Abstract
Simple SummaryPatients with cancer often suffer from severe weight loss as a result of the wasting of skeletal muscle and fat tissue. This has a strong negative impact on the patient’s prognosis and quality of life. Inflammation is thought to contribute to weight loss in cancer. To enable the future targeting of inflammation in patients with cancer who experience weight loss, we set out to characterize an important pro-inflammatory component of the immune system: the complement system. The blood levels of several elements of the complement system were analyzed in patients with and without weight loss and inflammation. We found that complement factors were activated specifically in patients with both weight loss and inflammation. Since complement inhibitory drugs are already on the market, these findings may open new opportunities for treating inflammation-mediated weight loss in patients with cancer.Systemic inflammation is thought to underlie many of the metabolic manifestations of cachexia in cancer patients. The complement system is an important component of innate immunity that has been shown to contribute to metabolic inflammation. We hypothesized that systemic inflammation in patients with cancer cachexia was associated with complement activation. Systemic C3a levels were higher in cachectic patients with inflammation (n = 23, C-reactive protein (CRP) ≥ 10 mg/L) as compared to patients without inflammation (n = 26, CRP < 10 mg/L) or without cachexia (n = 13) (medians 102.4 (IQR 89.4–158.0) vs. 81.4 (IQR 47.9–124.0) vs. 61.6 (IQR 46.8–86.8) ng/mL, respectively, p = 0.0186). Accordingly, terminal complement complex (TCC) concentrations gradually increased in these patient groups (medians 2298 (IQR 2022–3058) vs. 1939 (IQR 1725–2311) vs. 1805 (IQR 1552–2569) mAU/mL, respectively, p = 0.0511). C3a and TCC concentrations were strongly correlated (rs = 0.468, p = 0.0005). Although concentrations of C1q and mannose-binding lectin did not differ between groups, C1q levels were correlated with both C3a and TCC concentrations (rs = 0.394, p = 0.0042 and rs = 0.300, p = 0.0188, respectively). In conclusion, systemic inflammation in patients with cancer cachexia is associated with the activation of key effector complement factors. The correlations between C1q and C3a/TCC suggest that the classical complement pathway could play a role in complement activation in patients with pancreatic cancer.
Highlights
Cachexia is a severe complication of many types of cancer, with a high prevalence in pancreatic cancer [1]
Interactions between the tumor and host cells leading to systemic inflammation result in an acute-phase response characterized by the production of C-reactive protein (CRP) in the liver and increases in circulating proinflammatory cytokines [6,7]
Systemic inflammation in patients with cancer cachexia is associated with the activation of key effector complement factors
Summary
Cachexia is a severe complication of many types of cancer, with a high prevalence in pancreatic cancer [1]. Cancer cachexia is characterized by loss of body weight, which negatively impacts both adipose tissue and skeletal muscle mass [3]. Its precise underlying mechanisms remain unclear, many lines of evidence point towards an important role of the pro-inflammatory factors released by tumor cells, immune cells, or metabolic target tissues in the pathophysiology of cancer cachexia. Inflammation has been shown to be associated with both muscle wasting and fat depletion in patients with cancer cachexia [4,5]. Research has mainly focused on the role of pro-inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ), and confirmed their involvement in the pathogenesis of cachexia [8,9,10,11]
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