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PubMed2004

Cancer anorexia-cachexia syndrome: cytokines and neuropeptides.

PURPOSE OF REVIEW: Cancer anorexia-cachexia syndrome is observed in 80% of patients in the advanced stages of cancer and is a strong independent risk factor for mortality. Numerous cytokines produced by tumor and immune cells, interacting with the neuropeptidergic system, mediate the cachectic effect of cancer. Since there is currently no effective pharmacological treatment and the anorexia-cachexia syndrome continues to be defined biochemically, we review the role of cytokines and neuropeptides in this process. RECENT FINDINGS: Currently data suggest that cancer anorexia-cachexia syndrome results from a multifactorial process involving many mediators, including hormones (e.g. leptin), neuropeptides (e.g. neuropeptide Y, melanocortin, melanin-concentrating hormone and orexin) and cytokines (e.g. interleukin 1, interleukin 6, tumor necrosis factor alpha and interferon gamma). It is likely that close interrelation among these mediators exists in the hypothalamus, decreasing food intake and leading to cachexia. SUMMARY: In the pathogenesis of cancer anorexia, cytokines play a pivotal role influencing the imbalance of orexigenic and anorexigenic circuits that regulate the homeostatic loop of body-weight regulation, leading to cachexia. Interfering pharmacologically with cytokine expression or neural transduction of cytokine signals can be an effective therapeutic strategy in anorectic patients before they develop cancer anorexia-cachexia syndrome.

Animals↗
PubMed2005

Pathophysiology of peripheral muscle wasting in cardiac cachexia.

PURPOSE OF REVIEW: Many different mechanisms have been proposed to explain muscle wasting in patients with heart failure; however, the pathogenesis remains largely obscure. This manuscript looks at current developments concerning the pathophysiology of skeletal muscle wasting in cardiac cachexia. RECENT FINDINGS: Many studies have shown that malnutrition, malabsorption, metabolic dysfunction, anabolic/catabolic imbalance, inflammatory and neurohormonal activation, and cell death play an important role in the pathogenesis of wasting in cardiac cachexia. However, the aetiology of the muscle changes is not entirely clear. In biopsies of skeletal muscles from animals with cardiac cachexia increased rates of protein degradation have been observed, with increased activity of the ubiquitin-proteasome proteolytic pathway. Skeletal muscle apoptosis may also play a role in muscle atrophy and wasting and can be partly prevented by neurohormonal inhibition, but it has recently been reported that in cachectic patients with chronic heart failure apoptosis is not the main pathway of cell death and muscle loss. SUMMARY: Many hypotheses have been used to explain the pathogenesis of muscle wasting in cardiac cachexia. Cardiac cachexia is a multifactorial disorder, and the targeting of different pathways will be necessary for effective treatment. The immune and neurohormonal abnormalities present in chronic heart failure may play a significant role in the pathogenesis of the wasting process. It has been suggested that common pathogenetic mechanisms underlie the loss of muscle mass in different cachectic states. More studies are needed to show whether there is a common pathway in cardiac cachexia and the other cachectic states.

Apoptosis↗
PubMed2005

Systemic inflammation, cachexia and prognosis in patients with cancer.

