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PubMed2000

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

Tissue protein hypercatabolism (TPH) is an important feature in cancer cachexia, particularly with regard to the skeletal muscle. The Yoshida AH-130 rat ascites hepatoma is a model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle wasting, primarily due to TPH. The present study was aimed at investigating if IL-15, which is known to favour muscle fibre hypertrophy, could antagonize the enhanced muscle protein breakdown in this cancer cachexia model. Indeed, IL-15 treatment partly inhibited skeletal muscle wasting in AH-130-bearing rats by decreasing (8-fold) protein degradative rates (as measured by 14C-bicarbonate pre-loading of muscle proteins) to values even lower than those observed in non-tumour-bearing animals. These alterations in protein breakdown rates were associated with an inhibition of the ATP-ubiquitin-dependent proteolytic pathway (35% and 41% for 2.4 and 1.2 kb ubiquitin mRNA, and 57% for the C8 proteasome subunit, respectively). The cytokine did not modify the plasma levels of corticosterone and insulin in the tumour hosts. The present data give new insights into the mechanisms by which IL-15 exerts its preventive effect on muscle protein wasting and seem to warrant the implementation of experimental protocols involving the use of the cytokine in the treatment of pathological states characterized by TPH, particularly in skeletal muscle, such as in the present model of cancer cachexia.

Animals↗
PubMed2005

Change of the growth hormone-insulin-like growth factor-I axis in patients with gastrointestinal cancer: related to tumour type and nutritional status.

Changes in the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis, especially acquired GH resistance, develop in many severe illnesses, including cachexia. To study changes in the GH-IGF-I axis in patients with cancer cachexia, biochemical markers and body composition parameters were measured in eighty-eight gastric cancer patients, thirty colorectal cancer patients (subclassified according to the presence or absence of cachexia) and twenty-four healthy control subjects. Fifty-nine patients were defined as cachectic, based on the percentage of weight loss compared with their previous normal weight. The remaining fifty-nine patients were defined as non-cachectic. Measurements were repeated in twenty-seven patients (sixteen with gastric cancer and eleven with colorectal cancer) 3 months after radical operation. Compared with the controls, the cachectic gastric cancer patients had high GH levels (1.36 v. 0.32 ng/ml; P=0.001), a trend towards high IGF-I levels (223.74 v. 195.15 ng/ml; P=0.128 compared with non-cachectic patients) and a low log IGF-I/GH ratio (2.55 and 2.66 v. 3.00; P=0.002), along with a decreased BMI; the cachectic colorectal cancer patients showed the biochemical characteristics of acquired GH resistance: high GH (0.71 v. 0.32 ng/ml; P=0.016), a trend towards decreased IGF-I levels (164.18 v. 183.24 ng/ml; P=0.127) and a low log IGF-I/GH ratio (2.54 v. 2.99; P=0.005), with increased IGF-I levels following radical surgery (200.49 v. 141.91 ng/ml; P=0.046). These findings suggest that normal GH reaction and sensitivity occur in gastric cancer patients, controlled by nutritional status, whereas acquired GH resistance develops in cachectic colorectal cancer patients, which may be caused by tumour itself.

Adult↗
PubMed1993

Effects of increased beta 2-agonist dose in tumor-bearing animals.

Cachexia and malnutrition are major contributing causes of significant morbidity and mortality in the cancer patient. Although supplemental nutrition alone does not reverse the cachectic process, the use of anabolic beta 2-adrenergic agonists in conjunction with supplemental nutrition does significantly reverse cachectic processes in tumor-bearing (TB) animals. To determine the most efficacious dose of the beta 2-agonist cimaterol (CIM), male Fischer-344 rats with dorsal subcutaneous methylcholanthrene sarcomas were maintained on supplemental enteral nutrition via surgically placed gastrostomy tubes. TB rats were given daily subcutaneous injections of either saline (Sal) or one of three doses of CIM for seven days. TB-Sal animals demonstrated significant cachexia with decreased extensor digitorum longus and gastrocnemius muscle dry weight and protein content. There was a significant increase in both extensor digitorum longus and gastrocnemius muscle dry weight and protein content in all treatment groups compared with TB controls. The greatest increase was in the 0.30 mg/kg CIM treatment group. Increased cardiac mass was associated with increasing dosage, with the greatest effect being observed in the 0.60 mg/kg CIM treatment group. This dosage, however, was associated with a decreased effect on muscle weight and protein content compared with the 0.30 mg/kg CIM dose. Thus the peak anabolic effect in TB animals was reached with the 0.30 mg/kg dose of CIM. Therefore, use of the beta 2-agonist CIM may prove useful in the treatment of cancer-induced cachexia.

