaining four cancer cell lines the mechanism responsible for cachexia syndrome remains unknown.

CACHEXIA AND ANOREXIA IN MALIGNANCY

The cancer cachexia syndrome may be present in up to 80% of patients with cancer. Malnutrition resulting from cancer cachexia is a significant cause of morbidity and mortality. Anorexia, tissue wasting, and weight loss appear to be the result of metabolic abnormalities caused by host cytokine production in response to the tumor. The host cytokines include TNF-alpha, IL-1, IL-6, IFN-gamma, and D-factor. Nutritional support in the patient with cancer has been controversial, with the belief that tumor growth may be augmented; however, human studies fail to confirm that tumor growth occurs in excess of normal tissue growth. The efficacy of nutritional support in the cancer has not been adequately studied. Considerable interest exists in providing nutritional support pharmacologically to modify the response to malignancy.

A Pathogenetic Role for TNFα in the Syndrome of Cachexia, Arthritis, and Autoimmunity Resulting from Tristetraprolin (TTP) Deficiency

Tristetraprolin (TTP) is a widely expressed potential transcription factor that contains two unusual CCCH zinc fingers and is encoded by the immediate–early response gene, Zfp-36. Mice made deficient in TTP by gene targeting appeared normal at birth, but soon manifested marked medullary and extramedullary myeloid hyperplasia associated with cachexia, erosive arthritis, dermatitis, conjunctivitis, glomerular mesangial thickening, and high titers of anti-DNA and antinuclear antibodies. Myeloid progenitors from these mice showed no increase in sensitivity to growth factors. Treatment of young TTP-deficient mice with antibodies to tumor necrosis factor α (TNFα) prevented the development of essentially all aspects of the phenotype. These results indicate a role for TTP in regulating TNFα synthesis, secretion, turnover, or action. TTP-deficient mice may serve as useful models of the autoimmune inflammatory state resulting from chronic effective TNFα excess.

Triple paraneoplastic syndrome of hypercalcemia, leukocytosis and cachexia in two human tumor xenografts in nude mice.

Nude mice bearing the human oral cavity carcinoma cell line OCC-1, and the lung cancer cell line LC-1, developed a triple paraneoplastic syndrome consisting of hypercalcemia, cachexia and leukocytosis. All of these abnormalities disappeared rapidly after surgical resection of the tumors, suggesting their ectopic humoral nature. Search for the factors responsible for the respective abnormalities revealed that the production of parathyroid hormone-related protein and colony-stimulating factors (CSFs), mainly granulocyte-CSF, by the tumors could explain the hypercalcemia and leukocytosis, respectively. With regard to the severe cachexia, the production of two cachexia-associated cytokines, interleukin-6 and leukemia inhibitory factor, was able to explain the syndrome in OCC-1 bearing nude mice; however, the factor responsible in LC-1 bearing nude mice could not be identified. The triple paraneoplastic syndrome that developed in these two animal models could be explained partly by concomitant production of the peptide hormone and cytokines by cancer cells. These animal models may be very useful for the evaluation of diagnostic and therapeutic modalities for humoral abnormalities.

Asthenia: an important symptom in cancer patients

Asthenia, a symptom complex dominated by fatigue of a pathological degree, is a very common, but still insufficiently researched, symptom of many cancer patients (1, 2). Pathological or inadequate fatigue has to be differentiated from physiological fatigue following strenuous work or a lack of sleep. Besides being associated with cancer, asthenia may accompany a large variety of functional, endocrine, neurological and psychiatric disorders, metabolic disorders, drugs and various inflammatory diseases. In some cancer patients, asthenia may be the consequence of a variety of single or combined known causes, such as anaemia and metabolic disorders (e.g. hypercalcaemia or hyponatraemia). Some authors have postulated the secretion of specific ‘asthenins’ (31, muscular dysfunction (4) as well as the accumulation of lactic acid, to be implicated in the pathophysiology of asthenia of cancer patients. Various chemotherapy drugs, pain and psychotropic medications, radiation therapy and also surgery may be responsible for, or at least contribute to, asthenia in cancer patients. In recent years, newly discovered and characterized cytokines, such as tumour necrosis factor and intetferons have both been implicated in the pathogenis of asthenia. They have also been postulated to underlie the cachexia and anorexia syndrome. In particular, tumour necrosis factor (5) is pivotal in the scenario. Also events not directly related to the tumour, such as episodes of depression, or infectious complications, may exacerbate asthenia. In a previous pilot study, the author’s group had evaluated methods for assessing asthenia in a group of patients with advanced cancer using and correlating both a questionnaire and an interview (6). Evaluation of fatigue by linear analogue self-assessment (LASA) scales proved to be more apt for statistical analyses than categorical questions. Significant discrepancies

