The glycocalyx and its significance in human medicine

Abstract

Cells are covered by a surface layer of glycans that is referred to as the 'glycocalyx'. In this review, we focus on the role of the glycocalyx in vascular diseases (atherosclerosis, stroke, hypertension, kidney disease and sepsis) and cancer. The glycocalyx and its principal glycosaminoglycans [heparan sulphate (HS) and hyaluronic acid (HA)] and core proteins (syndecans and glypicans) are degraded in vascular diseases, leading to a breakdown of the vascular permeability barrier, enhanced access of leucocytes to the arterial intima that propagate inflammation and alteration of endothelial mechanotransduction mechanisms that protect against disease. By contrast, the glycocalyx on cancer cells is generally robust, promoting integrin clustering and growth factor signalling, and mechanotransduction of interstitial flow shear stress that is elevated in tumours to upregulate matrix metalloproteinase release which enhances cell motility and metastasis. HS and HA are consistently elevated on cancer cells and are associated with tumour growth and metastasis. Later, we will review the agents that might be used to enhance or protect the glycocalyx to combat vascular disease, as well as a different set of compounds that can degrade the cancer cell glycocalyx to suppress cell growth and metastasis. It is clear that what is beneficial for either vascular disease or cancer will not be so for the other. The overarching conclusions are that (i) the importance of the glycocalyx in human medicine is only beginning to be recognized, and (ii) more detailed studies of glycocalyx involvement in vascular diseases and cancer will lead to novel treatment modalities.

A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin–Drug Conjugate (LDC)

“…1, 2), are attractive therapies, but their clinical success rates have been limited (3). The targets of these drugs are usually peptides of cell transmembrane proteins; however, it is important to note that cell surfaces are covered by a glycan layer that is referred to as the glycocalyx (4). The glycomes of cancer cell surfaces are often unique, with aberrant glycosylation, including sialylation, fucosylation, O-glycan truncation, and N-and O-linked glycan branching (5)(6)(7).…”

“…The therapeutic effects of LDC on PDAC were tested in vivo using a cell line-based xenograft (cell-xeno) model and a patient-derived xenograft (PDX) model. September 19, 2013), BxPC-3 (CRL-1687, Aug. 4,2015), Capan-1 (HTB-79, July 26, 2013), MIAPaCa-2 (CRL-1420, September 5, 2013), and PANC-1 (CRL-1469, March 4, 2015) were purchased from ATCC, and SUIT-2 (JCRB1094, July 28, 2015) was obtained from the National Institute of Biomedical Innovation. The morphologies of their clinical PDAC origin were as follows: well differentiated for Capan-1; and those of the other five lines were poorly or poorly moderately differentiated (13).…”

Endothelial Glycocalyx: Novel Insight into Atherosclerosis

“…The glycocalyx has various functions [5,28]. The negatively charged glycocalyx surface forms an electrostatic barrier for plasma cells and proteins, like albumin.…”

“…However, high shear stress is thought to be atheroprotective as the high shear stress region (>10~15 dyn/cm 2 ) in the normal artery is not likely to develop AS [30]. It also well known that high shear stress induces the fusiform body arrangement of vascular ECs, and secretion of active substances such as nitric oxide (NO), prostacyclin (PGI2) and superoxide dismutase (SOD), thus protecting the vessels [11,28,49]. It is worth to investigate why high shear stress plays distinct roles in atherosclerotic lesions and normal vessels.…”

Modeling Loss of Microvascular Wall Homeostasis during Glycocalyx Deterioration and Hypertension that Impacts Plasma Filtration and Solute Exchange

“…On the other hand, glycocalyx proteins are damaged in vascular diseases, leading to inflammation, which in turn causes further damages in a sort of vicious circle [15]. Patients with type 1 diabetes mellitus and microalbuminuria have been shown to be more susceptible to glycocalyx degradation, compared to their normal buminuric counterparts [16].…”