Gösta Svaninger

Are cytokines possible mediators of cancer cachexia

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

Increased urinary excretion of cortisol and catecholami-NES in malnourished cancer patients.

Excretion of cortisol and catecholamines were measured from 24-hour urine samples collected over a period of 3 days from hospitalized cancer patients suffering from malnutrition and were compared with those of control patients equally malnourished and having a similar degree of inflammation. Compared with control patients, cancer patients had a higher excretion of cortisol, adrenaline, and noradrenaline, although noradrenaline excretion reached statistical significance only when normalized to creatinine excretion. Plasma glycerol concentrations after an overnight fast were significantly higher in cancer patients as compared with control patients, in keeping with an increased adrenal and adrenergic activity. This study demonstrates evidence of simultaneously elevated catecholamine and cortisol excretion in cancer patients, which could not be ascribed to alteration in body composition. The results may, in part, explain the mechanisms behind ongoing tissue breakdown in progressive cancer disease.

Thermic effect and substrate oxidation in response to intravenous nutrition in cancer patients who lose weight.

This study examined oxidative metabolism and thermogenesis in the acute response to controlled intravenous nutrition in seven cancer patients who lost weight. Six weight-losing and malnourished patients without cancer served as controls. Indirect calorimetry was used and measurements of arterial concentrations of various substrates, metabolic end products, and insulin were performed. Resting energy expenditure (REE) was measured after an overnight fast. The resting energy need was calculated for each patient according to REE. The nutrition program consisted of glucose and lipids (Intralipid KabiVitrum AB, Stockholm, Sweden) each as 50% of nonprotein calories and amino acids (6.9 mg N/kcal). These substrates were infused simultaneously at rates equivalent to one, two, and three times REE, over periods of 6.5 hours on 3 consecutive days after a 12-hour fast. Arterial substrate levels and energy expenditure were measured between 6 and 6.5 hours after the start of the infusion. The cancer patients had well-recognized metabolic changes in the fasted state, such as elevated plasma levels of glycerol, triglycerides, free fatty acids, and lactate, and higher energy expenditure than predicted. The cancer patients responded to strictly defined substrate challenge in a similar way as the malnourished patients without cancer. Whole body oxidative capacity and the proportion of infused glucose and lipids that were oxidized at different levels of infusion rates were not decreased in cancer patients compared with control patients. Similar arterial substrate concentrations among the groups during infusions argues for a maintained plasma clearance of the substrate in the cancer patients. This study supports the suggestion that cachectic cancer patients can generate and conserve energy normally in response to intravenous nutrition. This refers to cancer patients with a history of weight loss up to 15% of their normal body weight. Therefore, weight loss due to altered tumor-host metabolism in cancer patients is of quantitative importance in the fasted state rather than in the fed state.

Thyroid Hormones in Conditions of Chronic Malnutrition: A Study with Special Reference to Cancer Cachexia

Circulating levels of thyroid hormones (T4, free T4, T3) and reverse tri-iodo thyronine (rT3) and thyroid-hormone binding globulin were related to the nutritional state of patients with cancer cachexia, patients with malnutrition due to other reasons and to well-nourished patients with acute illness. Hospitalized weight-stable and well-nourished patients served as controls. Malnourished patients with or without cancer and acutely ill patients had a low T3 syndrome involving both peripheral metabolism of thyroid hormones and the hypothalamus-pituitary-thyroid gland axis. T3 levels were correlated to altered protein metabolism and protein nutritional state. There were pronounced elevations of circulating rT3 concentrations in patients with serum albumin concentration less than 35 g/l irrespective of diagnosis. The results indicate that the low T3 syndrome in our patients is secondary to insufficient caloric intake. It seems to be maintained by the abnormal nutritional state and is related closely to protein metabolism. The authors found no differences between the low T3 syndrome in cancer patients suffering from cachexia compared with that of patients with malnutrition caused by other factors.

The cause of death in non-metastasizing sarcoma-bearing mice: A study with relevance for tumor treatment experiments in mice

Adult sarcoma-bearing mice were used to demonstrate whether hypoglycemia was the immediate cause of death in experimental animals with rapidly growing tumors without metastases. This kind of tumor model is representative of the majority of animal models used in experimental cancer research. Tumor-bearing animals died with severe hypoglycemia under all experimental conditions, while pair-killed controls were normoglycemic. Anorexia prevented tumor-bearing animals from attenuating the hypoglycemia by drinking glucose-containing water while completely starved control animals survived more than 14 days with glucose-containing water as the only energy source. Adrenalectomy shortened survival in tumor-bearing animals, but survival of adrenalectomized tumor-bearing animals could be normalized by daily injections of pharmacologic doses of hydrocortisone (25 mg/25 g body wt/day) but not by physiologic replacement (20 micrograms/25 g body wt/day). Injections of pharmacologic doses of hydrocortisone did not influence on survival or body composition in tumor-bearing animals with intact adrenals. Glucagon was without effect on either survival, tumor growth or body composition. Based on the results in this study and in our previous reports we conclude that hypoglycemia is the cause of death in the majority of murine tumor models. This hypoglycemic theory is important, since any treatment modality in animal experiments that influences glucose metabolism in the host may indirectly change tumor growth and may thus be misinterpreted as a direct tumor effect.

The effect of clenbuterol on body composition in spontaneously eating tumour-bearing mice

The aim of this study was to investigate the effect of a selective β2-adrenoceptor agonist, clenbuterol, on body composition in tumour-bearing adult and growing mice. Therefore, adult female C57/BL6 mice (n=20) were inoculated subcutaneously with a 3-methylcholanthrene-induced sarcoma and divided into two identical groups. One group received injections twice a day of clenbuterol corresponding to 1 mg/kg body weight, the other group received sham injections. Growing mice (n=20) were similarly divided after tumour inoculation into one study group with clenbuterol injections and one control group. The growing animals were sacrificed on day 11 after commencement of treatment, the adult mice on day 16.Clenbuterol treatment had no statistically significant effect on accumulated food intake or body composition in the adult mice. However, fooe intake in these animals increased numerically compared to control animals after day 12 of the study. Tumour growth was also unaffected. The growing animals displayed an increased carcass dry weight with borderline significance (p=0.06) and an increased quadriceps muscle fat free dry weight after clenbuterol treatment. Tumour growth was not affected. Food intake measured on a daily basis was significantly increased in the growing clenbuterol treated animals and accumulated food intake was increased with a trend towards statistical significance (p=0.06). The results support the suggestion that treatment with a selective β2-adrenoceptor agonist does not improve body composition in tumour-bearing adult mice relying on spontaneous food intake while growing animals may benefit from such treatment.