Metabolic substrate utilization by tumour and host tissues in cancer cachexia

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SummaryThe effect of a proteolysis-inducing factor (PIF), produced by cachexia-inducing tumours on glucose utilization by different tissues and the effect of pretreatment with the polyunsaturated fatty acid eicosapentaenoic acid (EPA), has been determined using the 2-deoxyglucose tracer technique. Mice receiving PIF showed a profound depression of body weight (2.3 g) over a 24-h period, which was completely abolished by pretreatment with a monoclonal antibody to PIF or by 3 days pretreatment with EPA at 500 mg kg -1 . Animals receiving PIF exhibited a marked hypoglycaemia, which was effectively reversed by both antibody and EPA pretreatment. There was an increase in glucose utilization by brain, heart and brown fat, but a decrease by kidney, white fat, diaphragm and gastrocnemius muscle after administration of PIF. Changes in organ glucose consumption were attenuated by either monoclonal antibody, EPA, or both. There was a decrease in 2-deoxyglucose uptake by C 2 C 12 myoblasts in vitro, which was attenuated by EPA. This suggests a direct effect of PIF on glucose uptake by skeletal muscle. These results suggest that in addition to a direct catabolic effect on skeletal muscle PIF has a profound effect on glucose utilization during cachexia.

Section: contrasting

confidence: 46%

Effect of a cachectic factor on carbohydrate metabolism and attenuation by eicosapentaenoic acid

Hussey

Tisdale

1999

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“…Although tumour metabolism is almost exclusively glycolytic, lipids are utilised by the host to provide carbohydrates to the tumour (Mulligan & Tisdale, 1991). Despite similar tumoural composition and mass in young and adult rats, the deficit of reserve lipids in tumour-bearing rats was higher in adult than in young rats.…”

Section: Discussionmentioning

confidence: 98%

Body protein and lipid deficit in tumour-bearing rats in relation to age

Oudart¹,

Heitz²,

Bnouham³

et al. 1993

Summary Cancer cachexia is among the most dramatic situations of depletion in body energy reserves. To ascertain whether the pattern of body composition alteration during tumour development is influenced by aging as in uncomplicated starvation, we compared the difference of body composition between Yoshida sarcoma bearing rats and young (200 g, 7 weeks) and adult (400 g, 13 weeks) control rats. After the same duration of tumour bearing, mass and composition of tumours were similar in adult and young rats, indicating that they are independent of host age. Food intake decreased to a remarkably similar value in both young and adults. Body water content was elevated in hosts of both ages. The relative deficit of body lipid vs controls was similar for both, the absolute lipid deficit being therefore larger in adult than in young tumour-bearing rats (14.3 ± 4.4 g vs 6.8 ± 0.9 g; P<0.01). In contrast, there was a relatively larger deficit of body protein in young rats. Paradoxically, these rats still maintained a positive nitrogen balance whereas this balance was negative in adult tumour-bearing rats. In conclusion, as previously shown in uncomplicated undernutrition, the anorexia induced by Yoshida sarcoma development is still associated with some protein accretion in young rats whereas cachexia develops in adults.Cachexia, a wasting of the host reserves, is a common feature in tumour-bearing animals (Rechcigl et al., 1961) and humans (Costa, 1977). It is a major factor of mortality in cancer patients (Warren, 1932). Cancer cachexia is characterised by anorexia and depletion of lipid and proteins of the host (Mider et al., 1948;Rechcigl et al., 1961;Lundholm, 1986). However, the anorexia accompanying cancer cachexia is not entirely responsible for the concomitant metabolic alterations, since pair-fed rats show a better body mass conservation than tumour-bearing rats (Lundholm et al., 1980;Tisdale, 1991). Although cytokines seem to play a major role in the wasting of host reserves (Tracey, 1992), the reason for the depletion of lipid and protein reserves has not been totally elucidated.During starvation, another situation in which body fuel reserves are depleted, the age of rats plays a major role in the mobilisation of lipid and protein reserves, through the initial availability in body lipids (Goodman et al., 1980). Similarly, the changes in body protein and lipid during underfeeding differ between young and adult rats (Widdowson & McCance, 1956). In tumour-bearing rats, total starvation increases tumour growth rate in adult, not in immature rats (Sauer et al., 1986). Thus, one possible way to investigate how body fuel reserves of the host are depleted during tumour bearing and how they influence the tumour growth is to compare rats of different ages.As a first approach, we studied the protein and lipid deficit of the host after the same duration of tumour development in young (200 g, 7 weeks old) and adult rats (400 g, 13 weeks old).