PURPOSE OF REVIEW: Cachexia remains an important cause of morbidity and mortality among cancer patients. The mechanisms underlying this syndrome remain unclear and are almost certainly multifactorial. Evidence from animal models suggests a compelling link between cachexia and inflammation, and a variety of pro-inflammatory cytokines play an integral role. This review summarizes current thinking relating to inflammation, cachexia and prognosis in cancer patients, with particular emphasis on studies relating to recent therapeutic advances. RECENT FINDINGS: Pro-inflammatory cytokines induce the acute phase protein response, a key marker of systemic inflammation. Recent evidence has also implicated other tumour-derived mediators, such as proteolysis-inducing factor and parathyroid hormone-related peptide. In addition, systemic inflammation has been found in association with many malignancies, and has been correlated with weight loss, hypermetabolism, anorexia, and adverse prognosis. Treatments such as fish oil, monoclonal antibodies, and non-steroidal anti-inflammatory drugs, have all been utilized to attenuate systemic inflammation and influence weight loss. Recent clinical studies have suggested that eicosapentaenoic acid and cyclo-oxygenase 2 inhibitors promote weight gain and downregulate the acute phase protein response. SUMMARY: Pro-inflammatory processes are clearly implicated in the hypermetabolism and weight loss associated with cancer-associated cachexia. In addition, the presence of systemic inflammation is now clearly linked with adverse prognosis in patients with cancer, which cannot be fully explained by the association with weight loss. Systemic inflammation remains an important area for novel therapeutic targets in combating cachexia, and eicosapentaenoic acid and cyclo-oxygenase 2 inhibitors appear to be efficacious in the armory against cachexia.

Acute-Phase Proteins↗
PubMed2005

The cancer cachexia syndrome: a review of metabolic and clinical manifestations.

The progressive deterioration in nutrition status frequently seen in cancer patients is often referred to as cancer cachexia. Unlike starvation, in which fat stores from adipose are depleted and protein is spared from skeletal muscle, neither fat nor protein is spared in cachexia. Cachexia affects nearly half of cancer patients, causing the clinical manifestations of anorexia, muscle wasting, weight loss, early satiety, fatigue, and impaired immune response. Cachexia does not only impede the response to chemotherapy but also is a major cause of morbidity and mortality. According to clinical studies, increasing caloric intake does not necessarily reverse cachexia. The pathophysiology of cachexia involves more complex mechanisms than simply caloric deficiency. The process appears to be mediated by circulating catabolic factors, either secreted by the tumor alone or in concert with host-derived factors, such as tumor necrosis factor-alpha (TNF-alpha), interleukins (IL-1 and IL-6), interferon (IFN-y), and leukemia inhibitory factor (LIF). The successful reversal of this process will require in-depth knowledge of the mechanisms involved, which will then enable the development of effective pharmacologic interventions that may not only improve quality of life, but more importantly, improve survival among cancer patients.

Anorexia↗
PubMedDate not supplied

Cytokines and their role in the pathophysiology of cancer cachexia.

Cancer cachexia describes a syndrome that consists of weight loss, and abnormalities in carbohydrate, protein, and lipid metabolism, which result in a state of persistent net negative energy balance. Patients suffering from cancer cachexia have a significantly shortened survival after cancer treatment. Recent experimental studies have focused on the belief that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which through broad physiologic actions ultimately lead to a chronic state of wasting, malnourishment, and death. Cytokines that have been thought to play a role in the pathophysiology of cachexia include tumor necrosis factor, interleukin-1, interleukin-6, interferon-gamma and differentiation factor. It has become clear that these cytokines have overlapping physiologic activities, which makes it likely that no single substance is the sole cause of cachexia in most cancer patients. Only further investigation may make it possible to more clearly define the role of cytokines in the pathophysiology of cancer cachexia. Specific strategies to reverse the cachectic effects of these substances may then be developed to ultimately improve cancer treatment.

Animals↗
PubMed2003

Role of NF-kappaB and cytokine in experimental cancer cachexia.

