Metabolic Reprogramming in Adipose Tissue During Cancer Cachexia
Cachexia is a complex disorder characterised by the loss of adipose and skeletal muscle tissues leading to chronic and involuntary weight loss that cannot be fully reversed by conventional nutritional support.
Cachexia occurs in association with cancer and multiple other chronic diseases, including heart failure and kidney disease. The incidence of cachexia is particularly very high in cancer patients. About half of all cancer patients suffer from cachexia, which is the direct cause of at least 20% of all cancer deaths. Patients with pancreatic or gastric cancer have the highest frequency of weight loss at over 60-80% while the incidence of weight loss in patients with lung, colorectal or prostate cancer is above 50%. Cachexia remains as a significant risk factor for survival, as it reduces quality of life and leads to a poor response to therapies.
Cachexia ameliorates with the shrinkage of tumours and the treatment of underlying cancer to reverse cachexia is the best-thought management strategy so far. However, this method remains unsuccessful with advanced cancer types. Few anti-inflammatory drugs, mainly targeting tumour necrotic factor α (TNF-α) and interleukin-6 (IL-6), were tested clinically, and the trials yielded unsatisfactory results. Most recent therapeutic approaches target decreased appetite in cancer patients to counteract weight loss. However, treatment of malnutrition or anorexia by increasing nutritional intake has not been able to completely reverse the wasting. Cancer cachexia is still very common, treatment options are inadequate, and clinical markers are missing. Understanding the molecular and physiologic pathways involved in the aetiology of cancer cachexia is urgently needed.
At the present, cachexia is agreed to be an energy disorder, in which the peripheral energy metabolism plays a central role in elevated energy expenditure and excess catabolism with severe disruption of protein, lipid, and carbohydrate metabolism accompanied with chronic inflammation. Cancer cachexia affects multiple organs with most dramatic impacts on adipose and skeletal muscle tissues. In this review, we discuss how metabolic activities of different types of adipose tissue are altered by tumours and how this metabolic reprogramming contributes to the wasting problem.
Cancer cachexia is associated with altered adipokine secretion. While the role of adipokine dysregulation in cachexia remains unclear, cachectic patients often show altered circulating levels of adipokines, including leptin, adiponectin and resistin.
Assessment of nutritional status
Assessing nutritional status should include objective assessment of the following:
- Body weight (BW).
- Weight change during the preceding months.
- Body composition with a focus on muscle mass
- Food intake with a focus on energy and protein.
- Information regarding the presence and degree of systemic inflammation.
- Nutrition impact symptoms, such as anorexia, nausea, taste and smell alterations, mucositis, constipation, dysphagia, chronic pain, abdominal pain (e.g. cramping) and diarrhoea, as well as aspects of GI function potentially responsible for these symptoms.
- Fatigue, physical activity, shortness of breath and psychosocial distress.
While resting energy expenditure may be increased in cachexia, total energy expenditure is often normal (25-30 kcal/kg BW/day) because of corresponding reductions in physical activity, but may be unpredictably low or high in some patients. Even increased energy and protein intake may not be able to attenuate weight loss in all patients. Given the presence of anabolic resistance in older subjects and in chronic diseases, higher than normal amounts of protein (at least 1.2 and possibly up to 2 g/kg BW/day) may be required to balance protein synthesis.
Fat utilisation in weight-losing cancer patients is very efficient and may cover a major part of resting energy expenditure, whereas carbohydrate utilisation is impaired in the presence of systemic inflammation and insulin resistance. In addition, fats are energy-dense and allow for feeding of smaller volumes. Compared with standard food, an isonitrogenous, isocaloric, ketogenic diet low in carbohydrates maintains nitrogen balance and whole-body protein turnover rates.41 In a randomised controlled trial (RCT) carried out in malnourished cancer patients, a high-fat diet improved weight control, fat-free mass and body mass compared with normal food. Nutritional interventions should be accompanied by muscle training and efforts to normalise metabolic state (diminish systemic inflammation, alleviate distress).
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