Adrenergic beta-Agonists↗
PubMed2005

Parenteral nutrition in advanced cancer: indications and clinical practice guidelines.

Cachexia is a disturbing and disfiguring aspect of many advanced cancers. Parenteral nutrition (PN) is a controversial and expensive treatment for cancer cachexia. Guidelines for the use of PN for these patients have been suggested. These two case reports will highlight some of the issues around the etiology of cancer cachexia, the clinical dilemmas and the use of clinical practice guidelines.

Aged↗
PubMed2001

Nuclear export of phosphorylated C/EBPbeta mediates the inhibition of albumin expression by TNF-alpha.

Decreased albumin expression is a frequent feature of cachexia patients afflicted with chronic diseases, including cancer, and a major contributor to their morbidity. Here we show that tumor necrosis-alpha (TNF-alpha) treatment of primary mouse hepatocytes or TNF-alpha overexpression in a mouse model of cachexia induces oxidative stress, nitric oxide synthase (NOS) expression and phosphorylation of C/EBPbeta on Ser239, within the nuclear localization signal, thus inducing its nuclear export, which inhibits transcription from the albumin gene. SIN-1, a NO donor, duplicated the TNF-alpha effects on hepatocytes. We found similar molecular abnormalities in the liver of patients with cancer-cachexia. The cytoplasmic localization and association of C/EBPbeta-PSer239 with CRM1 (exportin-1) in TNF-alpha-treated hepatocytes was inhibited by leptomycin B, a blocker of CRM1 activity. Hepatic cells expressing the non-phosphorylatable C/EBPbeta alanine mutant were refractory to the inhibitory effects of TNF-alpha on albumin transcription since the mutant remained localized to the nucleus. Treatment of TNF-alpha mice with antioxidants or NOS inhibitors prevented phosphorylation of C/EBPbeta on Ser239 and its nuclear export, and rescued the abnormal albumin gene expression.

Active Transport, Cell Nucleus↗
PubMed1997

The influence of muscle mass, strength, fatigability and blood flow on exercise capacity in cachectic and non-cachectic patients with chronic heart failure.

BACKGROUND: The influence of age, skeletal muscle function and peripheral blood flow on exercise capacity in chronic heart failure patients is controversial, possibly due to variations in skeletal muscle atrophy. METHODS AND RESULTS: To assess predictors of exercise capacity in patients with clinical cardiac cachexia, we studied 16 cachectic and 39 non-cachectic male chronic heart failure patients of similar age and ejection fraction. All cachectic patients were wasted (% ideal body weight: 81.2 +/- 1.9 vs 105.2 +/- 2.1, P < 0.0001, mean +/- SEM) and had documented weight loss (5-30 kg). Peak oxygen consumption (14.9 +/- 1.4 vs 16.3 +/- 0.6 ml.kg-1, min-1, resting and peak blood flow (plethysmography) and 20 min fatigability (% baseline strength) were all similar between the two groups. Quadriceps strength, muscle size (all P < 0.0001), strength per unit muscle (right: P < 0.05: left: P < 0.001) and 5 min fatigability (P < 0.05) were all lower in cachectic patients. In non-cachectic patients, age (R = 0.48) and quadriceps strength (R = 0.43, all P < 0.01) predicted peak oxygen consumption. Only in cachectic patients did peak blood flow predict peak oxygen consumption significantly (R = 0.72, P = 0.005), whereas age and strength did not. Similar findings were confirmed using other previously published definitions of cardiac cachexia. CONCLUSIONS: The predictors of exercise capacity change with the development of cardiac cachexia from age and strength to peak blood flow. This shift may be caused by additional endocrine or catabolic, abnormalities active in end stage heart failure.

Adult↗
PubMed2006

Pharmacological approaches to ameliorating catabolic conditions.

