Molecular size-dependent specificity of hyaluronan on functional properties, morphology and matrix composition of mammary cancer cells.

High levels of hyaluronan (\u397\u391), a major extracellular matrix (ECM) glycosaminoglycan, have been correlated with poor clinical outcome in several malignancies, including breast cancer. The high and low molecular weight H\u391 forms exert diverse biological functions. Depending on their molecular size, \u397\u391 forms either promote or attenuate signaling cascades that regulate cancer progression. In order to evaluate the effects of different \u397\u391 forms on breast cancer cells' behavior, \u397\u391 fragments of defined molecular size were synthesized. Breast cancer cells of different estrogen receptor (ER) status \u2013 the low metastatic, ER\u3b1-positive MCF-7 epithelial cells and the highly aggressive, ER\u3b2-positive MDA-MB-231 mesenchymal cells \u2013 were evaluated following treatment with HA fragments. Scanning electron microscopy revealed that HA fragments critically affect the morphology of breast cancer cells in a molecular-size dependent mode. Moreover, the \u397\u391 fragments affect cell functional properties, the expression of major ECM mediators and epithelial-to-mesenchymal transition (\u395\u39c\u3a4) markers. Notably, treatment with 200\u202fkDa \u397\u391 increased the expression levels of the epithelial marker \u395-cadherin and reduced the expression levels of HA synthase 2 and mesenchymal markers, like fibronectin and snail2/slug. These novel data suggest that the effects of HA in breast cancer cells depend on the molecular size and the ER status. An in-depth understanding on the mechanistic basis of these effects may contribute on the development of novel therapeutic strategies for the pharmacological targeting of aggressive breast cancer

Heparan sulfate in the tumor microenvironment

The biology of tumor cells strictly depends on their microenvironment architecture and composition, which controls the availability of growth factors and signaling molecules. Thus, the network of glycosaminoglycans, proteoglycans, and proteins known as extracellular matrix (ECM) that surrounds the cells plays a central role in the regulation of tumor fate. Heparan sulfate (HS) and heparan sulfate proteoglycans (HSPGs) are highly versatile ECM components that bind and regulate the activity of growth factors, cell membrane receptors, and other ECM molecules. These HS binding partners modulate cell adhesion, motility, and proliferation that are processes altered during tumor progression. Modification in the expression and activity of HS, HSPGs, and the respective metabolic enzymes results unavoidably in alteration of tumor cell microenvironment. In this light, the targeting of HS structure and metabolism is potentially a new tool in the treatment of different cancer types