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Introduction

Debilitating weight-loss in cancer patients is part a syndrome known as cancer cachexia (CC), characterized by disease-induced starvation and wasting. Although there is no universally accepted definition of CC, clinical signs include progressive body weight loss, generalized wasting, immunosuppression, abnormalities in fluid and energy metabolism, anorexia, metabolic alterations, asthenia, depletion of lipid stores and severe loss of adipose tissue and skeletal muscle.[Giacosa 1994] Hence, CC is a multifactorial paraneoplastic syndrome, significantly impairing quality of life (QOL) response to anti-neoplastic therapies, hence increasing surgical, morbidity and mortality risk.[DeWys et al.,1980] The word “cachexia" comes from the Greek words "kakos" and "hexis", meaning "bad conditions", and affects about 50% of cancer patients, accounting for at least 20% of deaths.[Tisdale, 1997] The aetiology of this complex metabolic derangement is not entirely understood and can manifest in cancer patients with both metastatic and localized disease. CC is a common secondary diagnosis in patients with neoplastic disease and is a variant of protein-energy malnutrition (PEM).[Giacosa 1994]

CC is suspected if involuntary weight loss of greater than five percent of premorbid weight occurs within a six-month period.[Inui, 2002] 10% weight loss (from pre-illness weight) is often considered to be severe, hence the rate of weight loss is seen as of primary importance in the definition of CC. Categories of severe weight loss have been defined as more than 2% in one week, 5% in one month and 10% in six months.[Blackburn et al., 1977] Abnormalities in carbohydrate, fat, protein and energy metabolism, lead to weakness, lethargy, malaise, depression and the loss of skeletal muscle and adipose tissue.[Jaskowiak & Alexander, 1998] Patients have a ‘starved’ or ‘cachetic’ appearance and are often described as "looking ill”.[Lindsey, 1986] CC is particularly associated with solid cancer tumours of the stomach, lung and pancreas. [Lindgvist  et al., 2004]

Pathogenesis

The possible causes of CC appear to be multifactorial and will be examined in the following paragraphs. The following interrelated categories appear to be of major scientific interest and include: (1) Anorexia and reduced food intake; (2) Consequences of cancer treatment induced toxicity; (3) Mechanical obstruction of the cancer tumour itself; (4) Release of endogenous transmitter substances or products of tumours; (5) Alterations in energy and substrate metabolism in the host; (6) Protein energy malnutrition (PEM); (7) Accelerated fat and muscle loss; (8) Cytokine activity.

Reduced Food Intake Causes

Cancer can lead to a substantial reduction in nutrient intake, which certainly contributes to weight loss.[Laviano et al., 2003] Insufficient energy and protein availability may be the consequence of anti-neoplastic treatments and include mechanical obstruction in the gastrointestinal tract, mucositis, malaise, taste alterations, vomiting, malabsorption, pain, depression or the patient’s inability to self-administer food due to cancer or age.[Laviano et al., 2004] In addition, an abdominal tumour mass may cause motility disturbances, contributing to nausea and vomiting and therefore to reduced nutrient intake. In addition, previous surgery may affect the digestive capacity. Pancreatic as well as gastric resections can result in pancreatic exocrine and endocrine insufficiency, causing major nutrition problems such as steatorrhoea and hyperglycaemia. Extensive resection of the small bowel can lead to malabsorption, whereas small resections of the bowel usually do not lead to major nutrition problems.[Capra et al., 2004]

Cancer Anorexia

An important role is also played by anorexia, which is the decreased desire to eat, hence contributing to weight-loss in CC. Anorexia is frequently seen in head and neck, oesophageal and gastric malignancies, due to primary dysphagia. However, due to the multifactorial pathogenesis of cancer, anorexia may be associated with disturbances of the central physiological mechanisms controlling food intake. Under normal conditions, energy intake is controlled by the hypothalamus where peripheral signals convey information on energy and adiposity[King et al., 2000] status. The arcuate nucleus in the hypothalamus contains specific neuronal populations that transduce these inputs into neuronal responses, and via second-order neuronal signalling pathways, into behavioural responses. Cancer anorexia might be secondary to defective signals arising from the periphery, due to an error in the transduction process or a disturbance in the activity of the second-order neuronal signalling pathways.[Laviano et al., 2002]