PURPOSE OF REVIEW: Nutritional debilitation is among the most devastating and life-threatening aspect of various diseases. It arises from a complex interaction between the illness and the host. This process includes cytokine production, release of lipid-mobilizing and proteolysis-inducing factors, and alterations in intermediary metabolism. As a result, many patients develop cachexia with progressive body fat and muscle tissue wasting with associated worsening of their clinical status and a lower quality of life. In this review, up-to-date information about different approaches to pharmacologic management of cachexia will be addressed. RECENT FINDINGS: Until recently, the two major options for pharmacological therapy were either progestational agents or corticosteroids. Knowledge of the mechanisms of cachexia, however, has led to newer therapeutic interventions for treating several aspects of the syndrome. These include antiserotonergic agents, branched-chain amino acids, eicosapentaenoic acid, cannabinoids, melatonin, and thalidomide--all of which act on the feeding-regulatory circuitry to increase appetite and inhibit illness-derived catabolic factors. SUMMARY: Information from this review will guide health care providers in limiting weight loss and improving performance status of cachectic patients through pharmacological therapy, with the hope that such therapy will extend patients' survival and improve their qualities of life.

Adrenal Cortex Hormones↗
PubMed2006

Chronic obstructive pulmonary disease: effects beyond the lungs.

PURPOSE OF REVIEW: This article reviews the systemic effects of chronic obstructive pulmonary disease in general and the musculoskeletal effects and cachexia in particular. RECENT FINDINGS: Shift in muscle fiber type from I to II, reduction of capillary/mitochondria ratio, reduction of oxidative enzymes and oxidative capacity, alteration in amino acid profile, changes in respiratory muscle dynamics, activation of the ubiquitin-proteosome pathway with loss of contractile proteins are some of the factors found to cause muscle dysfunction in chronic obstructive pulmonary disease. Chemotaxis and capability to produce more reactive oxygen species and to cause extracellular proteolysis are enhanced in neutrophils of chronic obstructive pulmonary disease patients. Tumor necrosis factor-alpha is shown to cause loss of myosin chains in a time and dose-dependent fashion and to induce production of reactive oxygen species through activation of the cyclooxygenase pathway. Inflammation and oxidative stress caused by reactive oxygen species fuel each other. Weight loss due to muscle wasting (cachexia) in chronic obstructive pulmonary disease is not solely related to malnutrition and is an independent predictor of mortality. Causative factors for cachexia include cytokine effects, protein degradation enhanced by increased ubiquination, upregulation of mRNA for key enzymes, increased energy expenditure and neurohormonal effects such as leptin production and an imbalance in anabolic and catabolic hormone homeostasis. SUMMARY: The findings noted above may well have the common link of inflammation in and beyond the lungs.

Cachexia↗
PubMed2006

Peripheral administration of a melanocortin 4-receptor inverse agonist prevents loss of lean body mass in tumor-bearing mice.

Cachexia affects many different chronically ill patient populations, including those with cancer. It results in loss of body weight, particularly of lean body mass (LBM), and is estimated to be responsible for over 20% of all cancer-related deaths. Currently, available drugs are ineffective, and new therapies are urgently needed. Melanocortin 4-receptor (MC4-R) blockade has been shown recently to be effective in preventing cancer cachexia in rodent models. In the present study, we have tested a MC4-R blocker, ML00253764 [2-{2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorophenyl}-4,5-dihydro-1H-imidazolium hydrochloride] (Vos et al., 2004), in vitro and in vivo. In membranes of human embryonic kidney 293 cells expressing human MC4-R, ML00253764 displaced [Nle(4), d-Phe(7)]-alpha-melanocyte-stimulating hormone binding with an IC(50) of 0.32 microM. At concentrations above 1 microM, ML00253764 decreased cAMP accumulation (maximal reduction of -20%) indicative of inverse agonist activity. ML00253764 was administered twice daily (15 mg/kg s.c.) for 13 days to C57BL6 mice bearing s.c. Lewis lung carcinoma tumors. Food intake and body weight were measured, and body composition was assessed using magnetic resonance relaxometry. ML00253764 stimulated light-phase food intake relative to vehicle-treated controls (p < 0.05), although no effect was observed on 24-h food intake. During the 21 days of the experiment, the LBM of tumor vehicle-treated mice decreased (p < 0.05). In contrast, the tumor-bearing mice treated with ML00253764 maintained their LBM. These data support the view that MC4-R blockade may be a suitable approach for the treatment of cancer cachexia and that MC4-R inverse agonists may have potential as drug candidates.