AIM: To assess the putative involvement of NF-kappaB and pro-inflammatory cytokines in the pathogenesis of cancer cachexia and the therapeutic efficacy of indomethacin (IND) on cachexia. METHODS: Thirty young male BABL/c mice were divided randomly into five groups: (a) control, (b) tumor-bearing plus saline, (c) tumor-bearing plus IND (0.25 mg x kg(-1)), (d) tumor-bearing plus IND (0.5 mg x kg(-1)), and (e) tumor-bearing plus IND (2 mg x kg(-1)). Colon 26 adenocarcinoma cells of murine were inoculated subcutaneously to induce cachexia. Saline and IND were given intraperitoneally daily for 7 days from the onset of cachexia to sacrifice. Food intake and body composition were documented, serum levels of TNF-alpha and IL-6 and activity of NF-kappaB in the spleen were investigated in all animals. RESULTS: Weight loss was observed in all tumor-bearing mice. By day 16, body weights of non-tumor mice were about 72 % of healthy controls (P<0.01), and the weight of gastrocnemius was decreased by 28.7 % (P<0.01). No difference was found between groups in food intake (P>0.05). Gastrocnemius weight was increased markedly (P<0.01) after treatment of IND (0.5 mg x kg(-1)), while the non-tumor body weights were not significantly elevated. Tumor-bearing caused a 2-3 fold increase in serum levels of both TNF-alpha and IL-6 (P<0.01). The concentration of TNF-alpha (P<0.05) and IL-6 (P<0.01) in tumor-bearing mice was reduced after administration of 0.5 mg x kg(-1) IND for 7 days. But the level of IL-6 was slightly elevated following treatment of IND 2.0 mg x kg(-1). NF-kappaB activation in the spleen was increased in tumor-bearing mice in comparison with controls in electrophoretic mobility shift assay (EMSA). NF-kappaB activity was reduced in mice treated with 0.5 mg x kg(-1) of IND, whereas a higher NF-kappaB activity was observed in mice treated with 2.0 mg x kg(-1) of IND. CONCLUSION: Colon 26 adenocarcinoma cells can induce severe cancer cachexia experimentally, and the mechanism may be partially due to the enhanced TNF-alpha and IL-6 in tumor-bearing animals, which is controlled by NF-kappaB. Low dose of indomethacin alleviates the cachexia, decreases the activation of NF-kappaB and the serum levels of TNF-alpha and IL-6, and prevents body weight loss and muscle atrophy, while no further effect is gained by a higher dosage.

Adenocarcinoma↗
PubMed2000

Cachexia.

Cachexia represents the clinical consequence of a chronic, systemic inflammatory response, and its manifestations differ considerably from those of starvation. Although cachexia is classically associated with chronic infections and malignant conditions, some of its elements have been identified in a wide variety of chronic diseases and in aging persons. Cachexia has repeatedly been associated with adverse clinical outcomes. The changes seen in cachexia are multidimensional and highly coordinated. Most obvious is a redistribution of the body's protein content, with preferential depletion of skeletal muscle and an increase in the synthesis of proteins involved in the response to tissue injury-the so-called acute-phase response. The physiologic, metabolic, and behavioral changes of cachexia are tightly regulated by cytokines, which signal the synthesis of acute-phase proteins as well as changes in intermediary metabolism that provide substrate and energy. The metabolic adaptations, notably the increase in the rate of protein degradation, limit the ability of hypercaloric feeding to reverse the depletion of lean mass. Recent studies have demonstrated the ability of anabolic and anticatabolic agents to mitigate the loss of skeletal muscle and to improve clinical outcomes in selected circumstances. Preclinical initiatives target the cytokine regulation of protein metabolism. It should be stressed that metabolic manipulation in cachexia could have positive or negative clinical effects, which must be distinguished through appropriate clinical trials.

Acute-Phase Reaction↗
PubMed1997

[Mechanism and treatment of cancer cachexia in tumor-bearing mice].

OBJECTIVE: To evaluate the role of TNF-alpha in the development of cancer cachexia, and the effects of TNF-alpha antibody and high agglutinated staphylococcin (BM828) in the treatment of experimental cancer cachexia. METHODS: T739 mice bearing LA795 tumor were used as murine tumor cachexia model and also the T739 receiving TNF-alpha. The level of serum TNF-alpha was assayed by TNF-alpha RIA in each group. Comparisons were made in the food intake and body weight of all the five groups including BM828 and TNF-alpha AB groups. RESULTS: Two weeks after being inoculated with LA795, the tumor-bearing mice developed significant anorexia and weight loss. The level of serum TNF-alpha in tumor-bearing mice was significantly higher than that in the non-tumor bearing mice (P < 0.01). TNF-alpha administration to mice resulted also in marked anorexia and weight loss as in cancer cachexia. CONCLUSION: The results suggested that the mechanism of cachexia be correlated with TNF-alpha. BM828 and TNF-alpha AB have the potentiality of attenuating the development of cachexia in murine models.

