Exploring the impact of syndecans in prostate cancer: Stage-specific roles and therapeutic implications

Syndecans (SDCs) 1-4 are a family of transmembrane heparan sulfate proteoglycans (HSPGs) that regulate cell-cell communication, adhesion, extracellular matrix organization, and signaling pathways involved in tumor biology. In prostate cancer (PCa), accumulating evidence suggests that SDCs contribute to tumor progression, therapeutic resistance, and interactions within the tumor microenvironment. However, their specific, stage-dependent roles remain incompletely understood. This review provides an integrated synthesis of current experimental and clinical evidence on SDC1-SDC4 in PCa, complemented by exploratory analyses of publicly available transcriptomic, genomic, and proteomic datasets. In contrast, copy-number alteration (CNA) strata dichotomized by the mean for SDC1, SDC2, and SDC4 showed differences in progression-free interval. Specific CNA subclasses and relationships between CNA values and SDC mRNA or protein abundance could not be determined. Proteomic pseudotime analysis further suggested that SDC4 expression increases during PCa progression, supporting its potential involvement in advanced disease. We discuss the regulation and modulation of SDCs by androgen deprivation therapy (ADT), enzymatic shedding, integrin-mediated signaling, extracellular matrix interactions, lipid signaling pathways, and microRNA networks. In particular, SDC1-microRNA interactions may influence PCa cell proliferation, cellular senescence, epithelial-mesenchymal transition (EMT), and intracellular signaling pathways. Overall, this review highlights SDCs as context-dependent regulators of PCa biology with potential relevance as biomarkers or therapeutic targets. However, clinical translation will require independent validation, standardized assays, compartment-resolved analyses, and mechanistic confirmation.