Table 1.

Key proteoglycans organized per class, with cellular source(s), and selected functional roles indicated

Proteoglycan	Expression	Source(s)	Functional Role(s)	References
Serglycin	Intracellular	Immune cells, endothelial cells, fibroblasts, chondrocytes, smooth muscle cells, fetal liver, nasopharyngeal, and hematopoietic cancer cells	Complexes with and modulates the activities of mast cell proteases, e.g., chymases, tryptases, and carboxypeptidase A; acts as a vehicle for delivery of granzyme B in cytotoxic cells; triggers CD44 signaling in tumor cells; regulates IL-8 secretion in cancers; via tumor-derived exosomes, it protects human multiple myeloma from complement attack by binding C1q and MBL in the TME	21, 22–24, 25–42
Syndecan-1	Cell surface	Normal and malignant plasma cells; normal and malignant epithelial cells	Sequesters T-cell specific CC-chemokines, and in soluble form, with VEGFR2 and VLA-4; On the cell surface, engages CXCR4, VLA-4, and VEGFR2; upregulates IL-23 and Notch ligand DLL4, which polarizes CD4+ T cells toward the Treg, Th17, and Th1 phenotypes	21, 43–56, 57–64
Syndecan-2	Cell surface	Mesenchymal cells, tumor-associated stromal cells	Modulates TFG-β signaling to control tumorigenesis via TFG-β-induced genes PD-L1 and CXCR4 in TASC	21, 43–56, 65
Syndecan-3	Cell surface	Neuronal tissue; tumor-associated macrophages; tumor endothelial cells; bladder, prostate, breast, and pancreatic cancer cell lines	Accentuates the IFN-γ-regulome, including upregulation of CD274 and CD8; regulates hypoxia-resistance in a HIF1α-dependent manner	21, 43–56, 66,67
Syndecan-4	Cell surface	Ubiquitous expression	Ligand for dendritic cell-associated heparan sulfate proteoglycan-integrin ligand (DC-HIL) to attenuate T-cell activation; sequesters TFG-β on the cell surface	21, 43–56, 68–72
Chondroitin sulfate proteoglycan 4	Cell surface	Monocytes/macrophages	Activates monocytes to secrete IL-1β and induce monocyte-dependent B cell proliferation in vitro	21, 73–75
Betaglycan	Cell surface	Ubiquitous expression	Accentuates TGF-β signaling or interferes with TGF-β receptor type I and TGF- β receptor type II complexing; in soluble form, can sequester TGF-β; upregulates Cdc42 via β-arrestin-2 in vivo	76–81
Glypican-1	Cell surface	Ubiquitous expression	FGF signaling; PTEN attenuation; Akt and β-catenin signaling; recognition by NK cells via NKp46 and NKp30; interacts with VEGF via HS chains	21, 82, 83, 84
Glypican-2	Cell surface	Embryonic central nervous system tissue; neuroblastoma cells	Upregulates expression of N-Myc, which in turn promotes transcription of the glypican-2 in a positive feedback loop	21, 82, 83
Glypican-3	Cell surface	Ovary, breast, lung, and kidney epithelial cells	Sequesters VEGF in TME; inhibits Zeb1 transcription factor; influences PI3K/Akt, p38, ERK1/2, and Wnt signaling pathways (context dependent); induces cytotoxic T-cell and macrophage recruitment in HCC	21, 82, 83, 85–87
Glypican-4	Cell surface	Ubiquitous expression	Accentuates Wnt signaling and pluripotency; reduces sensitivity of pancreatic cancer cells to 5-fluorouracil	21, 82, 83
Glypican-5	Cell surface	Central nervous system	Acts through FGF, HGF, and Wnt1α to promote cell division; tumor suppressor in certain contexts, e.g., glioma	21, 82, 83
Glypican-6	Cell surface	Gallbladder, urinary bladder, liver, appendix, and kidney epithelial cells	CD8A mRNA transcription; Wnt signaling modulation; tumor infiltration of cytotoxic T-cells	21, 82, 83, 88
Perlecan	Pericellular	Stromal cells	Sequesters bioactive molecules (via GAG chains)	21, 89–93
Agrin	Pericellular	Stromal cells	Activates VEGF-VEGFR2 pathway; stimulates angiogenesis	21, 94
Biglycan	Extracellular	Stromal cells; macrophages; immune cells	Binds TLR2/4; forms complexes with CD14-TLR4 and P2X4/P2X7 respectively; promotes tumor progression	95, 96–104, 105
Decorin	Extracellular	Stromal cells	Binds TLR2/4; sequesters TGF-β; upregulates PDCD4; inhibits tumor growth	95, 105–107
Lumican	Extracellular	Stromal cells	Enhances LPS-dependent TLR4 signaling; tumor-dependent impact on EMT, immune infiltration and inflammation	21, 97, 108–110
Versican	Extracellular	Stromal cells; myeloid cells	Binds hyaluronan, P and L selectins, CD44, and TLR2; promotes accumulation of tumor-associated macrophages and decrease intraepithelial tumor infiltrating lymphocytes; positively correlated with Th2 and Treg transcriptional signatures, negatively correlated with cytotoxic T-cell signatures	22, 10–13, 111–148
Aggrecan	Extracellular	Cartilage and perineural net stromal cells	Forms aggregates for load-bearing structural support and mechanical properties to joints; protects neurons via cation sequestration and mechanically stabilization of synaptic connections	21
Brevican	Extracellular	Neural tissue stromal cells	Interacts with tenascin-R and fibulin-2; neural tissue injury and repair, Alzheimer’s disease, glioma tumorigenesis	21
Neurocan	Extracellular	Neural tissue stromal cells	Alleviates mechanical and ischemic damage in central nervous system; inhibits neurite outgrowth in vivo; assists in neural guidance during development	21
Hyaluronan and proteoglycan link protein 1	Extracellular	Stromal cells	Binds to aggrecan complexes in cartilage to offer structural support; NF-κB pathway activation; myeloma drug resistance	149–153