Adenocarcinoma↗
PubMed2003

[Cancer cachexia syndrome in patients with lung cancer].

UNLABELLED: Cancer cachexia syndrome is a common and important complication of cancer. It occurs in 30% to 80% cancer patients. It includes anorexia, loss weight, weakness and impaired immune function. The cause of the syndrome stays still unclear. Many endocrinological and metabolic abnormalities are observed, like hypermetabolism, glucose intolerance, increased proteolysis and lipolysis. Main role in the development of cancer cachexia is played by cytokines: TNF, interleukin 1 and 6, interferon alfa and gamma. The aim of the study was to collect information about cachexia in lung cancer patients, treated in Department of Pulmonology, Wrocław Medical University. We observed 76 patients with recent diagnosis of lung cancer (43 male, 33 female), 50 patients with non-small lung cancer and 26 with small lung cancer. Average age 61 +/- 9.76. We divided all patients in four groups, depending on percent of weight loss and compared these groups. We estimated extent of disease, anthropological and biochemical parameters. Among all patients we found cachexia in 23 (32%). There were only some differences between patients with and without cachexia. Bigger loss weight was observed in older men. CONCLUSIONS: Cachexia syndrome is not an important problem in lung cancer patients at the time of diagnosis.

Aged↗
PubMedDate not supplied

Are inflammatory cytokines the common link between cancer-associated cachexia and depression?

The prevalence of depression among patients diagnosed with cancer is higher than among the general medical population and is associated with faster tumor progression and shortened survival time. Cancer-related depression often occurs in association with anorexia and cachexia, although until recently the relationship between these conditions has not been well understood. Cachexia is associated with poorer quality of life and survival outcomes and is theeventual cause of death in approximately 30% of all patients with cancer. Recent evidence has linked elevated levels of inflammatory cytokines with both depression and cachexia, and experiments have shown that introducing cytokines induces depression and cachectic symptoms in both humans and rodents, suggesting that there may be a common etiology at the molecular level. Therapeutic agents targeting specific cytokine molecules, such as interleukin-6 or tumor necrosis factor-alpha, are currently being evaluated for their potential to simultaneously treat both depression and cachexia pharmacologically. This review summarizes the available data suggesting a dual role for cytokines in the development of cancer-related depression and cachexia and describes how biologic therapies targeting specific cytokines may improve outcomes beyond depression and cachexia, such as survival and quality of life.

Animals↗
PubMed2005

[Recent development in research and management of cancer anorexia-cachexia syndrome].