Cytokine production in five tumor cell lines with activity to induce cancer cachexia syndrome in nude mice.

To identify the so‐called toxohormone, which is a tumor‐derived factor with activity to induce cancer cachexla syndrome in tumor‐bearing animals, 5 human cancer cell lines with this activity were studied for cytokine production. Tumor cell products with activity to inhibit lipoprotein lipase (LPL) were shown to play an important role in the development of the cancer cachexia syndrome. All culture media conditioned by the 5 cell lines possessed LPL‐inhibitory activity. However, the activity differed with the cell line. In order to characterize the activity, we examined whether the cultured cells produced cytokines with activity to inhibit LPL. A melanoma cell line, SEKI, and a neuroepithelioma cell line, NAGAI, were found to express a large amount of leukemia inhibitory factor (LIF) mRNA. Furthermore, both of these cell lines were demonstrated to produce a large amount of LIF protein, and plasma levels of LIF were extremely elevated in SEKI‐ and NAGAI‐bearing nude mice, indicating that LIF produced by the tumor cells induced cancer cachexia syndrome in the animals. Thus, LIF fulfills the requirements for a toxohormone, except for suppressive activity on liver catalase. In contrast, the mechanisms responsible for cachexia in the MKN‐1‐, LX‐1‐ and LS180‐bearing mice remain unknown. These findings suggest that various types of bioactive substances produced by cancer cells could be toxohormones.

Cytokine-mediated alterations in host metabolism prevent nutritional repletion in cachectic cancer patients.

The clinical syndrome of cachexia is characterized by anorexia, continued losses of lean body mass, and altered carbohydrate and lipid metabolism. As early as the 1930s, this "chronic wasting" syndrome had been identified as the most frequent immediate cause of death in patients with cancer [Warren: Am J Med Sci 184:610-619, 1932]. At present, controversy remains as to the benefit of supplemental parenteral or enteral feedings in the nutritional repletion of cachectic cancer patients, since only selected patient groups have demonstrated clear benefit from their administration [Copeland et al.: Cancer 43:2108-2116, 1979; Copeland et al.: Cancer Res 37:2451-2456, 1977; Terepka and Waterhouse: Am J Med 20:225-238, 1956]. Despite having these advanced nutritional modalities firmly in our therapeutic armamentarium, the progression of cachexia in the nutritionally depleted cancer patient often continues unabated, and our ability to intervene successfully remains limited. This review proposes that host: tumor interactions lead to a nonspecific inflammatory response mediated in part by the chronic production and release of proinflammatory cytokines, including interleukin-1, tumor necrosis factor alpha, interleukin-6 and interferon-gamma, which antagonize the anabolic signals associated with enteral and parenteral nutrition support. Cytokine-mediated alterations can explain the inability of adequate dietary nitrogen and calories to result in lean tissue repletion. Based on this proposal, interrupting proinflammatory cytokine production or target organ action may be an appropriate therapeutic objective to improve nutrient utilization in patients with tumors.