Animals↗
PubMed2004

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

In cancer cachexia both cardiac and skeletal muscle suffer an important protein mobilization as a result of increased proteolysis. Administration of the beta2-agonist formoterol to both rats and mice bearing highly cachectic tumors resulted in an important reversal of the muscle-wasting process. The anti-wasting effects of the drug were based on both an activation of the rate of protein synthesis and an inhibition of the rate of muscle proteolysis. Northern blot analysis revealed that formoterol treatment resulted in a decrease in the mRNA content of ubiquitin and proteasome subunits in gastrocnemius muscles; this, together with the decreased proteasome activity observed, suggest that the main anti-proteolytic action of the drug may be based on an inhibition of the ATP-ubiquitin-dependent proteolytic system. Interestingly, the beta2-agonist was also able to diminish the increased rate of muscle apoptosis (measured as DNA laddering as well as caspase-3 activity) present in tumor-bearing animals. The present results indicate that formoterol exerted a selective, powerful protective action on heart and skeletal muscle by antagonizing the enhanced protein degradation that characterizes cancer cachexia, and it could be revealed as a potential therapeutic tool in pathologic states wherein muscle protein hypercatabolism is a critical feature such as cancer cachexia or other wasting diseases.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Hypoleptinemia in gastric cancer patients: relation to body fat mass, insulin, and growth hormone.

BACKGROUND: It remains elusive whether there are other causes besides body fat mass wasting contributing to decreased leptin level in cancer cachexia patients. This study attempts to explore possible factors influencing leptin levels in patients with gastric cancer. METHODS: Hormones levels (including leptin, insulin, growth hormone (GH), insulin-like growth factor I, glucagons, and cortisol), acute phase reactant, and body composition were measured in 88 gastric cancer patients and 24 healthy controls. All patients were divided into weight-loss (48 patients) or nonweight-loss (40 patients) groups and cachexia (body mass index <18; 13 patients) or noncachexia (75 patients) groups. The detection was repeated 3 months after radical surgery in 16 patients. RESULTS: Compared with the controls, leptin levels decreased in gastric cancer patients with and without weight loss (p < .001 and p = .003, respectively), even when the percentage of fat mass was adjusted (p = .004 and 0.018, respectively). GH and insulin levels also changed significantly. Similar results were also found in patients with and without cachexia. Multivariate regression analysis showed that the percentages of fat mass (standardized coefficient [SC] = 0.631, p < .001), GH (SC = -0.244, p = .005) and insulin (SC = 0.201, p = .020) were significantly correlated with leptin. In the 16 patients who underwent radical surgery, leptin levels remained low and no significant changes in the other hormones were detected. CONCLUSIONS: Our results showed that low leptin levels in gastric cancer patients depended not only on the percentage of fat mass, but also on GH and insulin levels. Chronic high GH and low insulin levels may inhibit the leptin secretion.

Adipose Tissue↗
PubMedDate not supplied

Hypocupremia in patients receiving total parenteral nutrition.

Although hypocupremia is a well-known consequence of long-term total parenteral nutrition (TPN), its incidence as well as the duration of TPN necessary to induce it are still unsettled. The purpose of this study is to review the changes in serum copper level in 25 patients receiving TPN for a period longer than 2 wk (mean duration 6 wk) at the Istituto Nazionale Tumori of Milan and to evaluate the possible relationship of cupremia with the basic disease. Main indications for TPN included enterocutaneous fistulas (11 patients), cancer cachexia (10 patients), radiation enteropathy (two patients), and severe postoperative stricture following esophagogastric resection (two patients). Mean value of serum copper at the beginning of the study was 143 micrograms/100 ml (normal value 65-165 micrograms/100 ml), and the regression analysis showed a mean fall of 5.64 micrograms/100 ml/wk. Hypocupremia occurred in four patients (three with intestinal fistulas and one with radiation obstructive enteritis) at 5th, 6th, 9th, and 6th wk of TPN, respectively. No patient with cancer cachexia developed hypocupremia. No patient with hypocupremia had clinical evidence of a copper deficiency syndrome. We conclude that 1) hypocupremia does not occur within the first month of TPN; 2) its incidence is about 16% in patients intravenously fed for period longer than 2 wk; 3) it is more frequent in patients with enterocutaneous fistulas, whereas it never occurs in patients with cancer cachexia, and 4) it is not necessarily associated to a clinicometabolic syndrome of copper deficiency. Finally, the "nutritional" meaning of serum copper should be questioned in cancer patients since it could represent a "tumor marker."

Adult↗
PubMed1983

Two lines of Walker carcinoma 256: their peculiarities and different interactions with the host.