Cachexia is among the most debilitating and life-threatening aspects of cancer, and is more common in children and elderly patients. Associated with anorexia, fat and muscle tissue wasting, psychological distress, and a lower quality of life, cachexia arises from a complex interaction between the cancer and the host. This process results from a failure of the adaptive feeding response seen in simple starvation and includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. Cytokines play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin, a hormone secreted by adipose tissue, which is an integral component of the homeostatic loop of body weight regulation. This could be done by persistent inhibition of feeding-stimulatory circuitry including neuropeptide Y. Cachexia should be suspected in patients with cancer if an involuntary weight loss of greater than five percent of premorbid weight occurs within a 3-6-month period. The two major options for pharmacological therapy have been either progestational agents or corticosteroids. However, knowledge of the mechanisms of cancer anorexia-cachexia syndrome has led to, and continues to lead to, effective therapeutic interventions for several aspects of the syndrome. These include antiserotonergic drugs, gastroprokinetic agents, branched-chain amino acids, eicosapentanoic acid, cannabinoids, melatonin, and thalidomide-all of which act on the feeding-regulatory circuitry to increase appetite and inhibit tumor-derived catabolic factors to antagonize tissue wasting and/or host cytokine release. The outcomes of drug studies in cancer cachexia should focus on the symptomatic and quality-of-life advantages rather than simply on nutritional end points, since the survival of cachexia cancer patients may be limited to weeks or months due to the incurable nature of the underlying malignancy. Communication among physicians and other health care professionals provides the patient with a multidisciplinary approach to care. The patient record will be an excellent resource to document a plan of care and patient responses to treatment. Psychological distress and psychiatric disorders are common among cancer patients. These problems are also as common among the family members of people with cancer. The use of psychological and behavioral interventions in cancer is increasing, and recent studies have suggested that some of these techniques may affect quality of life and, perhaps, survival rates. Evaluations of relaxation, hypnosis, and short-term group psychotherapy have suggested some benefit with regard to anorexia and fatigue, although the population most likely to benefit from these interventions has not yet been determined. Because weight loss shortens the survival time of cancer patients and decreases performance status, effective therapy would extend patient survival and improve quality of life.

Animals↗
PubMed1995

Molecular analysis of the cytokine network involved in cachexia in colon 26 adenocarcinoma-bearing mice.

Two clones, one cachexigenic (clone 20) and the other noncachexigenic (clone 5), from a murine colon adenocarcinoma, colon 26 cells, were used to analyze the involvement of immune reactions as well as the cytokine network in cachexia. Clone 20 induced cachexia in nude and SCID mice as well as in normal BALB/c mice, suggesting that lymphocytes played little, if any, role in the process. Both clones failed to express mRNA of interleukin (IL) 1 alpha, IL-1 beta, IL-6, and tumor necrosis factor alpha in vitro with or without the coculture of NIH3T3 cells or spleen cells. However, IL-6 mRNA was selectively detected at the tumor site of clone 20 but not at that of clone 5-bearing mice. In contrast, tumor necrosis factor alpha mRNA was detected at tumor sites and in spleens of only clone 5-bearing mice, suggesting a potential role of IL-6, but not tumor necrosis factor alpha, in inducing cachexia. Anti-IL-6 antibody partially reversed the weight loss induced by clone 20, whereas the continuous infusion of IL-6 failed to cause weight loss, despite being associated with an elevation of a serum acute phase protein. These results suggest that IL-6 is necessary but not sufficient for the induction of cachexia. Both clones expressed IL-6 mRNA in the presence of IL-1 in vitro, and mice bearing either clone expressed IL-1 beta mRNA at the tumor site. Moreover, IL-1 receptor antagonist (IL-1Ra) mRNA was detected at the tumor site of clone 5-bearing mice but not at that of clone 20-bearing mice, suggesting that IL-1Ra might block IL-1 activity to reduce IL-6 production in clone 5-bearing mice. However, the transfection of clone 20 with IL-1Ra cDNA failed to abolish its capacity to produce IL-6 and to cause cachexia. Collectively, additional factor(s) besides IL-1Ra and IL-1 beta may control IL-6 and some other cachexigenic factor production, thereby causing cachexia in this model.

Adenocarcinoma↗
PubMed1995

Involvement of human interleukin 6 in experimental cachexia induced by a human uterine cervical carcinoma xenograft.