Tumour necrosis factor and cachexia: a current perspective

Anorexia, net proteolysis of skeletal muscle and consumption of body fat are hallmarks of the cachexia syndrome associated with chronic disease states. While inanition contributes to cachexia, this wasting diathesis has little in common with simple starvation. The cachexia syndrome is characterized by progressive weight loss and depletion of lean body mass in excess to that resulting from comparable caloric restriction. Accelerated mobilization and consumption of host protein stores from peripheral tissues occurs to support gluconeogenesis and acute phase protein synthesis [1, 2]. In contrast, simple starvation is associated with a relative sparing of lean tissue with the preferential consumption of fat. While the clinical manifestations of cachexia are readily apparent, identification of the specific mechanisms responsible for the development of cachexia remains an enigma. In recent years, interest has focused on the role that the immune system plays in the development of cachexia. Investigators initially hypothesized that the chronic production of two inflammatory cytokines, tumour necrosis factorα (TNFα) and/or interleukin-1 (IL-1), could explain the host non-specific responses resulting in cachexia [3–5]. Other pro-inflammatory cytokines, including interleukin-6 (IL-6) [6, 7] and inter-feron-gamma [8, 9], have been more recently proposed to be involved in this complex process. Although no consensus exists for the exclusive role of any one cytokine in the pathogenesis of cachexia, there is growing acceptance that the progression of cachexia results in part from the inappropriate release of one or more pro-inflammatory cytokines [10, 11]. In the present review, the current role of TNF α as a mediator of cachexia is examined.

ANOREXIA IN PATIENTS WITH CANCER WITH SPECIAL REFERENCES ON ITS ASSOCIATION WITH EARLY CHANGES IN FOOD-INTAKE BEHAVIOR CHEMOTHERAPEUTIC TREATMENT AND ADJUVANT ENTERAL NUTRITION (REVIEW)

Anorexia defined as decreased appetite resulting in fatigue, change of body image and weight loss is stated to be fundamental to the syndrome of cancer cachexia. Weight loss is the most apparent symptom of anorexia and cachexia, and occurs quite frequently in patients with cancer. Interest in the pathogenetic mechanisms, is due to the strong association between weight loss and lower duality and quantity of life. This review discusses anorexia in the pathogenesis of cancer cachexia, particularly the effect of taste alterations and chemotherapy; and the long-term acceptability and effect of oral nutritional support and drug therapy.

Leukemia inhibitory factor induces changes in lipid metabolism in cultured adipocytes.

Cytokines induce a number of changes in lipid metabolism that can produce hyperlipidemia. Leukemia inhibitory factor (LIF), a recently discovered cytokine, has been suggested to play a role in the cancer cachexia syndrome through its ability to decrease lipoprotein lipase (LPL) activity. This study explores the mechanism by which LIP decreases LPL activity in cultured adipocytes and determines its effects on fatty acid synthesis and lipolysis to see if it shares the same catabolic effects on fat cells as seen with other cytokines, such as tumor necrosis factor (TNF). LIF decreased LPL activity in cultured adipocytes by 44% compared with an 85% decrease produced by TNF. Although the percent decrease in LPL activity is not as great in LIF-incubated adipocytes as in TNF-incubated adipocytes, the half-maximal doses for both cytokines are similar. LPL messenger RNA levels paralleled LPL activity in the LIF-treated adipocytes, suggesting that the effect of LIF on LPL activity is predominantly mediated through transcriptional regulation. In contrast to TNF, LIF tended to increase the de novo synthesis of fatty acids. Acetyl coenzyme-A carboxylase messenger RNA levels paralleled the changes seen in fatty acid synthesis for both cytokines. LIF caused a small increase in lipolysis, whereas TNF increased lipolysis by greater than 2-fold. These results demonstrate that the catabolic effects of LIF are weaker than those of TNF and are predominantly directed toward decreasing LPL activity, which may contribute to the hyperlipidemia associated with infection, inflammation, and cancer.

Growth Failure and AIDS-like Cachexia Syndrome in HIV-1 Transgenic Mice

The mechanisms which predispose to growth failure in infants and children infected with immunodeficiency virus type-1 (HIV-1) are not fully understood. The contributions of viral replication and CD4+ T cell depletion to growth failure in an HIV-1 transgenic mouse model were investigated. Mice homozygous for the transgene, a gag-pol deletion mutant of the HIV-1 provirus pNL4-3, exhibited marked cachexia, growth retardation, lymphoproliferation with a reduction in the percentage of CD4+ T cells but an increase in the absolute number of splenic CD4+ and CD8+ T cells, thymic hypoplasia, and early death. Despite the absence of T cells, athymic nude mice, homozygous for the HIV transgene, displayed comparable growth failure. The results indicate that AIDS-like cachexia may be produced by expression of viral envelope or accessory genes, need not be accompanied by absolute depletion of CD4+ T cells, and may occur independent of T cell function.

