Glycosaminoglycans (GAGs) in cancer. (A) Hyaluronan interacts multivalently with CD44, which interacts with several types of signaling molecules in lipid rafts in the plasma membrane, thus promoting cell survival, proliferation, invasion, and epithelial–mesenchymal transition (EMT) in developing, regenerating, and malignant cells. In cancers, hyaluronan interactions can act cell-autonomously at the tumor cell surface or via hyaluronan produced by stromal cells. (B) Heparan sulfate (HS) proteoglycans present at the cell surface (e.g., syndecans and glypicans), or sequestered in the extracellular matrix (ECM) and basement membrane (e.g., perlecan), can be released by proteases in the microenvironment. Bioactive HS fragments can also be released by heparanase cleavage. The HS chains interact with several growth factors and amplify their interactions with their respective receptors on various cell types, thus resulting in increased angiogenesis or increased proliferation and invasion by tumor cells. However, HS proteoglycans can have inhibitory as well as stimulatory effects on tumor progression (e.g., via sequestration vs. release of HS-bearing growth factors from the ECM).