Cancer cachexia

Abstract

CAUSATIVE FACTORS: Nutritional supplementation or pharmacological manipulation of appetite are unable to control the muscle atrophy seen in cancer cachexia. This suggests that tumour and/or host factors might be responsible for the depression in protein synthesis and the increase in protein degradation. An increased expression of the ubiquitin-proteasome proteolytic pathway is responsible for the increased degradation of myofibrillar proteins in skeletal muscle, and this may be due to tumour factors, such as proteolysis-inducing factor (PIF), or host factors such as tumour necrosis factor-alpha (TNF-alpha). In humans loss of adipose tissue is due to an increase in lipolysis rather than a decrease in synthesis, and this may be due to tumour factors such as lipid-mobilising factor (LMF) or TNF-alpha, both of which can increase cyclic AMP in adipocytes, leading to activation of hormone-sensitive lipase (HSL). Levels of mRNA for HSL are elevated twofold in adipose tissue of cancer patients, while there are no changes in lipoprotein lipase (LPL), involved in extraction of fatty acids from plasma lipoproteins for storage. TREATMENT FOR CACHEXIA: This has concentrated on increasing food intake, although that alone is unable to reverse the metabolic changes. Agents interfering with TNF-alpha have not been very successful to date, although more research is required in that area. The only agent tested clinically that is able to interfere with the action of PIF is eicosapentaenoic acid (EPA). EPA attenuates protein degradation in skeletal muscle by preventing the increased expression of the ubiquitin-proteasome pathway, but has no effect on protein synthesis. When used alone EPA prevents further wasting in cachectic patients, and, when it is combined with an energy- and protein-dense nutritional supplement, weight gain is seen, which is totally lean body mass. These results suggest that mechanistic studies into the causes of cancer cachexia will allow appropriate therapeutic intervention.

Adipose tissue in Walker 256 tumour-induced cachexia: possible association between decreased leptin concentration and mononuclear cell infiltration

“…Although the influence of the increased TNFα and PGE 2 plasma levels, characteristic of the tumour-bearing state (Tisdale 2004;Lieb 2001), must not be discarded, the fact that the infiltrating macrophages actively produce these factors and are present at an early stage of cachexia in the adipose tissue strongly suggests they may play a role in the decreased leptin tissue concentration, since the elevation of both circulating PGE 2 and TNFα is known to be time dependent (McCarthy 2003). The importance of local modulation of adipose tissue metabolism and function in health and disease is stressed by Pond (2001) Taken together, the results point out to a possible modulation of leptin secretion in three different adipose tissue depots of cachectic rats by factors produced by the macrophage infiltrate, which was present in all the analysed samples.…”

Possible links between behavioral and physiological indices of tiredness, fatigue, and exhaustion in advanced cancer

“…Tisdale [68] estimated that muscle wasting occurs in approximately 50% of all cancer patients. Most of this wasting occurs in skeletal muscle, appears to be due to accelerated muscle protein degradation, and is unresponsive to supplementary feeding [69]. This wasting is attributed in large part to the actions of a number of cytokines including TNF-α, IL-1, IL-6, and IFN-γ [3].…”

Molecular and neuroendocrine mechanisms of cancer cachexia

“…Importantly, TNF inhibits lipoprotein lipase activity (Price et al 1986), and increases HSL mRNA expression (Tisdale 2004, Agustsson et al 2007. Additionally, TNF has been shown to inhibit glucose transport, by reducing glucose transporter 4 protein and mRNA levels, decreasing substrates for lipogenesis (Hauner et al 1995).…”