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. 2020 Aug 12;41(8):1074-1082.
doi: 10.1093/carcin/bgaa065.

The interplay of growth differentiation factor 15 (GDF15) expression and M2 macrophages during prostate carcinogenesis

Sudha M Sadasivan  1 , Yalei Chen  1 , Nilesh S Gupta  2 , Xiaoxia Han  1 , Kevin R Bobbitt  1 , Dhananjay A Chitale  2 , Sean R Williamson  2 , Andrew G Rundle  3 , Deliang Tang  4 , Benjamin A Rybicki  1
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The interplay of growth differentiation factor 15 (GDF15) expression and M2 macrophages during prostate carcinogenesis

Sudha M Sadasivan et al. Carcinogenesis. .

Abstract

M2 (tumor-supportive) macrophages may upregulate growth differentiation factor 15 (GDF15), which is highly expressed in prostate tumors, but the combined utility of these markers as prognostic biomarkers are unclear. We retrospectively studied 90 prostate cancer cases that underwent radical prostatectomy as their primary treatment and were followed for biochemical recurrence (BCR). These cases also had a benign prostate biopsy at least 1 year or more before their prostate cancer surgery. Using computer algorithms to analyze digitalized immunohistochemically stained slides, GDF15 expression and the presence of M2 macrophages based on the relative density of CD204- and CD68-positive macrophages were measured in prostate: (i) benign biopsy, (ii) cancer and (iii) tumor-adjacent benign (TAB) tissue. Both M2 macrophages (P = 0.0004) and GDF15 (P < 0.0001) showed significant inter-region expression differences. Based on a Cox proportional hazards model, GDF15 expression was not associated with BCR but, in men where GDF15 expression differences between cancer and TAB were highest, the risk of BCR was significantly reduced (hazard ratio = 0.26; 95% confidence interval = 0.09-0.94). In addition, cases with high levels of M2 macrophages in prostate cancer had almost a 5-fold increased risk of BCR (P = 0.01). Expression of GDF15 in prostate TAB was associated with M2 macrophage levels in both prostate cancer and TAB and appeared to moderate M2-macrophage-associated BCR risk. In summary, the relationship of GDF15 expression and CD204-positive M2 macrophage levels is different in a prostate tumor environment compared with an earlier benign biopsy and, collectively, these markers may predict aggressive disease.

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Figures

Figure 1.
Figure 1.
Violin plot of CD68-positive macrophage density (A), CD204-positive macrophage density (B) and GDF15 expression (C) across prostate regions of benign biopsy, cancer and TAB. For (A) and (B), y-axis macrophage density levels represent natural log transformed percentage of positive expression within tissue area. GDF15 expression values on y-axis of (C) are the natural log-transformed percentage of positive expression within tissue area multiplied by the pixel intensity values. Individual data points are also plotted with intensity of red dots representing the level of inflammation in each specimen. Mean levels of marker by prostate region are represented by black bars.
Figure 2.
Figure 2.
Kaplan–Meier survival plots of prostate cancer BCR with respect to levels of CD204/CD68 Macrophage density in prostate cancer and benign biopsy (A) and the combined CD204/CD68 macrophage density and GDF15 expression in prostate TAB (B).
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