Two sublines of Walker 256 carcinoma have been characterized for their ability to metastasize and to induce cachexia. The invasive, metastasizing line A induced terminal anorexia in rats with a mean survival time of 27 +/- 1.5 days. The non-invasive line B induced early anorexia and cachexia with a mean survival time of only 15 +/- 1 days. At death, the line B tumor was still smaller than the line A one, and no metastases were detectable. These two sublines are discussed as a composite model for studying anorexia and cachexia together with invasion and metastasis.

Animals↗
PubMed1994

Anabolic effects of recombinant insulin-like growth factor-I in cachectic patients with the acquired immunodeficiency syndrome.

The loss of lean body mass accompanying acquired immunodeficiency syndrome (AIDS)-associated cachexia is refractory to current modes of therapy. GH and insulin-like growth factor-I (IGF-I) stimulate protein accretion, but resistance to GH action has been reported in malnutrition and infection. We hypothesized that GH resistance occurs in AIDS-associated cachexia, but that treatment with IGF-I would be anabolic. A single injection of GH produced a smaller increase in circulating IGF-I in 21 patients with AIDS compared to that in 23 age-matched controls (141 +/- 15 vs. 194 +/- 15 micrograms/L; P < 0.02), indicating partial GH resistance. Ten subjects received either low or high dose iv recombinant IGF-I 12 h daily for 10 days. Cumulative nitrogen retention was positive for both dosage groups (low dose, 15.42 +/- 6.37 g; high dose, 3.62 +/- 4.15 g), but a significant increase in daily nitrogen retention occurred only in the low dose group on days 2, 4, 5, 6, and 7. Nitrogen balance and protein turnover (estimated by [13C]leucine and [15N] glycine kinetics) during the final 3 days of treatment were unchanged compared to baseline values, confirming the transient nature of the anabolic response. Repeated administration of IGF-I decreased IGF-binding protein-3 levels, producing lower intrainfusion levels of IGF-I and limiting its therapeutic efficacy. The basal metabolic rate increased with high dose IGF-I and may have contributed to the lack of anabolic effect. We conclude that partial GH resistance occurs in AIDS-associated cachexia. Treatment with low dose recombinant IGF-I produces significant, but transient, nitrogen retention. Alternate routes of IGF-I administration or coadministration with GH may prevent attenuation of IGF-I action.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Effect of combination treatment with a vitamin D analog (OCT) and a bisphosphonate (AHPrBP) in a nude mouse model of cancer-associated hypercalcemia.

Hypercalcemia represents one of the important paraneoplastic syndromes affecting morbidity and mortality of cancer patients. We and others have demonstrated that vitamin D analogs with little calcemic activities suppress the transcription of the parathyroid hormone-related peptide (PTHrP) gene, a major humor responsible for cancer hypercalcemia, and thereby prevent the development of hypercalcemic syndrome. The present study was undertaken: to compare the therapeutic efficacy of a vitamin D analog, 22-oxa-1,25-dihydroxyvitamin D3 (OCT), and a bisphosphonate (disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate [AHPrBP]), an inhibitor of osteoclastic bone resorption, on cancer-induced hypercalcemia; and to see if the effect could be enhanced by combination treatment, using a nude mouse model implanted with a human pancreas carcinoma (FA-6). After a single intravenous administration, OCT (5 microg/kg of body weight [BW]) was as effective as AHPrBP (10 mg/kg of BW) in lowering blood ionized calcium levels in tumor-bearing nude mice, and their combination further enhanced the therapeutic effect. Although AHPrBP lost its efficacy after repeated injections, OCT was still effective after the third administration. The therapeutic effect of OCT in cancer hypercalcemia was observed in four other human tumors, including another pancreas carcinoma (PAN-7), two squamous cell carcinomas of the lung (KCC-C1 and LC-6), and a squamous carcinoma of the pharynx (PHA-1), all of which elaborated PTHrP into the circulation. Treatment with OCT resulted in a decrease in circulating PTHrP levels by approximately 50% in two representative models. However, the mechanism underlying the antihypercalcemic effect of OCT seemed complex, involving inhibition of PTHrP production, suppression of excessive bone resorption, and an antitumor activity. OCT also markedly inhibited the body weight loss with tumor growth, while AHPrBP, which exhibited a similar antihypercalcemic effect, was less effective than OCT in preventing cachexia. The anticachectic activity of their combination did not exceed that of OCT alone, suggesting a hypercalcemia-dependent as well as an independent mechanism of cancer cachexia. It is concluded that OCT may be useful, either as a single agent or in combination with bisphosphonates, for the treatment of cancer-associated hypercalcemia and cachexia.

