Cancer Cachexia

Morrison, S. D.

doi:10.1007/978-94-009-2528-1_15

Cited by 13 publications

(6 citation statements)

References 290 publications

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“…The catabolic changes observed in vivo are strongly influenced by indirect effects of TNF-a on hormones that regulate muscle growth (8)(9)(10)(11), on the expression of other cytokines (12,13), and on TNF-induced anorexia (14,15). To test for direct effects, previous investigators have incubated excised skeletal muscles with TNF-a for up to 3 h (5,(16)(17)(18).…”

Section: Hypothesis 1 Prolonged Exposure To Tnf-a Directly Stimulatementioning

confidence: 99%

“…It has long been recognized that TNF-a may stimulate catabolism via indirect mechanisms. TNF-a alters circulating levels of hormones that regulate muscle growth, including insulin, glucagon, thyroid hormone, glucocorticoids, and catecholamines (8,9,11), and affects tissue sensitivity to such factors (10). TNF-a also stimulates production of catabolic cytokines (e.g., prostaglandin E 2 and interleukin-1) (12,13) and promotes anorexia (14,15).…”

Section: Tnf-a Stimulates Protein Lossmentioning

confidence: 99%

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Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-κB activation in response to tumor necrosis factor α

Schwartz

Waddell³

et al. 1998

The FASEB Journal

423

377

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Skeletal muscle atrophy and weakness are thought to be stimulated by tumor necrosis factor alpha (TNF-alpha) in a variety of chronic diseases. However, little is known about the direct effects of TNF-alpha on differentiated skeletal muscle cells or the signaling mechanisms involved. We have tested the effects of TNF-alpha on the mouse-derived C2C12 muscle cell line and on primary cultures from rat skeletal muscle. TNF-alpha treatment of differentiated myotubes stimulated time- and concentration-dependent reductions in total protein content and loss of adult myosin heavy chain (MHCf) content; these changes were evident at low TNF-alpha concentrations (1-3 ng/ml) that did not alter muscle DNA content and were not associated with a decrease in MHCf synthesis. TNF-alpha activated binding of nuclear factor kappaB (NF-kappaB) to its targeted DNA sequence and stimulated degradation of I-kappaBalpha, an NF-kappaB inhibitory protein. TNF-alpha stimulated total ubiquitin conjugation whereas a 26S proteasome inhibitor (MG132 10-40 microM) blocked TNF-alpha activation of NF-kappaB. Catalase 1 kU/ml inhibited NF-kappaB activation by TNF-alpha; exogenous hydrogen peroxide 200 microM activated NF-kappaB and stimulated I-kappaBalpha degradation. These data demonstrate that TNF-alpha directly induces skeletal muscle protein loss, that NF-kappaB is rapidly activated by TNF-alpha in differentiated skeletal muscle cells, and that TNF-alpha/NF-kappaB signaling in skeletal muscle is regulated by endogenous reactive oxygen species.

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Section: Hypothesis 1 Prolonged Exposure To Tnf-a Directly Stimulatementioning

confidence: 99%

Section: Tnf-a Stimulates Protein Lossmentioning

confidence: 99%

Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-κB activation in response to tumor necrosis factor α

Schwartz

Waddell³

et al. 1998

The FASEB Journal

423

377

View full text Add to dashboard Cite

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“…Some of the systemic effects in cancer hosts have been ascribed to non-dialyzable circulating lipolytic and proteolytic factors produced by the tumour (Beck & Tisdale, 1987;Beck et al, 1990), which is consistent with the parabiotic transfer of cachexia reported by Norton et al (1985). High plasma levels of catabolic hormones, low levels of insulin, and insulin resistance of peripheral tissues are among the factors most commonly considered as a cause of cancer cachexia (Lawson et al, 1982;Morrison, 1989). However, it has been suggested that hormonal changes could rather reflect an adaptation to the metabolic alterations that lead to cachexia (Svaninger et al, 1987a,b,c).…”

Section: Humoral Mediatorsmentioning

confidence: 99%

“…Cachexia frequently accompanies advanced or terminal cancer states, though it can also develop early in the course of neoplastic diseases (Shapot, 1979;Lawson et al, 1982;Kern & Norton, 1988;Morrison, 1989). The underlying mechanisms are not well understood, either in humans or in experimental animals.…”

mentioning

confidence: 99%

“…Tissue protein waste implies a negative balance between anabolic and catabolic processes. In this regard hypophagia and proteincalorie malnutrition can play an important role (Kern & Norton, 1988;Morrison, 1989), yet most often parenteral or over-feeding are only transiently and partially effective in combating cancer cachexia (Theologides, 1972;Bozzetti et al, 1987). The view that protein depletion may primarily reflect enhanced protein turnover has been recently supported by both experimental (Tayek et al, 1986(Tayek et al, , 1988Tessitore et al, 1987a;Beck & Tisdale, 1989) and clinical evidence (Kien & Camitta, 1983Fearon et al, 1988;Melville et al, 1990;Beck et al, 1991).…”

mentioning

confidence: 99%

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Humoral mediation for cachexia in tumour-bearing rats

Tessitore

Costelli²,

Baccino³

1993

Br J Cancer

109

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Summary Early and severe loss of body weight associated with pronounced tissue changes developed in rats transplanted with a fast-growing ascites hepatoma (Yoshida AH-130). The protein content showed an early and marked fall in the skeletal muscle, while in the liver it transiently increased 4 days after implantation then declined to values lower than in control animals. Protein loss in gastrocnemius muscle and liver resulted mainly from enhancement of protein catabolism (Tessitore L. et al., Biochem. J., 241: 153-158, 1987). In contrast to the tumour-bearing rats, in the pair-fed animals the initial body weight was maintained, while the protein mass decreased sharply in the liver and moderately in the grastrocnemius muscle. In host animals total plasma protein decreased during the period of tumour growth, while both triglycerides and total cholesterol markedly increased. Glucose remained unchanged even when overt cachexia had developed. The total free amino acid concentration in the plasma of tumour-bearing rats decreased slightly by day 4 and returned to values close to those of controls in the late stages of tumour growth. By contrast, in the pair-fed controls the plasma levels of triglycerides and particularly of total free amino acids and glucose decreased over the whole experimental period, whereas total protein and cholesterol were unchanged. Marked perturbations in the hormonal homeostasis developed early after tumour transplantation. The plasma levels of glucagon, corticosterone and catecholamines rose sharply, while those of insulin and thyroid hormones decreased. Furthermore, high plasma concentrations of prostaglandin E2 (PGE2) and tumour necrosis factor (TNF) were observed over the whole experimental period. IL-I-like activity, TNF and PGE2 were released in vitro from AH-130 cells. These data suggest that the systemic effects of AH-130 tumour on the host rat reflected the interplay of a complex network of factors, including classical hormones and cytokines, all of which likely concur in enhancing tissue protein catabolism.

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