Increased Density of Growth Differentiation Factor-15+ Immunoreactive M1/M2 Macrophages in Prostate Cancer of Different Gleason Scores Compared with Benign Prostate Hyperplasia

SIMPLE SUMMARY: Prostate cancer (PCa) is the second most diagnosed cancer and cause of death in men worldwide. The main challenge is to discover biomarkers for malignancy to guide the physician towards optimized diagnosis and therapy. There is recent evidence that growth differentiation factor-15 (GDF-15) is elevated in cancer patients. Therefore, we aimed to decipher GDF-15+ cell types and their density in biopsies of human PCa patients with Gleason score (GS)6–9 and benign prostate hyperplasia (BPH). Here we show that the density of GDF-15+ cells, mainly identified as interstitial macrophages (MΦ), was higher in GS6–9 than in BPH, and, thus, GDF-15 is intended to differentiate patients with high GS vs. BPH, as well as GS6 vs. GS7 (or even with higher malignancy). Some GDF-15+ MΦ showed a transepithelial migration into the glandular lumen and, thus, might be used for measurement in urine/semen. Taken together, GDF-15 is proposed as a novel tool to diagnose PCa vs. BPH or malignancy (GS6 vs. higher GS) and as a potential target for anti-tumor therapy. GDF-15 in seminal plasma and/or urine could be utilized as a non-invasive biomarker of PCa as compared to BPH. ABSTRACT: Although growth differentiation factor-15 (GDF-15) is highly expressed in PCa, its role in the development and progression of PCa is unclear. The present study aims to determine the density of GDF-15+ cells and immune cells (M1-/M2 macrophages [MΦ], lymphocytes) in PCa of different Gleason scores (GS) compared to BPH. Immunohistochemistry and double immunofluorescence were performed on paraffin-embedded human PCa and BPH biopsies with antibodies directed against GDF-15, CD68 (M1 MΦ), CD163 (M2 MΦ), CD4, CD8, CD19 (T /B lymphocytes), or PD-L1. PGP9.5 served as a marker for innervation and neuroendocrine cells. GDF-15+ cell density was higher in all GS than in BPH. CD68+ MΦ density in GS9 and CD163+ MΦ exceeded that in BPH. GDF-15+ cell density correlated significantly positively with CD68+ or CD163+ MΦ density in extratumoral areas. Double immunoreactive GDF-15+/CD68+ cells were found as transepithelial migrating MΦ. Stromal CD68+ MΦ lacked GDF-15+. The area of PGP9.5+ innervation was higher in GS9 than in BPH. PGP9.5+ cells, occasionally copositive for GDF-15+, also occurred in the glandular epithelium. In GS6, but not in BPH, GDF-15+, PD-L1+, and CD68+ cells were found in epithelium within luminal excrescences. The degree of extra-/intra-tumoral GDF-15 increases in M1/M2Φ is proposed to be useful to stratify progredient malignancy of PCa. GDF-15 is a potential target for anti-tumor therapy.