Several factors are considered to be putative mediators of cancer anorexia, including hormones (e.g. ghrelin, cholecystokinin (CKK), insulin, leptin) neuropeptides (e.g. neuropeptide Y), cytokines (e.g. interleukin 1 (IL-1) and 6 (IL-6), tumour necrosis factor alpha (TNF-a), interferon-γ (IF-γ), and neurotransmitters such as serotonin and dopamine. These pathways are not isolated and are distinct pathogenic mechanisms, however they are closely inter-related.[Laviano et al., 2002] Some evidence suggests that cytokines have a vital role, triggering the complex neurochemical cascade, which leads to the onset of cancer anorexia and consequent weight-loss. Increased expression of cytokines during tumour growth prevents the hypothalamus from responding appropriately to peripheral signals, by persistently activating anorexigenic systems and inhibiting prophagic pathways. Hypothalamic monoaminergic neurotransmission may contribute to these effects.[Plata-Salaman, 2000]

Because of their central role in energy homeostasis a number of studies investigated the role of the prophagic (orexigenic) signal Neuropeptide Y (NPY) in the pathogenesis of cancer anorexia. In weight-loss conditions NPY is important in stimulating hunger and hyperphagia. Leptin and insulin are capable of blocking NPY production and, vice versa increased NPY decreases leptin and insulin production.[Sato et al., 2002] Next to orexigenic also anorexigenic signals are involved in energy homeostasis. The hypothalamic anorexigenic neuropeptides melanocortin, CFR and α-MSH, a product of pro-opiomelanocortin, have a role in normal control of food intake.[Wisse et al., 2003] α-MSH induces anorexia by activating the receptors MC3R and MC4R, which are both expressed in the hypothalamus and other brain regions. In experimental cancer model CC was ameliorated by central MC4R blockade.[Marks et al., 2001] The inability of the hypothalamus to respond appropriately to consistent peripheral signals in cancer anorexia seems to be related to the central effect of cytokines.[Mantovani et al., 1997] However, increasing food consumption alone is not always capable of reversing the cachectic process, but this is still an active area of research.

Alteration of Energy and Substrate Metabolism

The resting energy expenditure (REE) in cancer varies, as some patients show hypermetabolism. In addition, the competition for nutrients between the tumour and the host leads to an accelerated starvation state, which promotes severe metabolic disturbances in the host, including hypermetabolism, which leads to an increased energetic inefficiency. However, others patients show hypometabolism.[Dempsey et al. 1996] It appears that in patients with cachexia and asthenia, total energy expenditure is reduced as a consequence of reduced physical activity and the body’s adaptation to conserve energy and preserve body tissue.[Falconer et al., 1994] The difference in findings is most likely a result of the stages of illness, nutritional status among patients as well as differing methods used to measure individuals with cancer.

Energy metabolism is intimately related to carbohydrate, protein and lipid metabolism, all of which are altered by the tumour growth. Tumours exert consistent demand for glucose and neoplastic cells exhibit a high yield of anaerobic metabolism, yielding lactate as the end product. This expanded lactic acid pool requires an increased rate of host gluconeogenesis via Cori cycle activity, which is increased in some patients but not in others.[Muscaritoli et al., 2006] Protein breakdown and lipolysis take place at increasing rates to maintain high rates of glucose synthesis. Insulin resistance, glucose intolerance, increased gluconeogenesis, from amino acids and lactate, increased fat oxidation and reduced lipogenesis characterize the disturbance of energy substrate metabolism.[Puccio & Nathanson, 1997] Alterations in protein metabolism appear to be directed toward providing adequate amino acids for tumour growth. Most notable is the loss of skeletal muscle protein due to increased skeletal muscle synthesis, which is discussed further under section ‘muscle wasting’. However, visceral organ atrophy and hypoalbuminaemia also occur due to increased total body water associated with CC, which is more pronounced than the increase in albumin synthesis.[Fearon et al, 1998] Further protein metabolism abnormalities include inappropriate elevations in whole-body protein turnover, increased catabolism and liver protein synthesis. These changes occur in the presence of reduced nitrogen intake, thus suggesting inability to adapt to diminished protein intake by reducing protein turnover.[Langstein & Norton, 1991]

