Proteoglycans as Mediators of Cancer Tissue Mechanics

Abstract

Proteoglycans are a diverse group of molecules which are characterized by a central protein backbone that is decorated with a variety of linear sulfated glycosaminoglycan side chains. Proteoglycans contribute significantly to the biochemical and mechanical properties of the interstitial extracellular matrix where they modulate cellular behavior by engaging transmembrane receptors. Proteoglycans also comprise a major component of the cellular glycocalyx to influence transmembrane receptor structure/function and mechanosignaling. Through their ability to initiate biochemical and mechanosignaling in cells, proteoglycans elicit profound effects on proliferation, adhesion and migration. Pathologies including cancer and cardiovascular disease are characterized by perturbed expression of proteoglycans where they compromise cell and tissue behavior by stiffening the extracellular matrix and increasing the bulkiness of the glycocalyx. Increasing evidence indicates that a bulky glycocalyx and proteoglycan-enriched extracellular matrix promote malignant transformation, increase cancer aggression and alter anti-tumor therapy response. In this review, we focus on the contribution of proteoglycans to mechanobiology in the context of normal and transformed tissues. We discuss the significance of proteoglycans for therapy response, and the current experimental strategies that target proteoglycans to sensitize cancer cells to treatment.

Keywords: GAG; cancer; glycocalyx; mechanosignaling; proteoglycans.

FIGURE 1

Within a growing tumor, cells are subjected to mechanical forces, in response to which the cells exert tensile, compressive or shear stress. Tensile pressure (tissue tension), stems from ECM stiffening and remodeling; compressive pressure applied occurs when tumor cells proliferate in a confined space leading to vascular compression and damage; and shear force that is experienced by the cancer cells in the circulation.

FIGURE 2

Mechano-transduction in cells is mediated through integrin activation upon binding to the ECM components, such as fibronectin. Syndecans (S) facilitate this interaction by binding the ECM with HS chains. Intracellular syndecan domains activate signaling with PKCα (P) and via binding to PDZ-motif proteins. Integrin activation recruits a host of focal adhesion components, including integrin-binding adaptor proteins – talin and paxillin (PX); actin binding cytoskeletal proteins VASP and vinculin (V); and focal-adhesion associated kinases Src, FAK and ROCK. VASP and zyxin (Z) facilitate actin polymerization and connect it to the focal adhesion complex. Phosphorylation of p130Cas by Src allows docking and activation of several signaling pathways, such as the MAPK, the c-Jun N-terminal kinase (JNK) pathway and others.

FIGURE 3

Proteoglycans’ localization. Serglycin (SG) is the only intracellular proteoglycan, found in secretory vesicles (SV). It carries both HS (blue) and CS (red) GAG chains. Transmembrane proteoglycans include, but are not limited to phosphacan (P), betaglycan (B), syndecans (S) and glypicans (G). In the ECM, SLRPs are short proteoglycans that carry either a CS or a DS (green) GAG chain. Other proteoglycans include testican (T) and hyalectins that aggregate with hyaluronic acid (HA). Basement membrane (BM) contains agrin (A), perlecan (PR) and collagens XV (XV) and XVIII (XVIII).

FIGURE 4

Stiff matrix, rich in tenascin (T) and proteoglycans promote bulkier glycocalyx and up-regulate mechanosignaling through focal adhesions (FA) and down-stream pathways. Activation of mechanosignaling results in production of more proteoglycans that contribute to bulkier glycocalyx and stiffer ECM, thus concluding a positive-feedback loop in tumor tissue.