RAGE as a Novel Biomarker for Prostate Cancer: A Systematic Review and Meta-Analysis

Abstract

The receptor for advanced glycation end-products (RAGE) has been implicated in driving prostate cancer (PCa) growth, aggression, and metastasis through the fueling of chronic inflammation in the tumor microenvironment. This systematic review and meta-analysis summarizes and analyzes the current clinical and preclinical data to provide insight into the relationships among RAGE levels and PCa, cancer grade, and molecular effects. A multi-database search was used to identify original clinical and preclinical research articles examining RAGE expression in PCa. After screening and review, nine clinical and six preclinical articles were included. The associations of RAGE differentiating benign prostate hyperplasia (BPH) or normal prostate from PCa and between tumor grades were estimated using odds ratios (ORs) and associated 95% confidence intervals (CI). Pooled estimates were calculated using random-effect models due to study heterogeneity. The clinical meta-analysis found that RAGE expression was highly likely to be increased in PCa when compared to BPH or normal prostate (OR: 11.3; 95% CI: 4.4-29.1) and that RAGE was overexpressed in high-grade PCa when compared to low-grade PCa (OR: 2.5; 95% CI: 1.8-3.4). In addition, meta-analysis estimates of preclinical studies performed by albatross plot generation found robustly positive associations among RAGE expression/activation and PCa growth and metastatic potential. This review demonstrates that RAGE expression is strongly tied to PCa progression and can serve as an effective diagnostic target to differentiate between healthy prostate, low-grade PCa, and high-grade PCa, with potential theragnostic applications.

Keywords: RAGE; biomarker; meta-analysis; prostate cancer; receptor for advanced glycation end-products; systematic review.

Figure 1

Schematic of workflow for identifying relevant articles.

Figure 2

Forest plot of receptors for advanced glycation end-product (RAGE) expression in prostate cancer (PCa) [36,37,38,39,40,41,42,43]. These associations were indicated as odds ratio (OR) estimates with a corresponding 95% confidence interval (CI).

Figure 3

Forest plot of RAGE expression in high- vs. low-grade PCa [36,38,39,40,41,43]. These associations were indicated as OR estimates with the corresponding 95% CI.

Figure 4

Albatross plot of cell culture studies measuring RAGE association and modulation with (A) PCa cell proliferation, measured by growth assays [40,44,45,46,47]; and (B) PCa metastatic potential, measured by invasiveness, migration, and EMT expression assays [21,40,47]. Each point represents a single study, with the effect estimate (represented as a p-value), plotted against the total given sample size (n) included within each study. Contour lines are standardized mean differences (SMD). Non-exact p-values reported were plotted as stated in the manuscript (e.g., if p < 0.05, plotted p = 0.05) as a conservative estimate.