Extracellular Matrix Components and Mechanosensing Pathways in Health and Disease

Abstract

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are essential components of the extracellular matrix (ECM) with pivotal roles in cellular mechanosensing pathways. GAGs, such as heparan sulfate (HS) and chondroitin sulfate (CS), interact with various cell surface receptors, including integrins and receptor tyrosine kinases, to modulate cellular responses to mechanical stimuli. PGs, comprising a core protein with covalently attached GAG chains, serve as dynamic regulators of tissue mechanics and cell behavior, thereby playing a crucial role in maintaining tissue homeostasis. Dysregulation of GAG/PG-mediated mechanosensing pathways is implicated in numerous pathological conditions, including cancer and inflammation. Understanding the intricate mechanisms by which GAGs and PGs modulate cellular responses to mechanical forces holds promise for developing novel therapeutic strategies targeting mechanotransduction pathways in disease. This comprehensive overview underscores the importance of GAGs and PGs as key mediators of mechanosensing in maintaining tissue homeostasis and their potential as therapeutic targets for mitigating mechano-driven pathologies, focusing on cancer and inflammation.

Keywords: cancer; glycosaminoglycans; glypican; inflammation; mechanosensing; mechanotransduction; proteoglycans; syndecans.

Figure 1

Schematic representation of the major proteoglycan constituents of the extracellular matrix (ECM) and the cellular glycocalyx (GCX) (adapted from a depiction presented in [7]). The structures of the glycosaminoglycan components are displayed. HA, hyaluronan: 4-D-GlcA-β1-3-D-GlcNAc-β1. CS, (4S/6S)-chondroitin 4/6-sulfate: 4-D-GlcA-β1-3-D-GalNAc, 4S/6S-β1. DS, Dermatan sulfate: -4-L-IdoA-α1-3-DGalNAc, 4S-β1-. HS, heparan sulfate: -4-D-GlcNAc-α1, 4-D-GlcA-β1-. KS, keratan sulfate: -4-D-GlcNAc, 6S-β1-3-D-Gal-β1-. Color displayed in the monosaccharide units follows the SNFG recommendations. Perez, Serge; Nikitovic, Dragana (2024). Proteoglycans extracellular matrix. figshare. Figure: https://doi.org/10.6084/m9.figshare.26963677.v2 (accessed on 9 September 2024). CC by 4.0.

Figure 2

Integrins, cadherins, PIEZO, and GPRC receptors are involved in transmitting mechanical cues from the extracellular space to cells. Mechanical stimulation activates the receptors. Created in BioRender. Nikitovic, D. (2024) BioRender.com/g48k171 (accessed on 12 September 2024).

Figure 3

PG–integrin interactions in mechanotransduction (A) Force exerted on syndecan 4 activates the kindlin 2–β1 integrin–RhoA axis through PI3K and EGFR, causing a conformational change that helps form a syndecan 4–α-actinin–F-actin scaffold at adhesion sites. (B) α5β1 integrin and syndecan 4 bind to fibrillar fibronectin, initiating cell adhesion and activating signaling pathways involving Arp2/3, RhoA, paxillin, and PI3K. These pathways enhance adhesion to stiffer fibrillar FN through actin polymerization and myosin II-mediated contraction, which results in increased fibroblast proliferation and migration. Created in BioRender. Nikitovic, D. (2024) BioRender.com/j32l871 (accessed on 12 September 2024).

Figure 4

Snapshot of the glypican 1 system comprising: glypican 1 protein, N-glycans, GPI-anchor, and three heparan sulfate chains (degree of polymerization: 30) linked to the protein and membrane (adapted from Dong et al., 2021 [109]). Color displayed in the monosaccharide units follows the SNFG recommendations. Perez, Serge; Nikitovic, Dragana (2024). Glypican 1 system. figshare. Figure: https://doi.org/10.6084/m9.figshare.26983060.v1 (accessed on 12 September 2024). CC by 4.0.

Figure 5

PGs transduce shear stress to regulate endothelial cells’ functions. (A) Glypican 1 senses shear force to initiate the PECAM1–eNOS axis and increase NO production. (B) In response to shear stress, syndecan 1 interacts with Src and calmodulin (CaM), enhancing actin alignment and endothelial cell cytoskeleton reorganization. (C) Syndecan 1 perpetrates critical initial responses to shear stress, including Akt activation, creating paxillin phosphorylation gradients, and RhoA activation, which results in aligning the actin cytoskeleton with the flow. Created in BioRender. Nikitovic, D. (2024). BioRender.com/i78n493 (accessed on 12 September 2024).

Figure 6

Parameters of ECM stiffening in the cancer microenvironment. During cancer development, ECM stiffening and desmoplasia occur. ECM fiber alignment and fiber cross-linking together with the secretion of growth factors (GFs), cytokines, mitogens, and enzymes (MMPs) by cancer-associated fibroblasts (brown cells) and immune cells (green cells) lead to modulation of mechanosensing and mechanotransduction pathways (receptors, signaling molecules, and cytoskeletal proteins). Finally, all the above lead to changes in cancer cell functions, such as motility, survival, metastasis, and chemotherapy resistance. Created in BioRender. Nikitovic, D. (2024). BioRender.com/k83x155 (accessed on 12 September 2024).

Figure 7

Inflammatory network of the ECM components. Infiltrating immune cells that arrive at the inflamed tissue synthesize and secrete cytokines, chemokines (CXCL, CXC chemokine ligand, IL-6, interleukin 6, TNF, tumor necrosis factor), proteases, and MMPs. All these molecules activate resident cells in the interstitium, alter ECM synthesis and/or inflict cleavage of ECM components, releasing biglycan, tenascin, and generating HA fragments. These ECM components enhance the inflammatory response by modulating immune cell chemotaxis, activation, differentiation or survival, perpetuating the inflammatory response by activating Toll-like receptor (TLR) 2 and 4.

Figure 8

A standard pipeline implementing machine learning/deep learning to interpret and assess mechanotransduction cues. Created in BioRender. Nikitovic, D. (2024). BioRender.com/m58b525 (accessed on 12 September 2024).