Inflammation, Vol. 35, No. 3, June 2012 ( # 2011) DOI: 10.1007/s10753-011-9418-1
Serum Levels of Secreted Group IIA Phospholipase A2 in Benign Prostatic Hyperplasia and Prostate Cancer: A Biomarker for Inflammation or Neoplasia? Mario Menschikowski,1,4 Albert Hagelgans,1 Susanne Fuessel,2 Olga A. Mareninova,3 Volker Neumeister,1 Manfred P. Wirth,2 and Gabriele Siegert1
Abstract—Secreted group IIA phospholipase A2 (sPLA2-IIA) is markedly up-regulated in human prostate cancer (PCa) specimens and in some PCa-derived cell lines, indicating an important role of this enzyme in tumourigenesis. In this study, we measured levels of sPLA2-IIA, C-reactive protein (CRP), and prostate-specific antigen (PSA) in serum samples obtained from patients with benign prostatic hyperplasia (BPH) and with PCa of different stages. We found that serum levels of sPLA2IIA and CRP in BPH and PCa patients were significantly elevated compared to those of healthy individuals, but the concentrations of these inflammatory biomarkers did not differ between patients with BPH or PCa. Furthermore, serum levels of sPLA2-IIA correlated with concentrations of CRP, but not with PSA, Gleason grade or tumour stage. In conclusion, these findings suggest that cancerrelated changes are not exclusive factors contributing to elevated serum sPLA2-IIA levels and emphasize the utility of sPLA2-IIA as a circulating marker of inflammation in patients with BPH and PCa. KEY WORDS: prostate cancer; benign prostatic hyperplasia; secreted phospholipase A2; C-reactive protein; inflammation.
relatively low [1–4]. However, during acute inflammatory disorders such as sepsis, septic shock, acute pancreatitis, peritonitis or chronic rheumatoid arthritis, levels of sPLA2-IIA can rise 100–1,000 times of normal levels [1, 4–6]. Elevated serum levels of sPLA2-IIA were also found during neoplastic disorders involving a variety of different organ sites (lung, bile duct, stomach, liver, oesophagus, colon and pancreas) [7]. Furthermore, much greater concentrations of sPLA2-IIA were frequently seen in serum samples of patients with advanced and metastasized cancer versus those with early cancer stages [8]. Prostate cancer is one of the most frequently diagnosed malignancies in men [9]. Prostate-specific antigen (PSA) is widely used as serum biomarker for the detection and monitoring of human prostate cancer (PCa). However, its use as diagnostic marker has several limitations including the low diagnostic specificity caused by increased PSA levels also in BPH patients and in general during inflammatory responses [10, 11]. Therefore, better blood PCa biomarkers, especially for
INTRODUCTION Serum concentrations of secreted group IIA phospholipase A2 (sPLA2-IIA) of healthy individuals are 1
Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty “Carl Gustav Carus”, Technical University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany 2 Department of Urology, Medical Faculty “Carl Gustav Carus”, Technical University of Dresden, Dresden, Germany 3 Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, Los Angeles, CA, USA 4 To whom correspondence should be addressed at Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty “Carl Gustav Carus”, Technical University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany. E-mail:
[email protected] ABBREVIATIONS: BPH, Benign prostatic hyperplasia; CRP, Creactive protein; ELISA, Enzyme-linked immunosorbent assay; GS, Gleason grade; PCa, Prostate cancer; PSA, Prostate-specific antigen; pT2, Organ confined tumours; pT3/4, Non-organ confined tumours; SEM, Standard error of the mean; sPLA2-IIA, Secreted phospholipase A2 of group IIA
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Menschikowski, Hagelgans, Fuessel, Mareninova, Neumeister, Wirth, and Siegert Table 1. Characteristics of Patients
Group
Number
BPH PCa pT2 pT3/4 GS ≤7 GS >7
25 25 15 10 18 7
PATIENTS AND METHODS
Age (years)
Total PSA (μg/L)
66.9±1.2 64.1±1.0 64.3±1.4 63.8±1.7 64.1±1.2 64.0±1.9
2.6±0.6 16.4±3.5* 8.5±1.1* 28.2±7.2* 17.3±4.6* 14.2±4.2*
Mean ± SEM; the differences in the values of PSA among the treatment groups were analyzed by Kruskal–Wallis one-way test pT2 organ-confined tumours, pT3/4 non-organ-confined tumours*p< 0.001, significance of difference relative to BPH group
Gleason grade 4/5 tumours, are necessary [12]. Based on the established strong relationship between inflammation and PCa, C-reactive protein (CRP) is considered as a prognostic marker for androgen-independent and advanced PCa [13]. Concentrations of CRP in serum of cancer patients are usually higher than in healthy controls [14], and it is well-known that the serum concentrations of sPLA2IIA are positively correlated with those of CRP [2, 15, 16]. Recently, it was reported that serum levels of sPLA2-IIA in PCa patients are significantly higher in comparison to those in cancer-free control subjects [17]. In addition, sPLA2-IIA levels correlated with Gleason grade. Based on these findings, a prognostic significance of sPLA2-IIA as a surrogate prostate biomarker was proposed. However, it remains unclear whether increased serum sPLA2-IIA levels are cancer-specific or reflect inflammatory reactions during malignancy [18, 19]. In this study, we analyzed sPLA2-IIA and CRP levels as inflammatory marker in patients with benign prostatic hyperplasia (BPH) and PCa in addition to PSA serum levels.
Patients The study involving human material was approved by the Institutional Review Board. The serum samples were categorized to three groups: healthy individuals (n=40), BPH patients (n=25) and PCa patients (n=25). For patient characteristics, see Table 1. ELISA-Based Measurement of Serum sPLA2-IIA Concentrations of sPLA2-IIA in serum samples were determined using sPLA2-IIA-specific enzyme-linked immunosorbent assay (ELISA) kit (Cayman Chemical, MI, USA) according to the manufacturer’s protocol. In all groups, human serum samples were diluted 10-fold for ELISA. Extinction of reaction products was measured at 405 nm on a Victor3 1420 Multilabel Counter reader (Perkin-Elmer LAS GmbH, Rodgau, Germany). Amounts of sPLA2-IIA were calculated using standards included in the ELISA kit and software supplied with Victor3. CRP and PSA Assays Levels of CRP and PSA were measured using a turbidimetric measurement of agglutinated antigen-antibody complexes (Roche Diagnostics, Mannheim, Germany, and ARCHITECT total PSA, Abbott, Wiesbaden, Germany, respectively). Statistical Analyses The difference in the median values between two groups was analyzed with a paired t test and among all studied groups with Kruskal–Wallis one-way analysis of
Table 2. Serum Concentrations of sPLA2-IIA and CRP in Studied Groups Group
Parameter
Mean ± SEM
Median (min–max)
Healthy individuals
sPLA2-IIA (μg/L) CRP (mg/L) sPLA2-IIA (μg/L) CRP (mg/L) sPLA2-IIA (μg/L) CRP (mg/L) sPLA2-IIA (μg/L) CRP (mg/L) sPLA2-IIA (μg/L) CRP (mg/L)
1.11±0.09** 0.77±0.15** 2.15±0.25 1.95±0.36 2.28±0.33 3.16±0.99 2.19±0.48 2.19±1.10 2.42±0.44 4.62±1.82*
0.95 0.50 1.92 1.42 1.68 1.24 1.41 0.90 2.07 1.76
BHP PCa pT2 (n=15) pT3/4 (n=10)
The difference in the median values between BPH and other studied groups was analyzed with a paired t test *p
