Profiling (adipo)cytokines in cancer cachexia

Abstract

Cancer cachexia is an unmet clinical need that affects more than half of patients with cancer. Pro-inflammatory cytokines and adipokines could be involved in the pathogenesis and development of cachexia, but this relationship is not completely understood. This thesis aimed to examine and characterise the role of (adipo)cytokines in cancer cachexia. A systematic review was conducted to evaluate the relationship between cytokines and cachexia in people with incurable cancer (Chapter 2). Interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were considerably elevated in cachectic individuals, and a high degree of methodological heterogeneity was observed. Furthermore, data from the REVOLUTION trial were analysed to determine if adiponectin, leptin, intelectin-1 and resistin can predict the modified Glasgow Prognostic Score (mGPS) and cachexia status (Chapter 3). Although adipokines could not predict any of the outcome variables in this study, leptin was negatively associated with mGPS and cachexia, while a positive relationship was identified between resistin and mGPS. Previous research suggested that intelectin-1 might be involved in cancer cachexia. Given the limited availability of literature, a Bayesian meta-analysis was conducted to evaluate the role of intelectin-1 in cancer and its physiological concentration (Chapter 4). Intelectin-1 levels were substantially higher in patients with gastrointestinal cancer compared to controls. The meta-analysis also estimated that the physiological concentration of intelectin-1 ranges from 193ng/ml to 275ng/ml. Lastly, a cell culture model was designed to evaluate the effect of intelectin-1 on human myotubes (Chapter 5). Increased levels of intelectin-1 diminish insulin-mediated glucose uptake and downregulate the expression of genes involved in myogenesis. To conclude, IL-6 and TNF-α were highly expressed in cancer cachexia. Leptin and resistin could also contribute to the development of this wasting syndrome, but to a lesser extent. Besides these (adipo)cytokines, intelectin-1 is another potential biomarker of cachexia and future research should focus on elucidating its mechanisms of action.