Pathophysiology of cancer cachexia.

Patients with advanced cancer and cachexia typically demonstrate modestly increased rates of energy expenditure in the presence of diminished food intake due to anorexia and to gastrointestinal disturbances. Rates of glucose production by the liver, gluconeogenesis and glycolysis to lactate (Cori cycle) are increased, fat mobilisation and oxidation are accelerated. There is a redistribution of body proteins away from muscle towards visceral proteins, resulting in marked muscle protein loss. Cancer cachexia differs from simple starvation and demonstrates metabolic similarities to sepsis or polytrauma. The metabolic response in the patient with cancer is largely due to mediators released by the tumour or by the host; recently the role of cytokines such as tumour necrosis factor alpha (TNF alpha), interleukin-1 (IL-1) and -6 (IL-6) and interferon gamma (INF gamma) has been emphasized. Catabolic hormones such as glucocorticoids and adrenaline have also been implicated. Cytokines have the potential to reproduce experimentally the clinical syndrome of cancer cachexia. There is evidence of increased production of several of them in certain types of cancer. There are overlapping activities of the cytokines TNF alpha, IL-1, IFN gamma and IL-6. The contribution of each of them to cancer cachexia remains unclear. Inhibition of cytokine activity using specific antibodies in cancer-bearing experimental animals demonstrated partial prevention of cachexia. A positive feedback between macrophage-derived IL-1 and tumour-derived IL-6 has been demonstrated recently in experimental cancer cachexia. Cytokines may support tumour growth by acting as growth factors.

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 < 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 < 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 < 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.

No Serum Albumin in Myeloma-Reply

In Reply.— Dr Rubinstein proposed several possible pathogenetic mechanisms for hypoalbuminemia associated with multiple myeloma that we have recently described. 1 Some of these mechanisms have already been discussed in our article. We would like to elaborate on the following points: Agreeing with Rubinstein, we also feel that hypoalbuminemia is likely a part of the cachexia syndrome associated with neoplasia. It, however, merits reemphasizing, as we did in our article, that cachexia is not simply the result of inadequate nutritional intake in patients with cancer, but may represent a set of characteristic biochemical and metabolic changes,2 possibly mediated by various tumor- and/or host-derived cytokines. We have mentioned specific suppression of hepatocyte albumin gene expression by interleukin 1. Other cytokines, such as tumor necrosis factor α/cachectin33 and interleukin 6,4 may also act additively or synergistically. Thus, correction of nutritional deficiency or supplementation with excess calorie and protein by hyperalimentation is

The role of tumour necrosis factor‐α in acquired immunodeficiency syndrome

Tumour necrosis factor-alpha (TNF) is a primary mediator in the pathogenesis of infection, tissue injury and inflammation. It is synthesised by various activated, phagocytic and non-phagocytic cells, and a wide variety of infectious or inflammatory stimulae are capable of triggering TNF biosynthesis. Recent studies indicate that overproduction of TNF in septicaemia is a critical step in triggering septic shock and multiple organ damage. Intravenous administration of recombinant human TNF induced the same types of derangement in cardiovascular homatologic, inflammatory and metabolic homeostasis that are found with endotoxic or septic shock. Chronic TNF production causes a potentially lethal syndrome of cachexia, anaemia, and protein and lipid wasting. Several investigators have recently demonstrated elevated levels of serum TNF in patients with acquired immunodeficiency syndrome (AIDS), these levels being closely correlated with the severity of the disease. This review discusses the role of TNF in the pathophysiology of AIDS and of several disorders associated with the latter. In addition, it discusses the interactions between TNF and several agents used in AIDS therapy, and suggests the use of TNF-antagonists in combination as a therapeutic regimen for AIDS patients.