High Monocyte Count and Expression of S100A9 and S100A12 in Peripheral Blood Mononuclear Cells Are Associated with Poor Outcome in Patients with Metastatic Prostate Cancer

Abstract

Increasing evidence indicates calcium-binding S100 protein involvement in inflammation and tumor progression. In this prospective study, we evaluated the mRNA levels of two members of this family, S100A9 and S100A12, in peripheral blood mononuclear cells (PBMCs) in a cohort of 121 prostate cancer patients using RT-PCR. Furthermore, monocyte count was determined by flow cytometry. By stratifying patients into different risk groups, according to TNM stage, Gleason score and PSA concentration at diagnosis, expression of S100A9 and S100A12 was found to be significantly higher in patients with metastases compared to patients without clinically detectable metastases. In line with this, we observed that the protein levels of S100A9 and S100A12 in plasma were higher in patients with advanced disease. Importantly, in patients with metastases at diagnosis, high monocyte count and high levels of S100A9 and S100A12 were significantly associated with short progression free survival (PFS) after androgen deprivation therapy (ADT). High monocyte count and S100A9 levels were also associated with short cancer-specific survival, with monocyte count providing independent prognostic information. These findings indicate that circulating levels of monocytes, as well as S100A9 and S100A12, could be biomarkers for metastatic prostate cancer associated with particularly poor prognosis.

Keywords: S100A12; S100A9; metastases; monocytes; peripheral blood mononuclear cells; prostate cancer.

Figure 1

Evaluation of S100A9 and S100A12 according to patient risk group at diagnosis, stratified as low risk (LR), intermediate risk (IR), high risk (HR) and metastasis (M1). Shown are the relative mRNA levels of S100A9 (a) and S100A12 (b) in PBMCs; LR (n = 15), IR (n = 32), HR (n = 42), M1 (n = 30) and relative plasma protein levels of S100A9 (c) and S100A12 (d); LR (n = 15), IR (n = 31), HR (n = 32) and M1 (n = 18). Each dot represents one individual and horizontal bars indicate mean values with standard deviation. Group comparisons were performed using Kruskal–Wallis followed by the Mann–Whitney U test. Significant p-values from the Mann–Whitney U tests are indicated.

Figure 2

Kaplan–Meier survival analysis of patients in the metastatic group based on low (blue line) and high (red line) S100A mRNA expression and monocyte count, grouped by median values as cut off. Shown is PSA progression-free survival for S100A9 (a), S100A12 (b) and monocyte count (c), and prostate cancer-specific survival for S100A9 (d), S100A12 (e) and monocyte count (f).

Figure 3

Short progression free survival (PFS < 21 months, n = 15) compared to long progression free survival (PFS > 21 months, n = 15) for patients with metastases at diagnosis. The relative gene expression levels of S100A9 (a) and S100A12 (b), and monocyte count (c) are illustrated by box plots. Outlier values (o) and significant p-values from the Mann–Whitney U tests are indicated.

Figure 4

Evaluation in patients with metastases of (a) S100A9 and (b) S100A12 relative mRNA levels and (c) monocyte count in paired samples at diagnosis (untreated) and after approximately 3 months of androgen deprivation therapy (ADT). Wilcoxon rank sum test was used to compare samples from untreated metastatic patients at diagnosis with paired samples after ADT treatment. Significant p-values are shown.