The role of GDF15 (growth/differentiation factor 15) during prostate carcinogenesis
Sadasivan SM, Chen Y, Gupta NS, Taneja K, Maresh SA, Gonzalez A, Han X, Wu KHH, Chitale D, Rundle A, Tang D, and Rybicki BA. The role of GDF15 (growth/differentiation factor 15) during prostate carcinogenesis. Cancer Res 2018; 78(13).
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 a) benign biopsy, b) tumor-adjacent benign and c) tumor tissue using an automated multi-image processing macro developed in the ImageJ software. Expression measurements were log2 transformed and high-low cut-off points were selected that optimized the association of biomarker expression with BCR-free survival. A Cox proportional hazards model was used to test the association of time to BCR with low vs high biomarker expression. During follow-up, 23 cases (25.2%) experienced BCR (96% of men without BCR had at least one year of follow-up). An increased hazard ratio (HR) for BCR was found in men with a higher ratio of GDF15 expression in their tumor vs. tumor-adjacent benign tissue (HR: 3.74; 95% confidence interval (CI) = 1.27-10.99) Adjusting for tumor grade, pathological tumor stage and PSA at diagnosis did not alter risk estimates significantly. In these same prostate tumor specimens, increased hazard ratios for BCR were found among men who had elevated CD204 expression in tumor (HR = 5.24; 95% CI = 2.02-13.62) and in tumor-adjacent benign tissue (HR = 3.29; 95% CI = 1.32, 8.23). We found no association of BCR-free survival with either GDF15 or CD204 expression in pre-diagnostic benign biopsies. Our results suggest that men who have a larger difference in GDF15 expression levels between prostate tumor and tumor-adjacent benign tissue, and with increased levels of M2 macrophages in both tumor and tumor-adjacent benign tissue, are at greater risk of disease recurrence. Further evaluation of the differences in the prostate immune cellular profile in the pre-malignant and malignant state may offer additional insight into inflammatory mediated prostate carcinogenesis.