Profibrogenic Gremlin-1 expression in prostate cancer and the clinicopathologic association

Gremlin-1 (GREM1) is a profibrogenic molecule involved in TGF-β signaling. Recent studies have implicated GREM1 in androgen receptor (AR)-independent signaling and castration resistance in advanced prostate cancer. However, its compartment expression patterns and clinicopathologic significance in primary prostate cancer remain unclear.

GREM1 mRNA expression and clinicopathologic associations were analyzed in the Cancer Genome Atlas (TCGA) prostate adenocarcinoma (TCGA-PRAD), the Memorial Sloan Kettering Cancer Center (MSKCC), and the German Cancer Research Center (DKFZ) primary prostate cancer cohorts. Correlations between GREM1 and genes related to TGF-β signaling, extracellular matrix organization, fibroblast activation, and AR signaling were evaluated by Spearman analysis. GREM1 protein expression was examined by immunohistochemistry in commercial human prostate cancer tissue microarrays (TMAs) using compartment-specific QuPath-based H-scores.

GREM1 expression was relatively elevated in prostate and bladder cancers. Across the three prostate cancer cohorts, higher GREM1 expression was associated with adverse pathologic features and was most consistently correlated with FAP. Inverse correlations were observed with selected AR-related genes, whereas no significant correlation was found with AR itself. Higher GREM1 expression was associated with shorter disease-free survival only in MSKCC but was not an independent prognostic factor after clinicopathologic adjustment. Quantitative immunohistochemistry in 43 patients showed higher epithelial than stromal GREM1 H-scores (median, 3.10 vs 1.41; P < 0.0001), with heterogeneous staining in both compartments. Neither epithelial nor stromal H-scores were associated with Gleason score or pathologic T stage.

GREM1 mRNA expression in primary prostate cancer was associated with adverse clinicopathologic features, and a fibroblast-associated transcriptional context but did not demonstrate independent prognostic value. At the protein-level, GREM1 expression was heterogeneous in both epithelial and stromal compartments, with higher epithelial H-scores on average. These findings support further investigation of the biological significance of GREM1 expression in primary prostate cancer.