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Anorexia-cachexia syndrome [ 1 ] and lipodystrophy [ 2 ] [ 6 ] are two conditions frequently associated with the course of HIV infection. Under many circumstances, they can be included as components of a single disease, multifactorial in origin, leading to alterations of energetic metabolism and to body fat tissue modifications. The risk for the clinician is of only partially considering the two diseases, for which, until recently, a true definition [ 3 ] was lacking. The approach to therapy, due to the multifactorial origin, must be multidisciplinary, involving experts in nutrition, infectious diseases, physiology, gastroenterology, etc.

Cancer cachexia is one of the worst effects of malignancy, accounting for nearly a third of cancer deaths. It is a pathological state characterised by weight loss together with anorexia, weakness, anaemia, and asthaenia. The complications associated with the appearance of the cachectic syndrome affect both the physiological and biochemical balance of the patient and influence the efficiency of anticancer treatment, resulting in a considerably decreased survival time. At the metabolic level, cachexia is associated with loss of body lipid stores. Alterations in lipid metabolism are partially mediated by changes in circulating hormone concentrations (insulin, glucagon, and glucocorticoids, in particular) or in their effectiveness. However, a large number of observations point towards cytokines, polypeptides released mainly by immune cells, as the molecules responsible for the above-mentioned metabolic derangements. The role of humoral factors in fat metabolism in the cancer patient has been discussed; among cytokines, tumour necrosis factor-α (TNF-α) seems to have a key role in the lipid metabolic changes associated with cancer cachexia.

The cachectic syndrome, characterised by marked weight loss, anorexia, asthaenia, and anaemia, is invariably associated with the presence and growth of the tumour and leads to a malnutrition status due to the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host leads to an accelerated starvation state that promotes severe metabolic disturbances in the host, including hypermetabolism, which leads to decreased energetic efficiency. Although the search for the cachectic factor(s) started a long time ago, and although many scientific and economic efforts have been devoted to its discovery, we are still far from a complete understanding of cancer cachexia. The chapter discusses the different signalling pathways, particularly the role of transcriptional factors, involved in muscle wasting. The main aim is to summarise and evaluate the different molecular mechanisms and catabolic mediators (both humoral and tumoural) involved in cancer cachexia, since they may represent targets for promising future clinical investigations.

Cancer-related anorexia-cachexia syndrome (CACS) may result from circulating factors produced by the tumour or by the host immune system in response to the tumour, such as cytokines released by lymphocytes and/or monocyte/ macrophages. A number of proinflammatory cytokines, including interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, interferon (IFN)α and IFN-γ, have been implicated in the pathogenesis of cachexia associated with human cancer. TNF-α was first identified by Rouzer and Cerami [ 1 ] as a specific circulating mediator of the wasting resulting from a chronic experimental infectious disease. It was named cachectin and was subsequently found to be identical to TNF-α. However, data from numerous clinical and laboratory studies suggest that the action of cytokines, although important, may not alone explain the complex mechanism of CACS [ 2 ] [ 5 ]. IL-1 and TNF-α have been proposed as mediators of the host’s response to inflammation [ 6 ].

Progressive atrophy of skeletal muscle in cancer cachexia leads to reduced power output and weakness (asthenia), resulting in reduced physical activity and a lower quality of life of the cancer patient. Eventually, loss of respiratory muscle becomes so extensive that function becomes significantly impaired, resulting in death through hypostatic pneumonia. Death normally occurs when patients have lost about 35% of their ideal body weight.

During disease, a formidable biological fight occurs between invading cells and the defending host.As a consequence, both sides use all the available weapons to succeed: invaders will try to shut off the host defence systems while the host will try to isolate and destroy the invaders. Metabolic perturbations inevitably develop and, if the challenge is prolonged over time, changes in body composition occur. Thus, cachexia could be considered as ‘collateral damage’ in the fight between invading cells and the defending host.

Weight loss is frequently seen in patients with advanced cancer and has long been recognised to be associated with decreased survival [ 1 ]. Cancer cachexia is a complex syndrome depending on cytokines, eicosanoids, and classical hormones, and characterised by progressive weight loss with depletion of host reserves of skeletal muscle and adipose tissue. It is the net result of profound metabolic changes that appear in patients with advanced stages of cancer, and is characterised by net breakdown of skeletal muscle and alterations in fat and carbohydrate metabolism. Cachexia is the most common paraneoplastic syndrome, and is also referred to as the cancer anorexia-cachexia syndrome, with features of anorexia, early satiety, weakness, and fatigue.

Cancer cachexia (CC) is probably the most debilitating and life-threatening paraneoplastic syndrome. It is characterised by weight loss, anorexia, asthaenia, loss of skeletal muscle protein, depletion of lipid stores, and severe metabolic alterations. CC syndrome is present in about 50% of cancer patients, especially those with tumours of the gastrointestinal tract and lung, and less frequently in those with haematological malignancies and other solid neoplasms, such as breast and thyroid cancer. The majority of terminally ill cancer patients experiences CC, which accounts for about 20% of cancer deaths. This figure translates into approximately 2000000 deaths per year worldwide [ 1 ].

Approximately 80% of patients with advanced-stage cancer have cancer anorexia-cachexia syndrome (CACS), in which one of the main manifestations is malnutrition [ 1 ]. CACS is characterised by anorexia, decreased food intake, tissue wasting, and body weight loss. It is also associated with changes in lipid, protein, and carbohydrate metabolism, leading to a decrease in fat and muscle mass, which independently influence mortality in cancer patients [ 2 ] [ 5 ]. Anorexia and reduced food intake occur during growth of the tumour, thus compromising host defences which, in turn, detrimentally influences outcome [ 1 ]. Reduced food intake and malabsorption reduce energy intake, even though energy expenditure is increased [ 6 ] [ 8 ].

A number of novel pathways and mediators controlling food intake, body weight, and energy expenditure have been identified using molecular and genetic techniques [ 1 , 2 ]. It is now accepted that body weight is regulated by a feedback loop, in which peripheral signals from the gut, liver, and fat provide nutritional information via hormones and afferent vagal input to integrated centres in the brainstem and the hypothalamus. At these sites, monoaminergic and peptidergic neurons interact to integrate and transduce the incoming signals, thereby modulating food intake [ 2 ]. In this type of regulation, orexigenic and anorexigenic neuromediators are in a constant balance to maintain homeostasis. In several clinical diseases, ranging from inflammatory conditions such as obesity to cancer, an imbalance among these neuromediators occurs, leading, respectively, to either hyperphagia, with an increase in food intake, or to anorexia, with a decrease in food intake [ 3 , 4 ].