Mechanistic roles of PGs in regulating signaling-dependent biomarker outputs.
| Mechanism | PG example | Molecular process | Biomarker consequence | Clinical implication | References |
|---|---|---|---|---|---|
| Ligand sequestration | HSPGs (syndecans, perlecan) | HS-mediated ligand binding and presentation | Ligand abundance ≠ signaling activity | Limits interpretation of circulating growth factors and cytokines | [4, 15] |
| Co-receptor function | HSPGs | Stabilization of ligand-receptor interactions | Altered receptor activation thresholds | Explains variability in pathway-associated biomarkers | [4, 52] |
| Receptor organization | SDC1 | Integrin-RTK signaling complexes | Compartmentalized signaling responses | Influences predictive biomarker performance | [14, 54] |
| Pathway activation | GPC3 | Wnt/β-catenin signaling regulation | Distinct transcriptional biomarker signatures | Links PG expression to downstream signaling programs | [29] |
| RTK modulation | DCN | EGFR/MET/VEGFR2/IGF-IR interactions | Context-dependent signal attenuation and pathway rewiring | Reflects stromal control of tumor signaling | [26, 56, 57] |
| Oncogenic signaling | BGN | IGF-IR/LRP6/β-catenin and JAK/STAT activation | Enhanced proliferative and inflammatory signaling | Links ECM signaling to tumor progression and immune modulation | [27, 33, 60] |
| Receptor trafficking | Syndecans | Endocytosis and recycling pathways | Altered signal duration and transcriptional output | Affects biomarker kinetics and pathway persistence | [62] |
| Spatial compartmentalization | Multiple PGs | Formation of ECM signaling microdomains | Regional biomarker variability | Explains inconsistent biomarker performance across tumor regions | [1, 2] |
HSPGs: heparan sulfate proteoglycans; HS: heparan sulfate; SDC1: syndecan-1; GPC3: glypican-3; β-catenin: beta-catenin; RTK: receptor tyrosine kinase; PG: proteoglycan; DCN: decorin; EGFR: epidermal growth factor receptor; MET: mesenchymal-epithelial transition factor; VEGFR2: vascular endothelial growth factor receptor 2; IGF-IR: insulin-like growth factor I receptor; BGN: biglycan; LRP6: low-density lipoprotein receptor-related protein 6; JAK: Janus kinase; STAT: signal transducer and activator of transcription; ECM: extracellular matrix.
During the preparation of this work, the authors used ChatGPT (OpenAI) to assist with language editing, figure generation, text refinement, and improvement of readability. All scientific concepts, literature selection, interpretation of published findings, critical evaluation of the literature, and conclusions were developed and verified by the authors. Following the use of the tool, the authors reviewed and edited the content as necessary and take full responsibility for the accuracy, originality, and integrity of the published work.
AB: Conceptualization, Investigation, Formal analysis, Visualization, Writing—original draft, Writing—review & editing. IS: Writing—review & editing. AT: Writing—review & editing, Supervision. GT: Conceptualization, Writing—review & editing, Supervision. DN: Conceptualization, Supervision, Writing—review & editing, Project administration, Funding acquisition. All authors read and approved the submitted version.
The authors declare that they have no conflicts of interest.
Not applicable.
Not applicable.
Not applicable.
Not applicable.
This research was partly funded by the Special Account for Research Funds of the University of Crete (SARF UoC) KA 10082 to D.N. The funders had no role in decision to publish, or preparation of the manuscript.
© The Author(s) 2026.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.