AUTHOR=Deng Min , Aberle Merel R. , van Bijnen Annemarie A. J. H. M. , van der Kroft Gregory , Lenaerts Kaatje , Neumann Ulf P. , Wiltberger Georg , Schaap Frank G. , Olde Damink Steven W. M. , Rensen Sander S. 

TITLE=Lipocalin-2 and neutrophil activation in pancreatic cancer cachexia

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1159411

DOI=10.3389/fimmu.2023.1159411

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Cancer cachexia is a multifactorial syndrome characterized by body weight loss and systemic inflammation. The characterization of the inflammatory response in patients with cachexia is still limited. Lipocalin-2, a protein abundant in neutrophils, has recently been implicated in appetite suppression in preclinical models of pancreatic cancer cachexia. We hypothesized that lipocalin-2 levels could be associated with neutrophil activation and nutritional status of pancreatic ductal adenocarcinoma (PDAC) patients.</p></sec><sec><title>Methods</title><p>Plasma levels of neutrophil activation markers calprotectin, myeloperoxidase, elastase, and bactericidal/permeability-increasing protein (BPI) were compared between non-cachectic PDAC patients (n=13) and cachectic PDAC patients with high (≥26.9 ng/mL, <italic>n</italic>=34) or low (&lt;26.9 ng/mL, <italic>n</italic>=34) circulating lipocalin-2 levels. Patients’ nutritional status was assessed by the patient-generated subjective global assessment (PG-SGA) and through body composition analysis using CT-scan slices at the L3 level.</p></sec><sec><title>Results</title><p>Circulating lipocalin-2 levels did not differ between cachectic and non-cachectic PDAC patients (median 26.7 (IQR 19.7-34.8) <italic>vs</italic>. 24.8 (16.6-29.4) ng/mL, <italic>p</italic>=0.141). Cachectic patients with high systemic lipocalin-2 levels had higher concentrations of calprotectin, myeloperoxidase, and elastase than non-cachectic patients or cachectic patients with low lipocalin-2 levels (calprotectin: 542.3 (355.8-724.9) <italic>vs</italic>. 457.5 (213.3-606.9), <italic>p</italic>=0.448 <italic>vs</italic>. 366.5 (294.5-478.5) ng/mL, <italic>p</italic>=0.009; myeloperoxidase: 30.3 (22.1-37.9) <italic>vs</italic>. 16.3 (12.0-27.5), <italic>p</italic>=0.021 <italic>vs</italic>. 20.2 (15.0-29.2) ng/mL, <italic>p</italic>=0.011; elastase: 137.1 (90.8-253.2) <italic>vs</italic>. 97.2 (28.8-215.7), <italic>p</italic>=0.410 <italic>vs</italic>. 95.0 (72.2-113.6) ng/mL, <italic>p</italic>=0.006; respectively). The CRP/albumin ratio was also higher in cachectic patients with high lipocalin-2 levels (2.3 (1.3-6.0) as compared to non-cachectic patients (1.0 (0.7-4.2), <italic>p</italic>=0.041). Lipocalin-2 concentrations correlated with those of calprotectin (<italic>r<sub>s</sub></italic>=0.36, <italic>p</italic>&lt;0.001), myeloperoxidase (<italic>r<sub>s</sub></italic>=0.48, <italic>p</italic>&lt;0.001), elastase (<italic>r<sub>s</sub></italic>=0.50, <italic>p</italic>&lt;0.001), and BPI (<italic>r<sub>s</sub></italic>=0.22, <italic>p</italic>=0.048). Whereas no significant correlations with weight loss, BMI, or L3 skeletal muscle index were observed, lipocalin-2 concentrations were associated with subcutaneous adipose tissue index (<italic>r<sub>s</sub></italic>=-0.25, <italic>p</italic>=0.034). Moreover, lipocalin-2 tended to be elevated in severely malnourished patients compared with well-nourished patients (27.2 (20.3-37.2) <italic>vs</italic>. 19.9 (13.4-26.4) ng/mL, <italic>p</italic>=0.058).</p></sec><sec><title>Conclusions</title><p>These data suggest that lipocalin-2 levels are associated with neutrophil activation in patients with pancreatic cancer cachexia and that it may contribute to their poor nutritional status.</p></sec>