Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment

Abstract

In the last few decades, heparan sulfate (HS) proteoglycans (HSPGs) have been an intriguing subject of study for their complex structural characteristics, their finely regulated biosynthetic machinery, and the wide range of functions they perform in living organisms from development to adulthood. From these studies, key roles of HSPGs in tumor initiation and progression have emerged, so that they are currently being explored as potential biomarkers and therapeutic targets for cancers. The multifaceted nature of HSPG structure/activity translates in their capacity to act either as inhibitors or promoters of tumor growth and invasion depending on the tumor type. Deregulation of HSPGs resulting in malignancy may be due to either their abnormal expression levels or changes in their structure and functions as a result of the altered activity of their biosynthetic or remodeling enzymes. Indeed, in the tumor microenvironment, HSPGs undergo structural alterations, through the shedding of proteoglycan ectodomain from the cell surface or the fragmentation and/or desulfation of HS chains, affecting HSPG function with significant impact on the molecular interactions between cancer cells and their microenvironment, and tumor cell behavior. Here, we overview the structural and functional features of HSPGs and their signaling in the tumor environment which contributes to tumorigenesis and cancer progression.

Keywords: extracellular matrix; heparan sulfate proteoglycans; remodeling; signaling; tumor microenvironment.

Figure 1

Schematic representation of the main HSPG functions relevant to cancer cell biology. (A,D) HSPGs serve as a signaling co-receptor for growth factor activity, allowing a proper presentation of them to their cognate receptors, on the same or adjacent cells. In panel D, transcellular transport of a ligand (i.e., chemokine) bound to HS chains and its presentation at the cell surface is also shown. (B,D) HGPGs bind integrins modulating their downstream signaling that regulates cytoskeleton organization as well as cell adhesion, spreading and sensing mechanical stress. (C) HSPGs act as endocytic receptors and undergo constitutive as well as ligand-induced endocytosis: exosomes, cell-penetrating peptides, polycation–nucleic acid complexes, lipoproteins, growth factors, and morphogens enter cells through this mechanism. Internalized cargo can be sorted for lysosomal degradation, escape into the cytosol, or recycle back to the plasma membrane. (E) HSPGs are critical determinants of extracellular matrix (ECM) assembly and remodeling. If the HSPGs perlecan, agrin, and collagen type XVIII are directly secreted in the ECM, cell surface-tethered HSPGs (syndecans and glypicans) undergo proteolytic cleavage of their ectodomains or to cleavage of HS chains by heparanases and their truncated forms can be distributed in the ECM. Here, HSPGs act as a reservoir of growth factors and supply them to target cells when needed. Otherwise, they may act as a barrier for growth factors, by preventing their passive diffusion over longer distances, instead of confining them to the vicinity of producing cells. Overall, HSPGs control fundamental cellular processes (i.e., cell adhesion, migration, etc.) whose dysregulation underlies tumor development and progression.

Figure 2

Schematic representation of the interaction between HSPGs, growth factors, and receptors, and main downstream signaling pathways that lead to tumor development and progression.