A human tumor xenograft model for cancer cachexia was established by growing a uterine cervical carcinoma, Yumoto, in nude mice. The tumor transplanted into the mice induced severe body weight loss (30% of body weight) when the tumor weight was only 1 g. In addition, other indicators for cachexia, such as adipose tissue and muscle wasting and hypoglycemia, were also observed in the tumor-bearing mice, suggesting that this is a proper model for experimental cachexia induced by a human tumor. We then examined the association of this model with various cytokines, such as tumor necrosis factor alpha, interleukin (IL)-1alpha, IL-1beta, IFN-gamma, IL-6, and leukemia inhibitory factor, and identified human IL-6, which was produced by the tumor cells, as a mediator of cachexia. A neutralizing antibody against hIL-6 administered to the mice after the development of cachexia symptoms significantly improved body weight loss, adipose tissue wasting, hypoglycemia, acute phase reaction, and leukocytosis, although it did not suppress the tumor growth. These results demonstrate that the hIL-6 produced by the tumor cells is an essential mediator of the cachexia induction in this model.

Animals↗
PubMed1999

Cardiac cachexia: a syndrome with impaired survival and immune and neuroendocrine activation.

Chronic heart failure (CHF) is a complex syndrome affecting many body systems. Body wasting (ie, cardiac cachexia) is a serious complication of CHF long known but little investigated. Although no specific diagnostic criteria have been established, we have suggested that cardiac cachexia be defined on the basis of the presence of documented nonintentional and nonedematous weight loss > 7.5% of the premorbid normal weight, occurring over a time period of > 6 months. Using this definition, 16% of an unselected CHF outpatient population was found to be cachectic. The cachectic state is predictive of impaired prognosis independently of age, functional disease classification, left ventricular ejection fraction, and peak oxygen consumption. The mortality in the cachectic cohort is 50% at 18 months. Analyzing body composition in detail, it has been found that patients with cardiac cachexia suffer from a general loss of fat tissue (ie, energy reserves), lean tissue (ie, skeletal muscle), and bone tissue (ie, osteoporosis). Cachectic CHF patients are weaker and fatigue earlier, which is due to both reduced skeletal muscle mass and impaired muscle quality. The pathophysiologic alterations leading to cardiac cachexia remain unclear, but initial cross-sectional studies have suggested that humoral neuroendocrine and immunologic abnormalities are linked, independently of established heart failure severity markers, to the presence of body wasting. Comparing the features of cachectic and noncachectic CHF patients with those of healthy control subjects, it is mainly the cachectic CHF patients who show raised plasma levels of epinephrine, norepinephrine, and cortisol; the highest plasma renin activity and aldosterone plasma concentrations; and the lowest plasma sodium level. Several studies have shown that cardiac cachexia is linked to raised plasma levels of tumor necrosis factor-ac. The degree of body wasting is strongly correlated with neurohormonal and immune abnormalities. The available evidence suggests that cardiac cachexia is a multifactorial neuroendocrine and metabolic disorder with a poor prognosis. A complex imbalance of different body systems may cause the development of body wasting.

Body Composition↗
PubMed1996

Murine interleukin-12 prevents the development of cancer cachexia in a murine model.

Murine colon 26 carcinoma causes cachexia even when the tumor burden is small. In this tumor model, murine IL-12 suppressed the induction of cancer cachexia and also inhibited tumor growth. IL-12 reduced the serum levels of IL-6, a cachexia mediator in this model, and alleviated the body weight loss and other abnormalities associated with cachexia, such as adipose tissue wasting and hypoglycemia. The anticachectic activity was observed even at low doses of IL-12, insufficient to inhibit tumor growth. IL-12 greatly increased levels of IFN-gamma in the tumor tissue and, to a lesser extent, in the circulation. IFN-gamma given intraperitoneally also prevented cancer cachexia, although it did not reduce IL-6 levels either in the tumor or in the circulation. In athymic mice bearing the same colon 26 tumor, IL-12 was no longer anticachectic and did not induce IFN-gamma. These results indicate that the anticachectic activity of IL-12 is T-cell-dependent and results from at least 2 mechanisms, the down-regulation of IL-6 and the up-regulation of IFN-gamma.

Animals↗
PubMed2006

Adiponectin, ghrelin, and leptin in cancer cachexia in breast and colon cancer patients.

