Proteoglycans as Regulators of Receptor Trafficking and Spatial Signaling in Cancer

Abstract

Simple Summary Proteoglycans are complex molecules located on the cell surface and within the extracellular matrix that have traditionally been viewed as structural components or co-receptors. However, growing evidence shows that they actively regulate where receptors are located, how they move inside cells, and how long signaling persists. These processes are particularly important in cancer, where abnormal receptor trafficking contributes to uncontrolled growth, invasion, metastasis, and resistance to therapy. In this review, we summarize current knowledge on how proteoglycans regulate receptor clustering, endocytosis, intracellular trafficking, recycling, degradation, endosomal signaling, exosome biology, and nuclear receptor transport. We also discuss how alterations in proteoglycan expression, glycosaminoglycan composition, and extracellular matrix remodeling reshape signaling networks within the tumor microenvironment. Understanding these mechanisms identifies proteoglycans as central organizers of cancer signaling and highlights new opportunities for therapeutic intervention targeting receptor trafficking and spatial signaling regulation.