High levels of hyaluronan (ΗΑ), 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 HΑ forms exert diverse biological functions. Depending on their molecular size, ΗΑ forms either promote or attenuate signaling cascades that regulate cancer progression. In order to evaluate the effects of different ΗΑ forms on breast cancer cells' behavior, ΗΑ fragments of defined molecular size were synthesized. Breast cancer cells of different estrogen receptor (ER) status – the low metastatic, ERα-positive MCF-7 epithelial cells and the highly aggressive, ERβ-positive MDA-MB-231 mesenchymal cells – 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 ΗΑ fragments affect cell functional properties, the expression of major ECM mediators and epithelial-to-mesenchymal transition (ΕΜΤ) markers. Notably, treatment with 200 kDa ΗΑ increased the expression levels of the epithelial marker Ε-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.
The success of hyaluronic acid (HA)-based dermal fillers, with more than 2 million minimally invasive procedures conducted in 2016 in the US alone, is due to their hygroscopic properties of biocompatibility and reversibility. The type and density of HA cross-linkage, as well as the manufacturing technology, may influence not only the in vivo persistence but also the safety profile of dermal fillers. 1,4-Butanediol diglycidyl ether (BDDE) is the cross-linker used in most market-leading HA fillers; 1,4-butanediol di-(propan-2,3-diolyl) ether (BDPE) is the major impurity obtained from the HA–BDDE cross-linking (HBC) process. In this work, a new process to obtain high purity HBC fillers was developed. A new HPLC-MS method was validated for the quantification of BDPE content in HBC dermal fillers. In vitro cytotoxicity of BDPE was evaluated in fibroblasts (IC50 = 0.48 mg/mL). The viscoelasticity was monitored during the shelf-life of the HBC-10% hydrogel and was correlated with in vitro hyaluronidase resistance and in vivo residence time in a rabbit model. This analysis showed that elasticity is the best parameter to predict the in vivo residence time. Finally, a series of parameters were investigated in certain marketed dermal fillers and were compared with the results of the HBC-10% hydrogel.
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