Lipid metabolism is altered, as evidenced by inappropriate mobilization of free fatty acids from adipose tissue and subsequent depletion of total body fat: 30% of total body weight loss is equivalent to 85% of fat mass loss and mainly due to enhanced lipid mobilization, decreased lipogenesis and activity of lipoprotein lipase, the enzyme responsible for triglycerides clearance from plasma.[Fearon, 1992] Lipoprotein lipase inhibition, a consequence of cytokine action, would prevent adipocytes from extracting fatty acids from plasma proteins for storage. The lipid mobilization seems to be secondary to the action of a tumour catabolic factor called lipid mobilizing factor (LMF). LMF acts directly on adipose tissue with the release of free fatty acids (FFA) and glycerol, through elevation of the intracellular mediator cyclic AMP.[Tisdale, 2003]  LMF has been found in the urine of cancer patients.[Hirai et al., 1998] Hence, LMF production by cachexia-inducing tumours may cause loss of body fat and an increase in energy expenditure.[Todorov et al., 1998]

Muscle Wasting

Metabolically, CC is mainly characterized by the degradation of muscle protein, with a simultaneous increase in visceral protein synthesis. There are three metabolic pathways responsible for the catabolism of skeletal muscle protein: the liposomal system, concerned with the proteolysis of extracellular proteins and cell surface receptors and the cytosolic calcium-activated system, involved in tissue injury, necrosis, and autolysis. These two pathways are responsible for about 20% of protein degradation. The ATP-ubiquitin-dependent pathway appears to be responsible for the accelerated proteolysis in a variety of wasting conditions including CC.[Tisdale, 2001] In CC ubiquitin is bound covalently to the protein substrate, which acts as a signal for degradation by the multisubunit proteasome. This process requires ATP and might contribute to the elevated daily energy expenditure observed in CC. It appears that the major effect for the catabolism of skeletal muscle protein is due to the ubiquitin-proteasome mechanism, mainly targeting muscle fibrils.[Wyke & Tisdale, 2005]

Upregulation of components of the ATP-ubiquitin-dependent pathway has been reported in experimental models of wasting conditions including cancer.[Costello & Baccino, 2003] Recent studies have shown that in muscle biopsies obtained preoperatively in 20 patients undergoing surgery for gastric cancer ubiquitin, mRNA expression was markedly and significantly increased[Costelli et al., 2002] as well as proteasome activity.[Bossola et al., 2003] Three intracytoplasmic ubiquitin-ligating enzymes, namely E3α and ligases encoded by the genes MURF-1 (muscle ring finger protein 1) and MAFbx (muscle atrophy F-box protein, also called Atrogin-1), play a key role in the onset of muscle atrophy.[Bodine et al., 2001] Reports on TNF-α, IL-1, IL-6 or interferon-γ, in relation to ubiquitin production appear to be conflicting. Although both TNF-α and IL-6 increase the production of ubiquitin, sole addition to muscle cells in vitro do not lead to increased proteolysis[Lecker et al., 2004]

