Proteoglycans as regulators of cancer biomarker landscapes: implications for precision oncology

In this review, we discuss the dual role of proteoglycans (PGs) in cancer biomarker biology. In addition to serving as biomarkers, PGs regulate the extracellular availability, signaling competence, compartmentalization, and interpretation of numerous disease-associated molecules within the tumor microenvironment. By controlling ligand sequestration, stability, and presentation, PGs influence the biological significance of molecular readouts and signaling-associated signatures. We further examine how extracellular matrix (ECM) remodeling processes, including proteolytic shedding, glycan remodeling, and extracellular vesicle (EV) release, generate circulating molecular signatures that reflect dynamic interactions between tumor cells and their surrounding microenvironment. In parallel, PG-dependent regulation of receptor signaling influences downstream transcriptional and inflammatory response profiles, while regional differences in PG distribution contribute to the formation of distinct ECM niches associated with local variations in signaling activity and molecular expression patterns. Viewed as a whole, these observations indicate that the detectability and clinical interpretation of cancer-associated markers are strongly influenced by PG-dependent extracellular regulation. This framework provides a mechanistic basis for understanding variability in marker performance and supports the incorporation of ECM context into biomarker research. Greater diagnostic precision and improved patient stratification will likely depend on approaches that consider the regulatory roles of PGs within the tumor microenvironment.