Changes in GDF15 (Growth/Differentiation Factor 15) Expression and M2 Macrophages During Prostate Carcinogenesis

GDF15 (growth/differentiation factor 15), also known as MIC-1 (Macrophage inhibitory cytokine 1), is a divergent member of the TGFβ superfamily of cytokines and is highly expressed in prostate tumors, but its role in prostate carcinogenesis and utility as a prognostic biomarker is unclear. We studied 91 prostate cancer cases that underwent surgery as their primary treatment and were then subsequently followed for biochemical recurrence (BCR). These cases also had a benign prostate biopsy at least one year before their prostate cancer diagnosis. In both the benign biopsy and tumor specimens, we quantified the intensity of GDF15 expression and characterized the presence of tumor associated macrophages by measuring the density of CD68-positive stained cells, and the M2 macrophage marker CD204 by immunohistochemical analysis. Marker expression was measured in prostate a) benign biopsy (BS), b) tumor-adjacent benign (BGS) and c) tumor tissue (MGS) using an automated multi-image processing macro developed in the ImageJ software. A Cox proportional hazards model was used to test the association of time to BCR of the low expression group compared with medium or high biomarker expression. The risk of BCR differed with the extent of GDF15 expression in the prostatic epithelial tissue of benign and tumor regions of the prostate. For instance, in BGS, high expression of GDF15 was associated with increased risk of BCR (hazard ratio (HR)=2.58, p=0.07). After controlling for PSA at diagnosis, Gleason grade and pathologic stage, high expression of GDF15 in BGS had a stronger association with BCR (HR=3.30, p=0.04). The risk of BCR increased with increasing level of infiltration of CD204/CD68 positive macrophages in BGS (HR=4.19, p=0.02) and MGS (HR=4.16, p=0.01) even after controlling for PSA at diagnosis, Gleason grade and pathologic stage. The combined expression levels of GDF15 and CD204/CD68 showed that prostate cancer cases with small GDF15 expression changes between BGS and MGS and high CD204/CD68 expression in BGS were at 3-fold higher risk of BCR (HR=3.67, p=0.05). In summary, expression levels of GDF15 and CD204 M2 macrophages in different regions of the prostate can change as the disease progresses from benign to a tumorigenic state and serve as markers for aggressive disease. Further evaluation of these dynamic differences in the prostate immune cellular profile in the pre-malignant and malignant state may offer additional insight into inflammatory-mediated prostate carcinogenesis