Impaired anabolic response or an over-expression of negative regulators (i.e. myostatin) of skeletal muscle growth, are also important in the onset of muscle loss in CC. Myo-D is a member of a skeletal muscle-specific family of transcription factors, known as myogenic regulatory factors (MRFs), that play a determinant role in myogenesis in cooperation with other transcriptional modulators of the MEF2 family.[Guttridge et al., 2000] Myo-D induction is crucial for the muscle regenerative programme, which is activated after injury based on satellite cells. Recently, MyoD protein down-regulation has been documented in an experimental model of CC, supporting the hypothesis that Myo-D is implicated in the development of cancer-related muscle wasting.[Costelli et al., 2005]

Guttrigde et al., 2005 have shown, that combination of TNF-α and IFN-γ leads to post-transcriptional suppression of Myo-D and myosin expression through activation of NF-κB in myocytes. Myostatin, also known as GDF-8, belongs to the transforming growth factor-β superfamily that controls the growth and differentiation of tissues throughout the body. The myostatin gene is expressed predominantly in the skeletal muscle.[Kambadur et al., 1997] Myostatin has been proposed to act as a negative regulator of skeletal muscle mass[Szabo et al., 1998] by suppressing myoblast proliferation through the inhibition of cell cycle progression.[Gonzales-Cadavid, 2004] Systemic over-expression of the myostatin gene leads to a wasting syndrome characterized by extensive muscle loss.[Zimmers et al., 2002] Only recently, a case of a child with an extraordinary muscle mass, due to a mutation in the myostatin gene has been reported.[McCroskery et al., 2002]

Further Research on Possible Cytokine Activity in Cc

Interestingly, injections of TNF-α peripherally, or into the brain of laboratory animals, elicit rapid increases in basal metabolic rate, increased blood flow and thermogenic activity of brown adipose tissue, associated with the uncoupling protein-1 (UCP1).  During cachectic states increased thermogenesis is observed in brown adipose tissue in humans and experimental animals. Until recently, the UCP1 protein was considered to be the only mitochondrial protein carrier, stimulating heat production.[Adams, 2000] Two additional proteins sharing the same function, UCP2 and UCP3, have been described. Although the main function of those proteins is controversial, several studies have demonstrated that they could have a role similar to that of UCP1, by acting as uncouplers of oxidative phosphorylation.[Adams, 2000] Recent research suggested that UCP2 and UCP3 mRNAs may be increased in skeletal muscle during tumour growth and that TNF-α may be able to mimic the increase in gene expression[Busquets et al., 2003] contributing to weight-loss and CC.

Conclusions

Weight-loss a major symptom of CC is a common secondary diagnosis in patients with neoplastic disease and is a variant of protein-energy malnutrition (PEM). Various pathways appear to be involved in weight-loss and CC in cancer-patients, which can be grouped into the following interrelated categories to include: Insufficient energy and protein intake due to disturbances of the central physiological mechanisms controlling food intake, or due to anti-neoplastic treatments; tumours causing mechanical obstructions; surgery; malabsorption and depression. Alterations of energy and substrate metabolism, including muscle protein degradation and increased visceral protein synthesis, may contribute to substantial weight-loss. Cytokines may be involved in various pathways, including induced thermogenesis, hence contribute to weight-loss and CC. Present investigations are devoted to reveal the different signalling pathways, in particular transcriptional factors involved in muscle wasting. Although exploration of the role that cytokines play in the host response to invasive stimuli is an endeavour that has been underway for many years, considerable controversy remains over the mechanisms of lean tissue and body fat dissolution that occur in a patient with cancer or chronic inflammation and whether humoral factors regulate this process. A better understanding of the role of host and tumour-derived cytokines in interfering with the molecular mechanisms that account for protein wasting in skeletal muscle is essential for the design of future effective therapeutic strategies and no doubt future research will concentrate on this interesting field. In sum, decreased food intake is only one of many possible factors involved in weight-loss and CC in cancer patients, hence more research is required to the understanding of weight-loss mediators in cancer, for both prevention and treatment of wasting in cancer patients.

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