BACKGROUND: The hormone ghrelin and the adipocytokines leptin and adiponectin participate in body weight regulation. In response to weight loss, ghrelin and adiponectin levels increase and leptin decreases. Cancer cachexia is a complex metabolic state, characterized by loss of muscle mass and adipose tissue together with anorexia. The authors hypothesized that responses of these hormones may be attenuated in cancer cachexia. METHODS: Fasting plasma ghrelin, adiponectin, and leptin levels, as well as weight loss, were determined in 40 cancer patients: 18 of them suffered from cancer-induced cachexia, and 22 served as a comparison group. Hormone levels were measured before administration of cancer therapy. RESULTS: A similar distribution of age, gender, and diagnosis was observed in both study groups, but the cachectic patients had higher rates of metastatic disease and lower albumin levels. No significant correlation was observed between plasma adiponectin levels and weight loss. Mean plasma ghrelin levels were higher among cachectic compared with noncachectic patients. Notably, the association between ghrelin levels and weight loss was only modest, and in a third of the cachectic patients, ghrelin levels were equal to or lower than those in the noncachectic group. Plasma leptin levels showed gender-dependent associations, and significantly lower levels were found among cachectic women but not among cachectic men. CONCLUSIONS: Results suggested a gender-dependent attenuation of expected physiologic responses to weight loss among cancer cachexia patients. Thus, impaired response of adiponectin, ghrelin, and leptin may play a role in the pathogenesis of cancer cachexia syndrome.

Adiponectin↗
PubMed2001

Involvement of parathyroid hormone-related protein in experimental cachexia induced by a human lung cancer-derived cell line established from a bone metastasis specimen.

Cachexia often causes deterioration in the quality of life in cancer patients; however, its mechanism remains poorly understood. Cachexia has often been observed in experimental animals with bone metastases, and parathyroid hormone-related protein (PTHrP) plays an important role in the formation of such metastases. We therefore investigated the possible involvement of PTHrP in an experimental cachexia model using human lung-cancer cells (HARA-B). HARA-B cells produce a high amount of PTHrP but no TNF-alpha, IL-6 or leukemia inhibitory factor. The s.c. inoculation of HARA-B cells into nude mice caused reductions in body weight, adipose tissue weight, muscle weight and serum glucose levels. Serum levels of calcium and PTHrP increased. Neutralization of PTHrP with antibody caused rapid weight gain along with a rapid decrease in serum calcium levels. Our findings suggest that PTHrP plays an important role in the development of cancer cachexia. PTHrP therefore is a possible target molecule for the treatment of cancer cachexia.

Animals↗
PubMed1995

Manifestations of cancer cachexia induced by colon 26 adenocarcinoma are not fully ascribable to interleukin-6.

In order to further clarify the role of interleukin 6 (IL-6) in the pathogenesis of cachexia, recombinant human IL-6 (hIL-6) was administered s.c. by osmotic pump for 9 days at a dose of 1 or 10 micrograms/day into CDF1 mice inoculated with a non-cachexia-inducing subclone of colon 26 adenocarcinoma (clone 5), or with a cachexia-inducing subclone (clone 20) of this malignancy. The serum level of IL-6 in non-cachectic mice with clone-5 tumors was 35% lower than in cachectic mice bearing clone 20 of colon 26 adenocarcinoma on the 19th day after tumor inoculation. IL-6 administration induced anemia, thrombocytosis and visceral organ hypertrophy not only in mice with clone-5 tumors but also in control mice with no tumor burden. Lipolysis and proteolysis became conspicuous when a large dose (10 micrograms/day) of IL-6 was infused into mice with clone-5 tumors. However, IL-6 supplementation did not induce loss of body weight, a decline in food intake or lymphocytopenia, which were characteristically observed in cachectic mice with clone-20 tumors. In conclusion, IL-6 appears to be a permissive factor for the development of cachexia but, while it can induce some of the symptoms typical of cachexia, it cannot in itself induce the full cachectic syndrome.

Adenocarcinoma↗