Sulfated Hyaluronan Modulates the Functional Properties and Matrix Effectors Expression of Breast Cancer Cells with Different Estrogen Receptor Status

Abstract

Hyaluronan (HA) is an extracellular matrix glycosaminoglycan (GAG) that plays a pivotal role in breast cancer. While HA is the only GAG not normally substituted with sulfate groups, sulfated hyaluronan (sHA) has previously been used in studies with promising antitumor results. The aim of the present study was to evaluate the effects sHA fragments have on breast cancer cells with different estrogen receptor (ER) status. To this end, ERα-positive MCF-7, and ERβ-positive MDA-MB-231 cells were treated with non-sulfated HA or sHA fragments of 50 kDa. The functional properties of the breast cancer cells and the expression of key matrix effectors were investigated. According to the results, sHA attenuates cell proliferation, migration, and invasion, while increasing adhesion on collagen type I. Furthermore, sHA modulates the expression of epithelial-to-mesenchymal transition (EMT) markers, such as e-cadherin and snail2/slug. Additionally, sHA downregulates matrix remodeling enzymes such as the matrix metalloproteinases MT1-MMP, MMP2, and MMP9. Notably, sHA exhibits a stronger effect on the breast cancer cell properties compared to the non-sulfated counterpart, dependent also on the type of cancer cell type. Consequently, a deeper understanding of the mechanism by which sHA facilitate these processes could contribute to the development of novel therapeutic strategies.

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

“…38 For example, downregulation of RHAMM or CD44, was observed in prostate cancer cell lines, resulting in a diminished PI3K/Akt signaling pathway. 12 Recently, Koutsakis et al 15 have demonstrated that sHA (similar to our sHA) modulates the expression of HA synthase but not CD44 in breast cancer cells. Finally, when we used an in vivo xenograft breast cancer model, we found a significant decrease in vascularization in tumors inoculated with Mo/MØ preincubated with sHA1 or sHA3.…”

“…As mentioned above, it was previously shown that sHA reduced tumor aggressiveness in several cancer models as bladder, prostate, and breast cancer. [12][13][14][15] However, no reports were found about action on tumor-associated cells, which was evaluated in our study. It is important to note that sHA action is dependent on sulfation degree, thus our first objective was to assess if the sHA1 and sHA3 sHA as LMW or fragments, with different sulfation degrees but similar MW range 30-60 kDa (around 60-100 monomers, see Table 1) affect the behavior of immune cells, Mo/MØ or EC associated to a tumor context.…”

“…14 Recently, it was observed that sHA, of low molecular weight (LMW) range and with high sulfation degree, modified breast cancer cell properties with different estrogen receptor status. 15 Tumor-associated cells such as immune cells and endothelial cells (EC) are essential in the tumor microenvironment. 16 In concert with malignant cells, they allow tumor progression t. One of the most important immune cells of the tumor microenvironment are macrophages (MØ).…”

“…Sulfated HA was also found to be a promising molecule for the treatment of angiogenesis‐related disease because it inhibited human umbilical vein endothelial cell (HUVEC) survival and proliferation and human dermal microvascular endothelial cell tube formation 14 . Recently, it was observed that sHA, of low molecular weight (LMW) range and with high sulfation degree, modified breast cancer cell properties with different estrogen receptor status 15 …”

Preface of the Special Issue on the Role of Extracellular Matrix in Development and Cancer Progression

“…While HA is the only GAG not normally substituted with sulfate groups, several studies suggest that sulfated hyaluronan (sHA) exhibits promising antitumor results. Koutsakis et al show that sHA fragments attenuate breast cancer cell proliferation, migration, and invasion while increasing adhesion on collagen type I in a manner related to their estrogen receptor (ER) status [2]. Furthermore, sHA modulates the expression of epithelialto-mesenchymal transition (EMT) markers and downregulate matrix remodeling enzymes such as the matrix metalloproteinases (MMPs).…”