Role of HSPGs in cancer cell migration

Structural variations and heterogeneities associated with the amount and the position of sulfated groups of their glycosaminoglycan (GAG) chains allow heparan sulfate proteoglycans (HSPGs) to have distinct biological functions due to their ability to interact with different heparin binding ligands, such as growth factors, morphogens, chemokines, adhesion molecules and ECM components. They take part in many processes in both physiological and pathological conditions. Indeed, HSPGs are involved in multiple events of cancer progression, such as cancer cell adhesion, epithelial-mesenchymal transition, migration and invasion. Specifically, cell migration is a multistep process where the actin cytoskeleton, which is capable of reorganizing itself and forming specific structures for movement, plays a key role. Cells can move either as individual cells or collectively. Modification of cancer cell phenotype, through epithelial mesenchymal transition, allows them to leave the primary tumor, invade surrounding tissues and migrate to secondary sites, thus giving rise to metastasis. The tetra-branched peptide NT4 can recognize HSPGs, targeting their sulfated GAGs and selectively binding to cancer cells and tissues. Based on this specific binding, the possible effects produced by the peptide on cadherins and Eph receptors were analyzed, showing no interaction in either case. By studying the localization of HSPGs in migrating cells, it was possible to note a different distribution depending on the cell line. In addition, the effects induced by NT4 and heparin on the processes of colony formation, adhesion and migration were also evaluated and compared each other, suggesting a greater efficacy of the peptide. Finally, two tumor cell lines, in particular human pancreas adenocarcinoma and human rhabdomyosarcoma cells, were transfected with a plasmid able to mark actin, making it fluorescent.