Animals↗
PubMed1992

Tumor necrosis factor and regulation of metabolism in infection: role of systemic versus tissue levels.

Tumor necrosis factor (TNF), a pleiotropic cytokine, is produced by macrophages and other cells in a variety of infectious and noninfectious diseases. Ultimately, the net biological effects of TNF may be either beneficial or injurious to the host. For instance, during overwhelming bacterial infection, the acute overproduction of TNF causes septic shock syndrome characterized by hypotension, organ failure, and death. Antibodies against TNF prevent and reverse these sequelae in animal models of septic shock, and their use in humans is currently under investigation in clinical trials. In another instance, TNF has been implicated as an injurious mediator in the state of malnutrition that complicates the course of chronic infection and cancer. Termed cachexia, this chronic syndrome inevitably causes the afflicted host to succumb from weight loss, anorexia, and catabolism of protein and lipid. Experimental studies of animals exposed to TNF for protracted periods indicate that this cytokine is capable of causing cachexia, and the biochemical basis for these catabolic changes has been identified. More recent data indicate that the detrimental metabolic effects of TNF are not dependent upon its circulating levels in the bloodstream, but rather are dependent upon its actions locally in vital organs (e.g., brain). Thus, the metabolic basis for cachexia in infection may be largely dependent upon the amount of cytokine produced in metabolically important tissues. As a result, circulating TNF levels in cachectic patients may not accurately reflect the metabolic state of the host, and do not correlate to weight loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Skeletal muscle wasting in tumor-bearing rats is associated with MyoD down-regulation.

Cachexia is a syndrome characterized by profound skeletal muscle wasting that frequently complicates malignancies. A number of studies indicate that protein hypercatabolism, largely mediated by classical hormones and cytokines, is the major component of muscle depletion. Impaired regeneration has been suggested to contribute to the reduction of muscle size. In particular, it has been shown that the expression of MyoD, a muscle-specific transcription factor, is down-regulated by cytokines such as TNFalpha and IFNgamma in a NF-kappaB-dependent posttranscriptional manner. The present study investigated whether modulations of the transcription factor MyoD are associated with the onset of muscle wasting in a well established model of cancer cachexia. Rats bearing the Yoshida AH-130 hepatoma develop a condition of muscle protein hypercatabolism, largely dependent on TNFalpha bioactivity. In the gastrocnemius of these animals the expression of MyoD was markedly reduced, paralleling the decrease of muscle weight. This pattern is associated with increased nuclear translocation of AP-1, while DNA-binding assays did not detect any change in NF-kappaB activity. This is the first observation demonstrating that muscle depletion in tumor-bearing rats is associated with a down-regulation of MyoD levels. Although the underlying mechanisms remain to be clarified, this change is compatible with the hypothesis that a reduced expression of molecules involved in the regulation of the regenerative response may concur to muscle wasting in cancer cachexia.

Animals↗
PubMed2001

Zinc alpha-2-glycoprotein is expressed by malignant prostatic epithelium and may serve as a potential serum marker for prostate cancer.

Zinc alpha-2-glycoprotein (ZAG) is a M(r) 41,000 glycoprotein secreted by a variety of normal epithelia. ZAG was recently shown to stimulate lipolysis in adipocytes, leading to the development of cachexia in animals with ZAG-producing tumors. To understand the possible contribution of ZAG to the development of cachexia in men with prostate cancer, ZAG production by normal and malignant prostate tissue was investigated using immunohistochemical assays. Anti-ZAG monoclonal antibodies reacted strongly with normal prostate epithelium but not with other components of prostate or seminal vesicles. The majority of prostate cancers tested (35 of 48; 73%) also reacted with anti-ZAG antibodies. High-grade tumors expressed significantly less ZAG than moderate-grade tumors (mean ZAG score 1.1 versus 1.9; P < 0.01). Men with ZAG-producing prostate carcinomas had elevated levels of serum ZAG relative to their normal age- and race-matched controls (P < 0.02). Furthermore, s.c. growth of human ZAG-producing murine tumors in syngeneic mice and orthotopic growth of ZAG-producing human prostate carcinomas in nude rats resulted in readily detectable levels of human ZAG in the serum. Taken together, these studies show that ZAG production by prostate cancer can lead to systemically elevated serum ZAG levels that may be useful diagnostically. The effects of elevated systemic ZAG on cachexia-associated complications in patients with advanced prostate cancer deserves additional investigation.

Aged↗