“…This increased use of amino acids for gluconeogenesis would lead to catabolism of muscle proteins as observed with this tumour model (Beck & Tisdale, 1987). The difference in ability to maintain blood glucose levels in animals bearing the MAC16 and MAC13 tumours appears to be unrelated either to food intake or the glucose consumption by the tumour cells, since glucose utilisation by the MAC13 tumour has been shown to be significantly higher than by the MAC16 tumour (Mulligan & Tisdale, 1991). McFadzean and Yeung (1969) were able to separate two types of hypoglycaemia in patients with hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 88%

“…We have recently reported studies on glucose utilisation by tumour and host tissues in NMRI mice bearing the MAC16 colon adenocarcinoma, which is capable of inducing cachexia in recipient animals (Mulligan & Tisdale, 1991). Glucose consumption by the tumour was second only to brain and the increased demand for glucose was met by a decrease in glucose utilisation by host organs and in particular the brain.…”

Section: Discussionmentioning

confidence: 99%

“…The architecture of solid tumours also plays an important role in determining the metabolic substrate for energy production. Large solid tumours tend to have a poor blood supply, and consequently become hypoxic, in which case glucose will become the predominant metabolic substrate, since the Embden-Meyerhof pathway is the only means of ATP production in the absence of oxygen.We have recently reported studies on glucose utilisation by tumour and host tissues in NMRI mice bearing the MAC16 colon adenocarcinoma, which is capable of inducing cachexia in recipient animals (Mulligan & Tisdale, 1991). Glucose consumption by the tumour was second only to brain and the increased demand for glucose was met by a decrease in glucose utilisation by host organs and in particular the brain.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Tumour-associated hypoglycaemia in a murine cachexia model

Tisdale²

1992

SummaryAnimals bearing a cachexia-inducing tumour, the MAC16 adenocarcinoma, showed a progressive decrease in blood glucose levels with increasing weight loss, while animals bearing a histologically similar tumour, the MAC13 adenocarcinoma, showed no change in either body weight or blood glucose levels with growth of the tumour. The effect of the MAC16 tumour on blood glucose levels appeared to be unrelated to food intake, glucose consumption by the tumour, or to the production of increased levels of IGF-I and IGF-II mRNA by the tumour cells. The relationship between the induction of cachexia and alteration in blood glucose levels remains unknown.A high rate of glucose consumption under both anaerobic and aerobic conditions is a characteristic feature of both experimental (Weber et al., 1961;Weber, 1977) and human tumours (Nolop et al., 1987). Alterations in glucose metabolism in tumour cells are associated with an increased intracellular concentration of glucose, which is tightly coupled with an over-expression of facilitative glucose transporter genes (Yamamoto et al., 1990), an increased transcription of the hexokinase gene (Johansson et al., 1985), as well as alterations in isoenzyme profiles of the enzymes involved in glycolysis (Weber et al., 1961). The enhanced glucose transport is not insulin-dependent, since hypoglycaemia often develops in both tumour-bearing animals (Bibby et al., 1987) and cancer patients (Heber et al., 1985) with normal or even decreased blood insulin levels. The architecture of solid tumours also plays an important role in determining the metabolic substrate for energy production. Large solid tumours tend to have a poor blood supply, and consequently become hypoxic, in which case glucose will become the predominant metabolic substrate, since the Embden-Meyerhof pathway is the only means of ATP production in the absence of oxygen.We have recently reported studies on glucose utilisation by tumour and host tissues in NMRI mice bearing the MAC16 colon adenocarcinoma, which is capable of inducing cachexia in recipient animals (Mulligan & Tisdale, 1991). Glucose consumption by the tumour was second only to brain and the increased demand for glucose was met by a decrease in glucose utilisation by host organs and in particular the brain. This study further investigates changes in blood glucose levels and the possible role of insulin-like growth factors (IGF) in the MAC16 model. Since antibodies to both mouse IGFI and IGFII were not readily available, we have chosen to measure their production in the MAC16 tumour indirectly, through the study of gene expression. Materials and methodsPure strain NMRI mice were bred in our own colony and were fed on a rat and mouse breeding diet (Pilsbury, Birmingham, UK) and water ad libitum. Fragments (1 x 2 mm) of either the MAC16 or MAC13 tumour were implanted into the flank of male NMRI mice (starting weight 28 g) by means of a trocar as described (Bibby et al., 1987