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Cancer Cachexia and Related Metabolic Dysfunction.
Fonseca, GWPD, Farkas, J, Dora, E, von Haehling, S, Lainscak, M
International journal of molecular sciences. 2020;(7)
Abstract
Cancer cachexia is a complex multifactorial syndrome marked by a continuous depletion of skeletal muscle mass associated, in some cases, with a reduction in fat mass. It is irreversible by nutritional support alone and affects up to 74% of patients with cancer-dependent on the underlying type of cancer-and is associated with physical function impairment, reduced response to cancer-related therapy, and higher mortality. Organs, like muscle, adipose tissue, and liver, play an important role in the progression of cancer cachexia by exacerbating the pro- and anti-inflammatory response initially activated by the tumor and the immune system of the host. Moreover, this metabolic dysfunction is produced by alterations in glucose, lipids, and protein metabolism that, when maintained chronically, may lead to the loss of skeletal muscle and adipose tissue. Although a couple of drugs have yielded positive results in increasing lean body mass with limited impact on physical function, a single therapy has not lead to effective treatment of this condition. Therefore, a multimodal intervention, including pharmacological agents, nutritional support, and physical exercise, may be a reasonable approach for future studies to better understand and prevent the wasting of body compartments in patients with cancer cachexia.
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2.
The role of a disturbed arginine/NO metabolism in the onset of cancer cachexia: a working hypothesis.
Buijs, N, Luttikhold, J, Houdijk, AP, van Leeuwen, PA
Current medicinal chemistry. 2012;(31):5278-86
Abstract
Cancer cachexia is a complex catabolic state in patients with a malignancy, associated with increased morbidity and mortality. This syndrome is characterized by a redistribution of the body's protein content and a subsequent muscle wasting. The aetiology of this syndrome seems multifactorial, but remains unclear. It is suggested that this catabolic state occurs in response to the alterations in immune interactions between tumor and host. The amino acid arginine and its derivate nitric oxide (NO) play various roles in anti-tumor immune response and the body's homeostasis. Glutamine is the precursor for arginine de novo synthesis and the most abundant amino acid in the body, mainly stored in skeletal muscle. Tumors develop a protection mechanism against the specific anti-tumor attack of the immune system by recruiting myeloid derived suppressor cells (MDSC). The MDSC deplete arginine levels and disturb NO production. We here hypothesize that the perturbation of the arginine/NO metabolism plays a significant role in the aetiology of cancer cachexia. Arginine/ NO metabolism is disturbed in patients with cancer. The body will try to correct this perturbation by mobilizing arginine and glutamine from muscles. The decreased arginine levels and the disturbed NO production activate several cascades, which in turn inhibit protein synthesis and promote proteolysis, leading to cachexia. Cachexia remains one of the most frequent and damaging opportunistic syndromes in cancer patients. In this review we will elaborate on a new hypothesised concept and the underlying mechanisms of this syndrome. New studies are essential to ground this hypothesis and to develop interventions to break through the pathological mechanisms underlying cachexia.
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3.
The aetiology and impact of malnutrition in paediatric inflammatory bowel disease.
Gerasimidis, K, McGrogan, P, Edwards, CA
Journal of human nutrition and dietetics : the official journal of the British Dietetic Association. 2011;(4):313-26
Abstract
Disease-associated undernutrition of all types is very common in paediatric inflammatory bowel disease (IBD). Recent weight loss remains one of the triad of clinical manifestations and a cornerstone for the diagnosis of Crohn's disease (CD), although significantly fewer patients now present as being underweight. Recent evidence suggests that the introduction of medical treatment will quickly restore body weight, although this does not reflect concomitant changes in body composition. CD children present with features of nutritional cachexia with normal fat stores but depleted lean mass. Poor bone health, delayed puberty and growth failure are additional features that further complicate clinical management. Suboptimal nutritional intake is a main determinant of undernutrition, although activation of the immune system and secretion of pro-inflammatory cytokines exert additional independent effects. Biochemically low concentrations of plasma micronutrients are commonly reported in IBD patients, although their interpretation is difficult in the presence of an acute phase response and other indices of body stores adequacy are needed. Anaemia is a common extraintestinal manifestation of the IBD child. Iron-deficient anaemia is the predominant type, with anaemia of chronic disease second. Decreased dietary intake, as a result of decreased appetite and food aversion, is the major cause of undernutrition in paediatric IBD. Altered energy and nutrient requirements, malabsorption and increased gastrointestinal losses are additional factors, although their contribution to undernutrition in paediatric CD needs to be studied further.
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4.
Gut hormones and the treatment of disease cachexia.
Ashby, D, Choi, P, Bloom, S
The Proceedings of the Nutrition Society. 2008;(3):263-9
Abstract
Advances in the understanding of appetite are leading to a refined concept of disease cachexia and point to novel therapeutic strategies based on the manipulation of appetite. The complex social and psychological short-term influences on appetite obscure the fact that over the longer term appetite is tightly regulated by physiological considerations; the homeostatic control of energy balance. Like obesity, which is now viewed as a disorder of homeostasis, cachexia can be seen as an adaptive response to the disease state that becomes harmful when prolonged. Several lines of evidence implicate a disorder of appetite regulation in the pathogenesis of cachexia. As the only known circulating mediator of increased appetite the peptide hormone ghrelin has attracted attention as a potential therapy. Trials in patients with various chronic illnesses, including cancer and kidney failure, have demonstrated short-term increases in energy intake. Trials in patients with emphysema and heart failure have also shown benefits in clinical outcomes such as lean body mass and exercise capacity, and longer-term trials using oral analogues are being undertaken. As well as improving nutrition, ghrelin has a number of other actions that may be useful, including an anti-inflammatory effect; of interest since many cachexias are associated with inappropriate immune activation. The manipulation of appetite, in particular by ghrelin agonism, is emerging as an exciting potential therapy for disease cachexia. Future research should focus on the ascertainment of clinically-relevant outcomes, and further characterisation of the non-nutritional effects of this pathway.
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5.
Anorexia-Cachexia syndrome in cancer: implications of the ubiquitin-proteasome pathway.
Camps, C, Iranzo, V, Bremnes, RM, Sirera, R
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2006;(12):1173-83
Abstract
INTRODUCTION Malnutrition is a common problem in cancer patients. Its incidence varies according to disease stage (between 15 and 90%) and is considered a possible prognostic factor for therapeutic response and survival. It is also one of the causes contributing to the increase in morbidity and mortality in patients. Tumor cachexia is defined as a nutritional defect caused by tumor growth in the patient and presents as a significant weight loss. This weight loss is mainly caused by a degradation of skeletal muscle proteins. CONCLUSION The ubiquitin-proteasome system is the most important pathway of protein degradation. As a regulatory system governing protein half-life, it is involved in the regulation of the cell cycle, signal transmission, immune system response, apoptosis, and oncogenesis. Knowledge of the molecular pathways involved in the induction of cancer-associated cachexia will favor a more rational approach to its treatment as well as possible quality of life and survival benefit for the patient.