The effects of sulfated hyaluronan in breast, lung and colorectal carcinoma and monocytes/macrophages cells: Its role in angiogenesis and tumor progression

Abstract

Hyaluronan (HA) is a component of the extracellular matrix (ECM) it is the main non‐sulfated glycosaminoglycan able to modulate cell behavior in the healthy and tumor context. Sulfated hyaluronan (sHA) is a biomaterial derived from chemical modifications of HA, since this molecule is not naturally sulfated. The HA sulfation modifies several properties of the native molecule, acquiring antitumor properties in different cancers. In this study, we evaluated the action of sHA of ~30–60 kDa with different degrees of sulfation (0.7 sHA1 and 2.5 sHA3) on tumor cells of a breast, lung, and colorectal cancer model and its action on other cells of the tumor microenvironment, such as endothelial and monocytes/macrophage cells. Our data showed that in breast and lung tumor cells, sHA3 is able to modulate cell viability, cytotoxicity, and proliferation, but no effects were observed on colorectal cancer cells. In 3D cultures of breast and lung cancer cells, sHA3 diminished the size of the tumorsphere and modulated total HA levels. In these tumor models, treatment of monocytes/macrophages with sHA3 showed a downregulation of the expression of angiogenic factors. We also observed a decrease in endothelial cell migration and modulation of the hyaluronan‐binding protein TSG‐6. In the breast in vivo xenograft model, monocytes/macrophages preincubated with sHA1 or sHA3 decreased tumor vasculature, TSG‐6 and HA levels. Besides, in silico analysis showed an association of TSG‐6, HAS2, and IL‐8 with biological processes implicated in the progression of the tumor. Taken together, our data indicate that sHA in a breast and lung tumor context is able to induce an antiangiogenic action on tumor cells as well as in monocytes/macrophages (Mo/MØ) by modulation of endothelial migration, angiogenic factors, and vessel formation.

‘Two-faces’ of hyaluronan, a dynamic barometer of disease progression in tumor microenvironment

“…Recently, a research team finds out that HMW-HA exclusively facilitates the angiogenic action of breast cancer by modeling its immune microenvironment. HMW-HA promotes the migration of ECs by stimulating monocyte/macrophagocyte to secret an increased amount of angiogenic factors, although a similar action is not observed in other cancers [ 150 , 151 ] The infiltration and migration of monocyte/macrophagocyte are otherwise inhibited by increased concentration of HMW-HA in spinal nerves, maybe because HMW-HA competitive binds to receptors which block the activation of pro-inflammatory LMW-HA/receptor [ 152 ]. Based on current evidence, HMW-HA exerts anti-angiogenesis regulation among a majority of tumors, but still exhibits angiogenic action exclusively to specific one.…”

A Dual Reversible Cross‐Linked Hydrogel with Enhanced Mechanical Property and Capable of Proangiogenic and Osteogenic Activities for Bone Defect Repair

“…Previous studies have reported that sulfation and Mg 2+ can enhance the migration and tube formation of vascular endothelial cells. [29][30][31] Sulfation has also been shown to stimulate the proliferation and elongation of endothelial cells, thereby promoting angiogenesis. [32] This effect is attributed to the interaction between negatively charged sulfate groups and endogenous vascular endothelial growth factor-A (VEGF-A 165 ), which influences VEGF receptor phosphorylation and endothelial cell migration, ultimately facilitating the formation of new vascular networks.…”

A Comprehensive Review of Electrospun Fibers, 3D-Printed Scaffolds, and Hydrogels for Cancer Therapies

“…The molecules of HA natively occur in native ECM, and HA has easily tunable mechanical properties through adjustment of concentration and crosslinking degree. The great advantage of HA is the ability to modulate healthy and tumor cells’ fate [ 174 ].…”