Heparan Sulfates Regulate Angiogenic Signaling and Drug Response in Aggressive Ovarian Cancer

Introduction

Heparan sulfate proteoglycans (HSPGs) are critical regulators of growth factor availability and angiogenic signalling within the tumour microenvironment. Dysregulation of heparan sulfate (HS) biosynthesis has been implicated in tumour progression; however, the mechanisms by which altered HS architecture spatially controls angiogenic signalling and therapy response in ovarian cancer remain incompletely understood. This study investigates the role of exostosin glycosyltransferase 1 (EXT1), a central enzyme in HS biosynthesis, in regulating angiogenesis and platinum resistance.

Methods

EXT1 was overexpressed in ovarian cancer cells to modulate HS biosynthesis and deposition. HS accumulation was assessed, and levels of angiogenic mediators in conditioned media were quantified. Endothelial tube formation was evaluated using conditioned medium and direct co-culture assays with human umbilical vein endothelial cells (HUVECs). Platinum sensitivity was assessed in EXT1-high cells, with or without enzymatic degradation of HS using heparinase, to determine the functional impact of HS-mediated sequestration.

Results

EXT1 overexpression significantly increased pericellular HS deposition, creating a localized reservoir for chemokines and pro-angiogenic growth factors. Conditioned medium from EXT1-overexpressing cells contained reduced levels of VEGFR, EDN1, IL6, and IL8 and exhibited diminished capacity to induce endothelial tube formation. In contrast, direct co-culture of EXT1-overexpressing ovarian cancer cells with HUVECs markedly enhanced tube formation, indicating that HS promotes angiogenesis through localized, contact-dependent paracrine signalling rather than freely diffusible factors. Additionally, elevated HS levels contributed to platinum resistance by sequestering therapeutic agents, impairing drug penetration, and altering receptor–ligand interactions. Enzymatic degradation of HS restored platinum sensitivity in EXT1-high cells.

Conclusions

These findings demonstrate that EXT1-driven HS remodelling regulates angiogenesis by spatially controlling growth factor bioavailability and contributes to therapy resistance, positioning HS structures as promising therapeutic targets and potential scaffolds for ligand-mediated drug delivery strategies in ovarian cancer.