Cell microenvironment, influencing cell behavior by binding signaling molecules or by modulating intracellular signaling cascades, has critical roles in several physiological as well as pathological processes. This review focused on new aspects of the regulation of the synthesis of hyaluronan, a key component of extracellular matrix ubiquitously distributed in human tissues and with multifaceted properties.

We review heparan sulfate (HS) proteoglycans in neural differentiation and discuss their impact on brain development. We also examine the role of structural modifications of HS in glioma growth and invasion. Targeting invasive mechanisms of glioma cells through modulation of HS structure and HS-mediated pathways may be an attractive therapeutic attempt to cure these highly malignant tumors.

MicroRNAs are post-transcriptional regulators of gene expression. In cancer, miRNA dysregulation results in aberrant expression of proteoglycans, suggesting a mechanistic role in disease progression. Tumor cell proliferation and apoptosis, metastasis, epithelial-to mesenchymal transition and cancer stem cell properties are affected due to the multifunctional properties of proteoglycans. The pharmacological targeting of the miRNA-proteoglycan axis emerges as a new therapeutic concept.

Proteolysis is a highly regulated and specific process. Here, we highlight recent findings, which suggest that PGs/GAG interplay regulates proteinases' activity, stability, substrate specificity and localization. The interaction between proteinases and proteoglycans may occur either through the GAG chains or the core protein of PGs. Such findings introduce a new avenue for specific cancer therapeutics.