Heparan sulfate proteoglycans in cancer: Pathogenesis and therapeutic potential

Yang, Hua; Wang, Lianchun

doi:10.1016/bs.acr.2022.08.001

Cited by 5 publications

(4 citation statements)

References 218 publications

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“…Regarding possible in vivo studies, we hypothesize that the native CPAb variant, without charge shielding of the paratope, would bind all cell types indiscriminately, due to the ubiquitous presence of HSPG on cell surfaces [ 12 ]; thus, we assume only a fraction would internalize and accumulate in desired target cells. Furthermore, we suspect that the CDR residues involved in electrostatic interactions with HSPG are prone to saturation and blocking via negatively charged serum components, resulting in low biodistribution and bioavailability of active antibodies in the organism.…”

Section: Discussionmentioning

confidence: 99%

“…In the past, it has been observed that some antibodies associated with the autoimmune disease Systemic Lupus Erythematosus (SLE) bind to double-stranded DNA (anti-dsDNA antibodies) and can penetrate the cytosol [ 8 , 9 , 10 , 11 ]. Further studies have shown that cellular uptake is initiated by binding to heparan sulfate proteoglycan (HSPG), a glycoprotein that is found on the surface of most cell types [ 8 , 12 ]. HSPGs are covalently attached to one or more heparan sulfate (HS) side chains [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…The decrease in pH within the endosomes induces local conformational changes in the antibody loop, promoting pore formation in the endosomal membrane through the hydrophobic aromatic triple residue motif, ultimately leading to the release of the antibody into the cytosol [ 23 ]. Notably, HSPG is present on the surface of most cell types, making cytosol penetration unspecific [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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A Conditionally Activated Cytosol-Penetrating Antibody for TME-Dependent Intracellular Cargo Delivery

Dombrowsky,

Happel,

Habermann

et al. 2024

Antibodies

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Currently, therapeutic and diagnostic applications of antibodies are primarily limited to cell surface-exposed and extracellular proteins. However, research has been conducted on cell-penetrating peptides (CPP), as well as cytosol-penetrating antibodies, to overcome these limitations. In this context, a heparin sulfate proteoglycan (HSPG)-binding antibody was serendipitously discovered, which eventually localizes to the cytosol of target cells. Functional characterization revealed that the tested antibody has beneficial cytosol-penetrating capabilities and can deliver cargo proteins (up to 70 kDa) to the cytosol. To achieve tumor-specific cell targeting and cargo delivery through conditional activation of the cell-penetrating antibody in the tumor microenvironment, a single-chain Fc fragment (scFv) and a VL domain were isolated as masking units. Several in vitro assays demonstrated that fusing the masking protein with a cleavable linker to the cell penetration antibody results in the inactivation of antibody cell binding and internalization. Removal of the mask via MMP-9 protease cleavage, a protease that is frequently overexpressed in the tumor microenvironment (TME), led to complete regeneration of binding and cytosol-penetrating capabilities. Masked and conditionally activated cytosol-penetrating antibodies have the potential to serve as a modular platform for delivering protein cargoes addressing intracellular targets in tumor cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Conditionally Activated Cytosol-Penetrating Antibody for TME-Dependent Intracellular Cargo Delivery

Dombrowsky,

Happel,

Habermann

et al. 2024

Antibodies

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“…Glypicans have also been associated with liver carcinoma. The role of heparan sulfate proteoglycans in cancer has been found to be of diagnostic value, but has also been reported as tumor‐suppressive, depending on the heparan sulfate proteoglycans and the cancer cell type 177 …”

Section: Heparan Sulfate and Heparan Sulfate Proteoglycans In Diseasementioning

confidence: 99%

Control of tissue homeostasis by the extracellular matrix: Synthetic heparan sulfate as a promising therapeutic for periodontal health and bone regeneration

Miguez,

Bash,

Musskopf

et al. 2023

Periodontology 2000

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Proteoglycans are core proteins associated with carbohydrate/sugar moieties that are highly variable in disaccharide composition, which dictates their function. These carbohydrates are named glycosaminoglycans, and they can be attached to proteoglycans or found free in tissues or on cell surfaces. Glycosaminoglycans such as hyaluronan, chondroitin sulfate, dermatan sulfate, keratan sulfate, and heparin/heparan sulfate have multiple functions including involvement in inflammation, immunity and connective tissue structure, and integrity. Heparan sulfate is a highly sulfated polysaccharide that is abundant in the periodontium including alveolar bone. Recent evidence supports the contention that heparan sulfate is an important player in modulating interactions between damage associated molecular patterns and inflammatory receptors expressed by various cell types. The structure of heparan sulfate is reported to dictate its function, thus, the utilization of a homogenous and structurally defined heparan sulfate polysaccharide for modulation of cell function offers therapeutic potential. Recently, a chemoenzymatic approach was developed to allow production of many structurally defined heparan sulfate carbohydrates. These oligosaccharides have been studied in various pathological inflammatory conditions to better understand their function and their potential application in promoting tissue homeostasis. We have observed that specific size and sulfation patterns can modulate inflammation and promote tissue maintenance including an anabolic effect in alveolar bone. Thus, new evidence provides a strong impetus to explore heparan sulfate as a potential novel therapeutic agent to treat periodontitis, support alveolar bone maintenance, and promote bone formation.

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Genomic analyses identify 15 susceptibility loci and revealHDAC2,SOX2-OT, andIGF2BP2in a naturally-occurring canine model of gastric cancer

Cook,

Hugen,

Hayward

et al. 2024

Preprint

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Gastric cancer (GC) is the fifth most common human cancer worldwide, but the genetic etiology is largely unknown. We performed a Bayesian genome-wide association study and selection analyses in a naturally-occurring canine model of GC, the Belgian Tervuren and Sheepdog breeds, to elucidate underlying genetic risk factors. We identified 15 loci with over 90% predictive accuracy for the GC phenotype. Variant filtering revealed germline putative regulatory variants for theEPAS1(HIF2A) andPTENgenes and a coding variant inCD101. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois atSOX2-OTandIGF2BP2. Among Tervuren and Sheepdogs,HDAC2putative regulatory variants were present at comparatively high frequency and were associated with GC. Here, we describe a complex genetic architecture governing GC in a dog model, including genes such asPDZRN3, that have not been associated with human GC.

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Heparan sulfate proteoglycans in cancer: Pathogenesis and therapeutic potential

Cited by 5 publications

References 218 publications

A Conditionally Activated Cytosol-Penetrating Antibody for TME-Dependent Intracellular Cargo Delivery

A Conditionally Activated Cytosol-Penetrating Antibody for TME-Dependent Intracellular Cargo Delivery

Control of tissue homeostasis by the extracellular matrix: Synthetic heparan sulfate as a promising therapeutic for periodontal health and bone regeneration

Genomic analyses identify 15 susceptibility loci and revealHDAC2,SOX2-OT, andIGF2BP2in a naturally-occurring canine model of gastric cancer

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