Abstract
Cancer cachexia, of which the most notable symptom is severe and rapid weight loss, is present in the majority of patients with advanced cancer. Inflammatory mediators play an important role in the development of cachexia, envisaged as a chronic inflammatory syndrome. The white adipose tissue (WAT) is one of the first compartments affected in cancer cachexia and suffers a high rate of lipolysis. It secretes several cytokines capable of directly regulating intermediate metabolism. A common pathway in the regulation of the expression of pro-inflammatory cytokines in WAT is the activation of the nuclear transcription factor kappa-B (NF-κB). We have examined the gene expression of the subunits NF-κBp65 and NF-κBp50, as well as NF-κBp65 and NF-κBp50 binding, the gene expression of pro-inflammatory mediators under NF-κB control (IL-1β, IL-6, INF-γ, TNF-α, MCP-1), and its inhibitory protein, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α). The observational study involved 35 patients (control group, n = 12 and cancer group, n = 23, further divided into cachectic and non-cachectic). NF-κBp65 and its target genes expression (TNF-α, IL-1β, MCP-1 and IκB-α) were significantly higher in cachectic cancer patients. Moreover, NF-κBp65 gene expression correlated positively with the expression of its target genes. The results strongly suggest that the NF-κB pathway plays a role in the promotion of WAT inflammation during cachexia.
Highlights
Cancer cachexia is mainly characterized by involuntary weight loss
(A) Gene expression analysis of NF-κBp65 showed higher values (p = 0.0147) in cachectic cancer patients compared to controls; (B) Gene expression of NF-κBp50 protein showed no differences among the patients (p = 0.1719); (C) IL-6 gene expression showed no differences among the patients (p = 0.1458); (D) IL-1β gene expression was higher in cachectic cancer patients (p = 0.049) compared to non-cachectic patients; (E)
We did not evaluate lean body mass among the groups, groups were matched by body mass index (BMI)
Summary
Cancer cachexia is mainly characterized by involuntary weight loss. This syndrome is present in around fifty percent of all cancer patients and may be found in more than two thirds of those in the advanced stage of the disease [1]. We have previously provided evidence that the white adipose tissue is a potential contributor to the maintenance of systemic inflammation in cachexia, as it secretes several inflammatory cytokines and adipokines [4,6,7] These factors directly regulate several functions related with metabolism, body composition, activity of the complement system and vascular homeostasis [8]. Given the potential role of the white adipose tissue to maintain systemic inflammation in cancer cachexia, and the high circulating levels of cytokines that are characteristic of the syndrome, we performed an observational study in which we examined, for the first time, the correlation of the dimer NF-κBp65-p50 with the induction of gene expression of pro-inflammatory cytokines and chemokines in the subcutaneous adipose tissue of cachectic cancer patients, as compared with non-cachectic
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